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T cells: Types and Functions

T cells, also called T lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology, are important components of the adaptive immune system Immune system The body's defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs. Production starts from the hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis in the bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis, from which T-cell progenitor cells arise. These cells migrate to the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy for further maturation. A functional mature T cell develops from a step-by-step process creating a T-cell receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors ( TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity) complex, selecting T cells with appropriate affinity to self-antigens associated with major histocompatibility molecules (positive selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions), and expressing either CD4 or CD8. In this series, cells predisposed to autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity undergo apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage (negative selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions). When released from the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy, the naive mature T cells travel to the secondary lymphoid organs Lymphoid organs A system of organs and tissues that process and transport immune cells and lymph. Primary Lymphatic Organs for activation. Two signals, an antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination-specific binding of TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity and costimulation Costimulation Adaptive Cell-mediated Immunity, are required to be activated (ready to mount an immune response). In the case of CD8+ T cells, additional cytokine stimulation is necessary. Depending on the cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response they are exposed to during antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination stimulation, the undifferentiated mature T cell (Th0) develops into cells with different functions: CD4+ become T helper (Th) cells and CD8+ become cytotoxic Cytotoxic Parvovirus B19, or cytolytic, cells. Th cells have other subtypes; the most characterized are Th1, Th2, Th17, follicular Th cells, and regulatory T cells Regulatory T cells Autoimmunity. Other types include natural killer T cells and memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment T cells. These mature differentiated T cells ensure effective surveillance Surveillance Developmental Milestones and Normal Growth and immediate response to pathogens, tumor Tumor Inflammation cells, and foreign tissues and provide immunologic memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment.

Last updated: 14 Apr, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

T-Cell Development

Introduction

  • T ( thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy-derived) cells: responsible for cell-mediated immunity Cell-mediated immunity Manifestations of the immune response which are mediated by antigen-sensitized T-lymphocytes via lymphokines or direct cytotoxicity. This takes place in the absence of circulating antibody or where antibody plays a subordinate role. Squamous Cell Carcinoma (SCC)
  • Production:  hematopoietic stem cells Hematopoietic stem cells Progenitor cells from which all blood cells derived. They are found primarily in the bone marrow and also in small numbers in the peripheral blood. Bone Marrow: Composition and Hematopoiesis (in the bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis) → common lymphoid progenitor → early thymic progenitor cells → thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy
  • In the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy:
    • T cell progenitors are seen by 9 weeks of gestation.
    • The developing T cells in the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy are also called thymocytes Thymocytes Hematopoietic progenitor cells that have migrated to the thymus where they differentiate into T-lymphocytes. Thymocytes are classified into maturational stages based on the expression of cell surface antigens. Primary Lymphatic Organs.
    • Gene rearrangements Gene rearrangements The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development. Humoral Adaptive Immunity take place to form the T-cell receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors ( TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity):
      • The majority (> 85%) of T cells contain chains ɑ and β, as well as 1 of the co- receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors CD4 or CD8.
      • The remaining T cells contain chains ɣ and δ.
      • TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity + CD3 form the TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity complex.
      • CD3: marker most commonly used to identify T cells 

Development

The initial process takes place in the outer cortex of the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy, and the cells move into the deeper cortex as they mature. 

  • In the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy, progenitor cells express CD3 but lack cell-surface expression of CD4 and CD8 molecules CD8 molecules Differentiation antigens found on thymocytes and on cytotoxic and suppressor T-lymphocytes. T8 antigens are members of the immunoglobulin supergene family and are associative recognition elements in mhc (major histocompatibility complex) class i-restricted interactions. Adaptive Cell-mediated Immunity, thus are double-negative (DN) cells/ thymocytes Thymocytes Hematopoietic progenitor cells that have migrated to the thymus where they differentiate into T-lymphocytes. Thymocytes are classified into maturational stages based on the expression of cell surface antigens. Primary Lymphatic Organs. 
  • The TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure of these DN cells are rearranged.
    • Like immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions, TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis are encoded in following gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics regions:
      • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables (V)
      • Diversity (D)
      • Joining (J)
      • Constant (C)
    • The β chain has VDJ rearrangements, which involve the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination-binding site.
    • The ɑ chain involves VJ rearrangements in the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination-binding site.
    • Rearrangements also occur in a minority of T cells with δ and ɣ chains.
    • This process gives rise to TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity diversity.
  • There are 4 DN stages, and these can be distinguished by the expression of CD44 and CD25:
    • DN1: CD44+,CD25–
    • DN2: CD44+,CD25+
    • DN3: CD44–,CD25+
    • DN4: CD44–,CD25–
  • By stage DN3, rearrangements of the β chain occur (pre- TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity); failure to do so results in apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage.
  • By DN4, ɑ-chain gene rearrangements Gene rearrangements The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development. Humoral Adaptive Immunity is completed:
    • With this, signals are produced to move forward with maturation. 
    • Rearrangement of the TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity α-chain genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure corresponds to the up-regulation Up-Regulation A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (gene expression regulation), mRNAs, and proteins. Pharmacokinetics and Pharmacodynamics of both CD4 and CD8 expression (becoming double-positive (DP) cells).
    • If ɑ-chain gene rearrangements Gene rearrangements The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development. Humoral Adaptive Immunity do not occur, the cell dies.
  • The α–β TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity–CD3 receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors complex is completed when ɑ chains assemble with β chains.
  • Subsequent maturation stages:
    • Positive selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions:
      • In the thymic cortex
      • T cells with TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity having moderate interaction (just enough affinity) with self-antigens (in the context of MHC molecules) are selected.
    • Negative selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions:
      • In the medulla
      • T cells with TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity with high affinity or strong interaction with self-antigens → apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
      • This central tolerance Tolerance Pharmacokinetics and Pharmacodynamics mechanism (in the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy) is where T cells that react strongly to identified self-antigens are removed.
      • Prevents release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of dysfunctional T cells (that recognize self-antigens and can activate autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity)
      • Facilitated by autoimmune regulator (AIRE) protein

Stages

To reach functionality, the T cell goes through stages, released from the bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis as progenitor cells to continue development in the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy. The table summarizes the general steps taken. 

  • In the initial stages, the aim is to build the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (requiring no antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination). 
  • Further steps involve the interaction of the T cell with self-antigens, and differentiation into either T helper cells or cytotoxic Cytotoxic Parvovirus B19 T cells.
Table: T-cell maturation stage
Maturation stage T-cell receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors Associated events
Progenitor cell None
  • From bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis → to the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy for further maturation
  • Become DN cells (still lacking CD4 and CD8)
DN cells Rearrangement of β chain (pre- TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity): failure to rearrange leads to apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
  • Express CD3
  • CD4–, CD8– (no CD4 and CD8)
DP cells Rearrangement of ɑ chain → ɑ chains assemble with β chains → complete ɑ–β TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity–CD3 receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors complex (expressed on the surface)
  • CD4+, CD8+
  • DP cells then interact with self-antigens (in the context of MHC molecules).
  • With MHC presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor, some cells undergo positive selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions in the thymic cortex:
    • Intermediate or moderate interaction between MHC and TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity occurs.
    • Produces the functional cells
  • Some cells undergo negative selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions in the thymic medulla:
    • High affinity or strong interaction between MHC and TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity occurs.
    • Cells die ( apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage).
    • Prevents release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of dysfunctional T cells (can activate autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity)
  • Some fail to interact → apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage
Single positive T cells
  • Cell signals trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation cells to express either CD4 or CD8, not both:
    • Th: with CD4 and interact with cells expressing MHC class II
    • Tc: with CD8 and interact with cells expressing MHC class I
  • Naive Th and Tc circulate (blood to lymphoid tissues to lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs), and await activation by antigen-presenting cells Antigen-presenting cells A heterogeneous group of immunocompetent cells that mediate the cellular immune response by processing and presenting antigens to the T-cells. Traditional antigen-presenting cells include macrophages; dendritic cells; langerhans cells; and B-lymphocytes. Follicular dendritic cells are not traditional antigen-presenting cells, but because they hold antigen on their cell surface in the form of immune complexes for b-cell recognition they are considered so by some authors. Adaptive Immune Response carrying a complementary peptide–MHC complex.
Tc: cytotoxic Cytotoxic Parvovirus B19 T cells
Th: T helper cells
T-cell differentiation stages

Differentiation stages of T cell:
From the bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis, progenitor cells go to the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy for further maturation. The DN cells (no expression of CD4/CD8 or CD4–/CD8–) have not developed the TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity. The DN cells undergo rearrangement of the TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics and become pro-T cells, then pre-T cells. Through the series, CD4 and CD8 are expressed, and the TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity becomes assembled through gene rearrangements Gene rearrangements The ordered rearrangement of gene regions by DNA recombination such as that which occurs normally during development. Humoral Adaptive Immunity (DP cells). The thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy then presents MHC molecules to the developing T cells. Some cells undergo positive selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions (intermediate interaction between MHC and TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity takes place) and produce functional cells. Some cells undergo negative selection Selection Lymphocyte activation by a specific antigen thus triggering clonal expansion of lymphocytes already capable of mounting an immune response to the antigen. B cells: Types and Functions (strong interaction between MHC and TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity), which results in cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death. The release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of dysfunctional T cells, which can activate autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity, is prevented. Some T cells fail to interact, leading to apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage. Mature T cells express either CD4 (T helper cells) or CD8 ( cytotoxic Cytotoxic Parvovirus B19 T cells), not both.

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Mnemonic

Remember the “rule of 8”

  • MHC restriction: The T cell is “restricted” to bind BIND Hyperbilirubinemia of the Newborn an antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination only when it is presented by the appropriate class of MHC protein.
  • CD4-positive T cells recognize antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination associated with class II MHC Class II MHC Genetic loci in the vertebrate major histocompatibility complex that encode polymorphic products which control the immune response to specific antigens. The genes are found in the hla-d region in humans and include h-2m, i-a, and i-e loci in mice. Adaptive Cell-mediated Immunity proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (4 × 2 = 8).
  • CD8-positive T cells recognize antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination associated with class I MHC Class I MHC Genetic loci in the vertebrate major histocompatibility complex which encode polymorphic characteristics not related to immune responsiveness or complement activity, e.g., B loci (chicken), dla (dog), gpla (guinea pig), h-2 (mouse), rt-1 (rat), hla-a, -b, and -c class I genes of man. Adaptive Cell-mediated Immunity proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis (8 × 1 = 8).

T-Cell Activation and Differentiation

Release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology from the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy

  • Before T cells emerge from the thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy, they have interacted with self-antigens, undergone MHC restriction, and either have CD4 or CD8 expression.
  • The released T cells expressing surface α–β TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity–CD3 complex with co- receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors CD4 or CD8 are considered naive mature T cells: 
    • Not enough for proliferation and activation, as the released T cells have not interacted with a foreign antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination
    • These T cells circulate in the blood and go to the secondary lymphoid tissues.
    • These secondary lymphoid organs Lymphoid organs A system of organs and tissues that process and transport immune cells and lymph. Primary Lymphatic Organs (e.g., lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs nodes) filter antigenic material, allowing the naive mature T cells to:
      • Interact with antigen-presenting cells Antigen-presenting cells A heterogeneous group of immunocompetent cells that mediate the cellular immune response by processing and presenting antigens to the T-cells. Traditional antigen-presenting cells include macrophages; dendritic cells; langerhans cells; and B-lymphocytes. Follicular dendritic cells are not traditional antigen-presenting cells, but because they hold antigen on their cell surface in the form of immune complexes for b-cell recognition they are considered so by some authors. Adaptive Immune Response, such as macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation or dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions
      • Sample the antigens to become activated
    • If no activation takes place, the T cells recirculate.
Structure and functional regions of a lymph node

Structure and functional regions of a lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node comprising a collagen Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin; connective tissue; and the organic substance of bones (bone and bones) and teeth (tooth). Connective Tissue: Histology-rich fibrous Fibrous Fibrocystic Change capsule Capsule An envelope of loose gel surrounding a bacterial cell which is associated with the virulence of pathogenic bacteria. Some capsules have a well-defined border, whereas others form a slime layer that trails off into the medium. Most capsules consist of relatively simple polysaccharides but there are some bacteria whose capsules are made of polypeptides. Bacteroides and an underlying subcapsular sinus Subcapsular sinus Secondary Lymphatic Organs.
Cells are segregated into (1) the cortex (consisting of B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions, T follicular helper cells, and follicular dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions arranged in primary follicles Primary follicles Secondary Lymphatic Organs, in which B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions survey antigens presented on the follicular dendritic cell stromal network); and (2) the paracortex Paracortex Secondary Lymphatic Organs (accommodates T cells, dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions, and fibroblastic reticular cells, which form stromal cell networks and reticular fibers).
The inner medulla is composed of lymphatic tissues (medullary cords) separated by medullary sinuses consisting of lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs.

Image: “The structure of the lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node” by Colbeck, Ager, Gallimore and Jones. License: CC BY 4.0

Activation

  • Full activation of T cells ready to mount an immune response requires 2 signals:
    1. TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity recognizes its cognate antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination, as presented by the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination-presenting cell (e.g., dendritic cell).
    2. Costimulation Costimulation Adaptive Cell-mediated Immunity:
      • Provided by a costimulatory molecule (e.g., CD28) 
      • Best characterized by B7 protein in the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination-presenting cell interacting with CD28 of the T cell
      • Needed for survival and proliferation
      • Required to induce differentiation (effector or memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment status)
      • Allows cell-to-cell cooperation
  • Without the costimulatory signal, the T cell can adopt a state of anergy (cell is alive but with partial or total unresponsiveness due to partial activation).
  • Effects:
    • Costimulation Costimulation Adaptive Cell-mediated Immunity helps avoid activation of T cells by benign Benign Fibroadenoma antigens.
    • In addition, CD8+ T cells, which are cytotoxic Cytotoxic Parvovirus B19, require an additional “signal” given by cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response from CD4+ T cells (preventing inadvertent activation).
  • Inhibitory mechanisms or “checkpoints” in T cells prevent uncontrolled T-cell activation:
    • Cytotoxic Cytotoxic Parvovirus B19 T-lymphocyte antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination-4 (CTLA-4)
    • PD PD Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability. Parkinson’s Disease-1 (programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death-1)
2-signal model - t-cell dependence on costimulation

2-signal model of T-cell dependence on costimulation Costimulation Adaptive Cell-mediated Immunity:
When both signal 1 ( TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity binding the cognate antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination presented by the MHC molecule in the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination-presenting cell) and signal 2 (costimulatory molecule interaction between the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination-presenting cell and the T cell) are present, the mature T cell is fully activated.
The orange spot in the left panel indicates proper binding between antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination and TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity. However, when either signal 1 (middle image shows no antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination and TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity binding) or signal 2 (right image shows no costimulation Costimulation Adaptive Cell-mediated Immunity) is missing, the T cell will not be fully activated.
Outcomes would be anergy (state of unresponsiveness), apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage ( cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death), or ignorance (T cell does not notice or does not get affected by the antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination).
TCR TCR Molecules on the surface of T-lymphocytes that recognize and combine with antigens. The receptors are non-covalently associated with a complex of several polypeptides collectively called CD3 antigens. Recognition of foreign antigen and the major histocompatibility complex is accomplished by a single heterodimeric antigen-receptor structure, composed of either alpha-beta or gamma-delta chains. Adaptive Cell-mediated Immunity: T-cell receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors

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Proliferation and differentiation

  • Clonal proliferation: 
    • End of activation
    • Release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology of IL-2 (the T-cell growth factor) from the T cells leads to T-cell multiplication.
  • Depending on the cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response that they are exposed to during antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination stimulation, the undifferentiated mature T cell (Th0) develops into cells with different functions:
    • CD4+ T cells become:
      • Follicular helper (Tfh) cells
      • Effector/helper T (Th) cells
      • Regulatory (Treg) or suppressor T cells
    • CD8+ T cells become cytotoxic Cytotoxic Parvovirus B19 T cells.
  • A number of activated T cells Activated T cells Adaptive Cell-mediated Immunity stay in the secondary lymphoid organ, and some proceed to areas of tissue inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation to perform effector functions.

CD4+ T Cells

General overview of T helper cell differentiation

T helper cells have different cytokine profiles and roles in the immune response.

Table: General overview of Th cell differentiation
CD4+ T cells Differentiation stimulated by Functions Cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response produced
Th1
  • IL-12
  • IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons
  • Activate macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation
  • Activate cytotoxic Cytotoxic Parvovirus B19 T cells
  • IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons
  • TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)
  • IL-2
Th2
  • IL-2
  • IL-4
  • Activate eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation, ↑ IgE IgE An immunoglobulin associated with mast cells. Overexpression has been associated with allergic hypersensitivity. Immunoglobulins: Types and Functions
  • Activate mast cells Mast cells Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the basophils, mast cells contain large amounts of histamine and heparin. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the stem cell factor. Innate Immunity: Phagocytes and Antigen Presentation
  • IL-4
  • IL-5
  • IL-6
  • IL-9
  • IL-10
  • IL-13
Th17
  • IL-1
  • IL-6
  • IL-23
  • TGF-β
Promote neutrophilic inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • IL-17
  • IL-21
  • IL-22
Tfh IL-6 Facilitate B-cell activation and maturation
  • IL-4
  • IL-21
Treg
  • TGF-β
  • IL-2
  • TGF-β
  • IL-10
  • IL-35
IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons: interferon
TGF: transforming growth factor
TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF): tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)
Subsets of cd4-+ helper t cells

Subsets of CD4-positive helper T cells:
After activation by a dendritic cell, in the presence of particular cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response, a naive CD4-positive T cell divides and differentiates into effector/helper (Th1, Th2 or Th17) or follicular helper (Tfh) subsets. Each type of cell produces cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response that facilitate activation of other immune-cell partners.
IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons: interferon
TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF): tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)

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Th1

  • Differentiation stimulated by: IL-12 and IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons
  • Inhibited by: IL-4 and IL-10 (from Th2)
  • Produce cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons-γ, IL-2, and tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF))
  • Express transcription factors Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Stages of Transcription T-BET and signal transducer Transducer A device placed on the patient’s body to visualize a target Ultrasound (Sonography) and activator of transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription 4 (STAT4)
  • Functions:
    • Activates macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation → enhanced phagocytosis Phagocytosis The engulfing and degradation of microorganisms; other cells that are dead, dying, or pathogenic; and foreign particles by phagocytic cells (phagocytes). Innate Immunity: Phagocytes and Antigen Presentation, granuloma formation
    • Activates cytotoxic Cytotoxic Parvovirus B19 lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology
    • Helps B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions produce antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions
    • Inhibits Th2 cells
    • Defense against bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology, fungi Fungi A kingdom of eukaryotic, heterotrophic organisms that live parasitically as saprobes, including mushrooms; yeasts; smuts, molds, etc. They reproduce either sexually or asexually, and have life cycles that range from simple to complex. Filamentous fungi, commonly known as molds, refer to those that grow as multicellular colonies. Mycology, and viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology
  • Clinical relevance:
    • Involved in delayed hypersensitivity reactions
    • Deficiencies in IL-12 or IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons-γ predisposes to mycobacterial infections Mycobacterial Infections Antimycobacterial Drugs, particularly tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis.
    • Overactivity of Th1 cells: linked autoimmune and inflammatory diseases (e.g., Crohn’s disease, rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis)

Th2

  • Differentiation stimulated by: IL-2 and IL-4
  • Inhibited by: IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons-γ (from Th1)
  • Produce cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13
  • Express transcription factors Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Stages of Transcription GATA3 and STAT6.
  • Functions:
    • Activate eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation and mast cells Mast cells Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the basophils, mast cells contain large amounts of histamine and heparin. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the stem cell factor. Innate Immunity: Phagocytes and Antigen Presentation
    • Inhibit Th1 cells
    • Help B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions
  • Clinical relevance: 
    • Dysregulation of Th2 cells leads to allergic disease (e.g., allergic asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma, atopic dermatitis Atopic Dermatitis Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema)).
    • Responds to infection by certain helminth worms, such as Schistosoma Schistosoma Schistosomiasis is an infection caused by Schistosoma, a trematode. Schistosomiasis occurs in developing countries with poor sanitation. Freshwater snails are the intermediate host and are transmitted to humans through skin contact with contaminated fresh water. The clinical presentation occurs as a result of the host’s immune response to antigens from the eggs. Schistosoma/Schistosomiasis and Strongyloides

Th17

  • Differentiation stimulated by: IL-1, IL-6, IL-23, and TGF-β
  • Inhibited by: IL-4 and IFN IFN Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Interferons-γ 
  • Produce cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response IL-17, IL-21, and IL-22
  • Express transcription factors Transcription Factors Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. Stages of Transcription RORC and STAT3.
  • Functions:
    • Activate neutrophilic response
    • Barrier tissue defense
  • Clinical relevance:
    •  Increased susceptibility to mucocutaneous infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease from the yeast Yeast A general term for single-celled rounded fungi that reproduce by budding. Brewers’ and bakers’ yeasts are saccharomyces cerevisiae; therapeutic dried yeast is yeast, dried. Mycology Candida Candida Candida is a genus of dimorphic, opportunistic fungi. Candida albicans is part of the normal human flora and is the most common cause of candidiasis. The clinical presentation varies and can include localized mucocutaneous infections (e.g., oropharyngeal, esophageal, intertriginous, and vulvovaginal candidiasis) and invasive disease (e.g., candidemia, intraabdominal abscess, pericarditis, and meningitis). Candida/Candidiasis albicans in IL-17 deficiency 
    • Overactivity is associated with autoimmune disease.

Tfh

  • Differentiation stimulated by: IL-6
  • Inhibited by: IL-2
  • Produce cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response IL-4 and IL-21
  • Express transcription factor Transcription factor Generic term for proteins necessary for transcription Regulation of Transcription Bcl-6.
  • Other markers: CXCR5, CXCL13, PD PD Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disorder. Although the cause is unknown, several genetic and environmental risk factors are currently being studied. Individuals present clinically with resting tremor, bradykinesia, rigidity, and postural instability. Parkinson’s Disease-1, and ICOS
  • Functions: 
    • Found in germinal centers of secondary lymphoid tissues and assist in the activation of B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions.
    • Expression of CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome ligand (CD40L) interacts with CD40 CD40 Members of the tumor necrosis factor receptor superfamily with specificity for CD40 ligand. They are found on mature B-lymphocytes, some epithelial cells; and lymphoid dendritic cells. Evidence suggests that CD40-dependent activation of B-cells is important for generation of memory B-cells within the germinal centers. Mutations in the CD40 antigen gene result in hyper-igm immunodeficiency syndrome, type 3. Signaling of the receptor occurs through its association with tnf receptor-associated factors. Hyper-IgM Syndrome of the B cell.
  • Clinical relevance: 
    • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics encoding CD40L leads to hyper-IgM syndrome Hyper-IgM syndrome The hyperimmunoglobulin M (hyper-IgM) syndrome, is a group of rare inherited immunodeficiency disorders characterized by low or absent serum levels of IgA, IgG, and IgE and normal or elevated levels of IgM. Hyper-IgM syndrome is most commonly caused by X-linked mutations in the CD40 ligand gene, which results in abnormal signaling between B and T lymphocytes. Hyper-IgM Syndrome.
    • Overactivity leads to autoimmune disease.

Tregs

  • Differentiation stimulated by: TGF-β and IL-2
  • Inhibited by: IL-6
  • Produce cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response TGF-β, IL-10, and IL-35
  • Express transcription factor Transcription factor Generic term for proteins necessary for transcription Regulation of Transcription FOXP3.
  • Functions: 
    • Unrestrained T-cell response can become pathologic, so Tregs are present to prevent excessive inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and tissue damage.
    • Part of the peripheral tolerance Tolerance Pharmacokinetics and Pharmacodynamics mechanism
    • Can down-regulate the activity of many immune cells, including:
      • CD4+ cells
      • CD8+ T cells
      • Dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions (via cell-surface CTLA-4 and lymphocyte-activation gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (LAG-3))
      • B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions
      • Natural killer cells Natural killer cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes: Histology
      • Eosinophils Eosinophils Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. Innate Immunity: Phagocytes and Antigen Presentation, basophils Basophils Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. Innate Immunity: Phagocytes and Antigen Presentation, mast cells Mast cells Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the basophils, mast cells contain large amounts of histamine and heparin. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the stem cell factor. Innate Immunity: Phagocytes and Antigen Presentation
  • Clinical relevance:
    • Boosting Treg activity (or ↓ immune response) can help with transplant rejection and autoimmune disease.
    • Reducing Treg activity (or ↑ immune response) is helpful in cancer immunotherapy Cancer Immunotherapy Cancer immunotherapy is a rapidly advancing medical therapy that takes advantage of the immune system to contain or eliminate cancer cells. Currently, immunotherapies have been incorporated into treatment regimens for different types of cancer. Various therapeutic approaches exist, including using cytokines, vaccines, oncolytic viruses, T-cell manipulation or cellular adoptive immunotherapy, or antibodies to immune checkpoint molecules. Cancer Immunotherapy and chronic infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease.
    • Significant role in preventing graft Graft A piece of living tissue that is surgically transplanted Organ Transplantation rejection and graft Graft A piece of living tissue that is surgically transplanted Organ Transplantation-versus-host disease (GVHD) 
    • Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics encoding FOXP3 leads to IPEX (Immunodysregulation Polyendocrinopathy Enteropathy X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID)) syndrome.

CD8+ T Cells

  • Cytotoxic Cytotoxic Parvovirus B19 or cytolytic T cells
  • Requires cytokine (IL-2) stimulation (from Th1 cells) to be activated, then leaves the secondary lymphoid organ, circulating in search of targets
  • Produce cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response IFNγ, TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)-α, and TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)
  • Express transcription factor Transcription factor Generic term for proteins necessary for transcription Regulation of Transcription RUNX3
  • Functions include killing of:
  • Cytotoxicity occurs via:
    • Granule exocytosis Exocytosis Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. The Cell: Cell Membrane
      • Following contact with the target cell, lytic granules gather near the immunologic synapse Synapse The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. Synapses and Neurotransmission
      • The membranes of the granules fuse with the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane.
      • Granule contents, including granzymes Granzymes A family of serine endopeptidases found in the secretory granules of leukocytes such as cytotoxic T-lymphocytes and natural killer cells. When secreted into the intercellular space granzymes act to eliminate transformed and virus-infected host cells. Lymphocytes: Histology and perforins, enter the target cell. 
      • Caspase pathway is activated, leading to apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage.
    • Expression of Fas ligand Fas ligand A transmembrane protein belonging to the tumor necrosis factor superfamily that was originally discovered on cells of the lymphoid-myeloid lineage, including activated T-lymphocytes and natural killer cells. It plays an important role in immune homeostasis and cell-mediated toxicity by binding to the fas receptor and triggering apoptosis. Tumor Necrosis Factor (TNF) (FasL):
      • Fas is expressed on the surface of many cells.
      • FasL, expressed on the surface of CD8+ T cell, is induced when a cognate antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination is recognized.
      • Fas–FasL interaction ensues, caspase pathway is activated, leading to cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death.
    • Recruitment Recruitment Skeletal Muscle Contraction and modulation of additional inflammatory effector cells Effector cells Cells have been activated by a matching antigen Adaptive Immune Response, such as macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation
  • Clinical relevance:
    • Prominent role in intracellular pathogens Intracellular pathogens IL-12 Receptor Deficiency (e.g., Listeria monocytogenes Listeria monocytogenes Listeria spp. are motile, flagellated, gram-positive, facultative intracellular bacilli. The major pathogenic species is Listeria monocytogenes. Listeria are part of the normal gastrointestinal flora of domestic mammals and poultry and are transmitted to humans through the ingestion of contaminated food, especially unpasteurized dairy products. Listeria Monocytogenes/Listeriosis), as these pathogens spend little time in circulation Circulation The movement of the blood as it is pumped through the cardiovascular system. ABCDE Assessment (less susceptibility to antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions).
    • Similar importance in the immune defense against viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology (e.g., HIV HIV Anti-HIV Drugs)

Other Types of T Cells

Gamma–delta T cells

  • TCRs consists of γ and δ chains.
  • Do not pass through double-positive stage, but have a distinct role complementary to that of αβ T cells
  • Represent < 5% of T cells 
  • Found in gut mucosa, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy, and uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Uterus, Cervix, and Fallopian Tubes: Anatomy
  • Can bind BIND Hyperbilirubinemia of the Newborn to non-MHC molecules for activation
  • Recognize phosphoantigens from:
    • Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
    • Plasmodium Plasmodium A genus of protozoa that comprise the malaria parasites of mammals. Four species infect humans (although occasional infections with primate malarias may occur). These are plasmodium falciparum; plasmodium malariae; plasmodium ovale, and plasmodium vivax. Species causing infection in vertebrates other than man include: plasmodium berghei; plasmodium chabaudi; p. Vinckei, and plasmodium yoelii in rodents; p. Brasilianum, plasmodium cynomolgi; and plasmodium knowlesi in monkeys; and plasmodium gallinaceum in chickens. Antimalarial Drugs spp.

Natural killer (NK) T cells

  • Branch from T cells at the double-positive (CD4+, CD8+) stage of development.
  • Have morphologic and functional features of T cells and NK cells NK cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes: Histology
  • Recognize antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination presented by MHC class I–like CD1d molecules
  • Produce both Th1 and Th2 cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response when activated

Memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment T cells

  • Can be either CD4+ or CD8+
  • Mount immune response years after initial exposure Exposure ABCDE Assessment
  • Naive T cells not exposed to dendritic cells Dendritic cells Specialized cells of the hematopoietic system that have branch-like extensions. They are found throughout the lymphatic system, and in non-lymphoid tissues such as skin and the epithelia of the intestinal, respiratory, and reproductive tracts. They trap and process antigens, and present them to T-cells, thereby stimulating cell-mediated immunity. They are different from the non-hematopoietic follicular dendritic cells, which have a similar morphology and immune system function, but with respect to humoral immunity (antibody production). Skin: Structure and Functions carrying antigens, express the following markers:
    • Positive for CD45RA
    • Negative for CD45RO
    • Express CD62L and CCR7
  • Following exposure Exposure ABCDE Assessment to antigens, some T cells develop into memory cells Memory cells Cells that outlived a previous infection Adaptive Immune Response:
    • Initially reside within lymphoid tissues (central memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment T cells).
    • Become CD45RO+ and CD45RA–
    • CD62L+ and CCR7+
  • T memory cells Memory cells Cells that outlived a previous infection Adaptive Immune Response that take residence in peripheral tissues (effector memory cells Memory cells Cells that outlived a previous infection Adaptive Immune Response):
    • CD45RO+ and CD45RA–
    • CD62L– and CCR7–
  • Following reinfection by the same antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination, they become T effector cells Effector cells Cells have been activated by a matching antigen Adaptive Immune Response:
    • CD45RA+, CD45RO–, CD62L–, and CCR7–
    • Essential components of secondary immunity.
    • Can be immediately activated upon pathogen invasion.
Memory t cells and expressed cellular markers

Memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment T cells and expressed cellular markers:
The central memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment T cells are in the lymphoid organs Lymphoid organs A system of organs and tissues that process and transport immune cells and lymph. Primary Lymphatic Organs, while the peripheral memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment T cells are in peripheral tissues.

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Clinical Relevance

  • Chronic mucocutaneous candidiasis (CMCC): autoimmune syndrome with features that include chronic, noninvasive Candida infections of the skin, nails, and mucous membranes. The condition is associated with autoimmune manifestations (most commonly endocrinopathies). Hypoparathyroidism is the most common endocrine abnormality, occurring in 30% of individuals. Adrenal insufficiency occurs in > 60% of cases by the age of 15 years. CMCC is due to genetic defects in the immune system, including those affecting AIRE, signal transducer and activator of transcription 1 (STAT1), and the IL-17 pathway, among others.
  • IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome: caused by mutations in the gene for the transcription factor FOXP3. The defining feature of IPEX syndrome is regulatory T-cell impairment, manifesting as autoimmune disease with allergic inflammation. The syndrome typically presents in male infants with a triad of enteropathy, dermatitis, and autoimmune endocrinopathy (usually type 1 diabetes or thyroiditis). Diarrhea can be profound, associated with dehydration, malabsorption, metabolic acidosis, renal insufficiency, and failure to thrive. Other manifestations include severe food allergies, chronic autoimmune hepatitis, autoimmune cytopenias, interstitial nephritis, and developmental delays. Diagnosis is by mutational analysis of the FOXP3 gene. Hematopoietic cell transplantation is the only curative therapy available.
  • Adult T-cell leukemia/lymphoma: rare, but often aggressive mature T-cell malignancy caused by chronic infection of CD4+ T cells with the human T-lymphotropic virus, type I (HTLV-I). The infection is endemic in Japan, the Caribbean region, and Central Africa. The general presentation is widespread involvement of lymph nodes, peripheral blood, and/or skin. Several clinical variants are known—acute, lymphomatous, chronic, and smoldering—and each has a different clinical course. The most characteristic features seen in the peripheral blood are “clover leaf” or “flower cells” (cells with bizarre hyperlobulated nuclei). Diagnosis is based on clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor, morphologic and immunophenotypic changes of the malignant cells, and confirmed HTLV-I HTLV-I Acute Lymphoblastic Leukemia infection. The treatment is tailored to the subtype, and options include antiviral Antiviral Antivirals for Hepatitis B agents, monoclonal antibody therapy, chemotherapy Chemotherapy Osteosarcoma and allogeneic stem-cell transplantation.

References

  1. Braskett, M.J., Chatila T. (2021). IPEX: immune dysregulation, polyendocrinopathy, enteropathy, X-linked. UpToDate. Retrieved July 10, 2021, from https://www.uptodate.com/contents/ipex-immune-dysregulation-polyendocrinopathy-enteropathy-x-linked
  2. Frauwirth, K., Thompson, C. (2002). Activation and inhibition of lymphocytes by costimuation. J Clin Invest 109:295–299. https://doi.org/10.1172/JCI14941
  3. Freedman, A.S., Aster, J.C., Suzuki, R. (2021). Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma. UpToDate. Retrieved July 10, 2021, from https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-adult-T cell-leukemia-lymphoma
  4. Kumar, B.V., Connors, T.J., Farber, D.L. (2018). Human T cell development, localization, and function throughout life. Immunity 48: 202–213. https://pubmed.ncbi.nlm.nih.gov/29466753/
  5. Lechler, R., Chai, J. G., Marelli-Berg, F., & Lombardi, G. (2001). The contributions of T cell anergy to peripheral T cell tolerance. Immunology 103:262–269. https://doi.org/10.1046/j.1365-2567.2001.01250.x
  6. Levinson, W., et al. (Eds.). (2020). Adaptive immunity: T cell–mediated immunity. In: Review of Medical Microbiology & Immunology: A Guide to Clinical Infectious Diseases, 16th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2867&sectionid=24276830
  7. Lucas, F., Gribben, J. (2021). Functions of T lymphocytes: T cell receptors for antigen. In Kaushansky, K., et al. (Eds.), Williams Hematology, 10e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2962&sectionid=252540548
  8. Martin, M.D., Badovinac, V.P. (2018). Defining memory CD8 T cell. Front Immunol 9:2692. https://doi.org/10.3389/fimmu.2018.02692
  9. Notarangelo, L. (2021). T cell receptor genetics. UpToDate. Retrieved July 16, 2021, from https://www.uptodate.com/contents/T cell-receptor-genetics
  10. Raphael, I., Nalawade, S., Eagar, T. N., & Forsthuber, T. G. (2015). T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 74(1), 5–17. https://doi.org/10.1016/j.cyto.2014.09.011
  11. Roifman, C.M. (2019). Chronic mucocutaneous candidiasis. UpToDate. Retrieved July 10, 2021, from https://www.uptodate.com/contents/chronic-mucocutaneous-candidiasis
  12. Salaman, M., Gould, K. (2020). Breakdown of T cell ignorance: the tolerance failure responsible for mainstream autoimmune diseases? In: Gershwin, E., et al. (Eds.), Journal of Translational Autoimmunity. https://doi.org/10.1016/j.jtauto.2020.100070

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