Adaptive Cell-mediated Immunity

Cell-mediated immunity is an integral part of the adaptive immune system, mounting a highly specific defense against pathogens. Cell-mediated immunity develops over a longer period of time than innate immunity. Cell-mediated adaptive response occurs in cells/tissues (intracellular infections or aberrant cells (e.g., tumors)) and involves the T cells or T lymphocytes. The cells, which arise from bone marrow, migrate to the thymus for further maturation. A T cell receptor is assembled and activation is facilitated by antigen-presenting cells in secondary lymphoid organs. Influenced by cytokines, activated T cells can differentiate into subsets (e.g., CD4+ T helper cells, CD8+ cytotoxic T cells, memory T cells). T helper cells aid in the eradication of pathogens by helping the partners of immune cells (e.g., macrophages and granulocytes). With mechanisms activating the caspase pathway, cytotoxic T cells have the capacity to kill microbes. Memory T cells develop after initial exposure to the antigen and become effector T cells on reinfection. T cells also activate B cells (a major component in humoral immunity), which enhance the ability to eliminate pathogens.

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Overview

Immune system definition

The immune system provides defense (immunity) against invading pathogens ranging from viruses to parasites. Components are interconnected by blood and the lymphatic circulation.

Two lines of overlapping defense:

  • Innate immunity (nonspecific) 
  • Adaptive immunity (based on specific antigen recognition):
    • Cell-mediated immunity: adaptive response in the cells/tissues involving the T cells
    • Humoral immunity: adaptive response in fluids (“humoral”) involving B cells and immunoglobulins

Innate vs adaptive immunity

Table: Innate versus adaptive immunity
Innate immunityAdaptive immunity
GeneticsGermline encodedGene rearrangements involved in lymphocyte development
Immune responseNonspecificHighly specific
Timing of responseImmediate (minutes to hours)Develops over a longer period of time
Memory responseNoneResponds quickly upon recognition of antigen with memory response
Recognition of pathogenPattern recognition receptors (PRRs) such as toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs)
  • Memory cells (T and B cells)
  • Activated B cells
Components
  • Anatomical barriers (e.g., skin)
  • Chemical and biological barriers (e.g., gastric acid, vaginal flora)
  • Cells (e.g., granulocytes)
  • Secreted proteins:
    • Enzymes (e.g., lysozyme)
    • Other PRRs (e.g., antimicrobial peptides (AMPs))
    • Cytokines*
    • Complement*
  • Cell-mediated immunity: T cells
  • Humoral immunity: B cells, immunoglobulins
*The mediators also have roles in adaptive immunity.

Components of the Adaptive Immune System

Responding to microbial invaders is the responsibility of the immune system. Often the innate immune system has the capability to contain the pathogens, but invaders may evolve to evade innate immunity. The next line of defense is the adaptive immune system.

Adaptive immune system definition

  • Cell-mediated immunity and humoral adaptive immunity
  • Composed of lymphocytes (T helper cells, cytotoxic T cells) and secreted proteins (antibodies produced by B cells)
  • Functionality takes days; however, once engaged, repeat encounters with the offending agent elicit a faster response.
  • The B and T cell components:
    • Diversity: respond to millions of antigens
    • Specificity: immune response tailored to the specific antigen
    • Memory: can respond many years later

Cell-mediated immunity

  • Primary effectors: T cells
    • CD4+ T (helper) cells: Different subsets perform multiple functions, including cytokine production and activation of macrophages.
    • CD8+ T (cytotoxic) cells: defend against intracellular bacteria and viruses via destruction of infected cells
    • Memory T cells: respond to antigen reexposure
  • Other components:
    • T cells are dependent on cytokines (soluble proteins released by different cells, which play overlapping roles in both innate and adaptive immunity).
    • Dendritic cells and macrophages in the innate immune system present antigens to T cells.

Humoral adaptive immunity

  • Antibody-mediated immunity
  • B cells:
    • Differentiate into plasma cells, producing antibodies with the help of T cells
    • Differentiate into memory cells, briskly responding to reinfection
    • Act as antigen-presenting cells to T cells (expressing class II MHC)
  • Antibodies, along with complement, help the cells of the innate system against extracellular, encapsulated bacteria.
  • Antibodies can neutralize toxins and viruses.

Development of T Cells

T cells

  • Derived from common lymphoid progenitors
  • Unlike B cells, T cells from bone marrow migrate to the thymus to complete development.
  • Before entering the thymus, T cells lack the T cell receptor (TCR) (the protein complex binding to a specific antigen)
  • Development stages:
    • TCR assembly
    • Interaction with self antigens
    • Positive and negative selection: leads to MHC restriction and elimination of autoreactive cells
    • Expression of CD4 (become helper T cells) or CD8 (become cytotoxic T cells)
  • Released naive mature T cells from the thymus express surface TCR with coreceptors CD4 or CD8. 
T-cell differentiation stages

Differentiation stages of T cell:
From the bone marrow, progenitor cells go to the thymus for further maturation. The DN cells (no expression of CD4/CD8 or CD4–/CD8–) have not developed the TCR. The DN cells undergo rearrangement of the TCR gene and become pro-T cells, then pre-T cells. Through the series, CD4 and CD8 are expressed, and the TCR becomes assembled through gene rearrangements (DP cells). The thymus then presents MHC molecules to the developing T cells. Some cells undergo positive selection (intermediate interaction between MHC and TCR takes place) and produce functional cells. Some cells undergo negative selection (strong interaction between MHC and TCR), which results in cell death. The release of dysfunctional T cells, which can activate autoimmunity, is prevented. Some T cells fail to interact, leading to apoptosis. Mature T cells express either CD4 (T helper cells) or CD8 (cytotoxic T cells), not both.

Image by Lecturio. License: CC BY-NC-SA 4.0

TCR

  • A heterodimer consisting of 2 transmembrane polypeptide chains: α and β chains (the majority of T cells) or γ and δ chains (the minority of T cells)
  • Assembly of the 2 chains requires gene rearrangements, which contribute to TCR diversity.
  • Structurally, each TCR α and β chain has:
    • Variable regions and a constant region
    • Hydrophobic transmembrane region 
    • Short cytoplasmic region 
  • Spans the cytoplasmic membrane with variable binding regions projecting into the extracellular space to bind antigens (similar to the antigen-binding fragment (Fab) of an antibody):
    • The processed antigens are associated with class I or class II MHC molecules.
    • CD4 molecules bind to class II MHC molecules; CD8 molecules bind to class I MHC molecules.
T cell receptor

T cell receptor:
Heterodimer that consists of 2 transmembrane polypeptide chains, with α and β chains found in the majority of T cells. Both chains have a variable, constant, transmembrane and a short cytoplasmic region.

Image: “T cell receptor” by OpenStax College. License: CC BY 3.0

T cell activation

  • For proliferation and activation to occur, naive mature T cells must interact with a foreign antigen.
  • T cells circulate in the blood and go to the secondary lymphoid tissues.
  • The secondary lymphoid organs (e.g., lymph nodes) filter antigenic material allowing the naive mature T cells:
    • To interact with antigen-presenting cells such as macrophages or dendritic cells
    • To sample the antigens to become activated
  • The full activation of a T cell ready to mount an immune response requires 2 signals (see image):
    • Signal 1: TCR recognizes the cognate antigen presented by the antigen-presenting cell (e.g., dendritic cell).
    • Signal 2: costimulation: 
      • Provided by a costimulatory molecule
      • Best characterized by a B7 protein in the antigen-presenting cell interacting with CD28 of the T cell 
  • Activated T cells proliferate and may become: 
    • Effector T cells:
      • Migrate from the lymphoid organs into the circulation and tissues to reach sites of infection
      • Able to further differentiate to memory cells
    • Memory T cells
2-signal model - T-cell dependence on costimulation

2-signal model of T-cell dependence on costimulation:
When both signal 1 (TCR binding the cognate antigen presented by the MHC molecule in the antigen-presenting cell) and signal 2 (costimulatory molecule interaction between the antigen-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 and TCR. However, when either signal 1 (middle image shows no antigen and TCR binding) or signal 2 (right image shows no costimulation) is missing, the T cell will not be fully activated.
Outcomes would be anergy (state of unresponsiveness), apoptosis (cell death), or ignorance (T cell does not notice or does not get affected by the antigen).
TCR: T-cell receptor

Image by Lecturio. License: CC BY-NC-SA 4.0

T Cells in the Immune System

Activated T cells

  • Activated T cells become effector CD4+ or CD8+ T cells and memory T cells:
    • CD4+ T cells: functional categories of activated CD4+ T cells are influenced by secreted cytokines.
      • T helper (Th) cells: Th1 and Th2 (most studied), Th9, Th17, Th22, and T follicular helper (Tfh) 
      • Subset of regulatory T cell (Treg)
    • CD8+ T cells: cytotoxic T cells (Tc)
    • Memory T cells
  • Cell surface markers:
    • T cells: TCR, CD3
    • Th cells: CD4, CD40L, CXCR4 and CCR5 (coreceptors for HIV-1 entry into CD4+ cells)
    • Tregs: CD4, CD25
    • Tc: CD8
  • Aside from surface markers, T cells and subsets are identified by cytokine profiles.

Description of CD4+ T cell subsets

Table: CD4+ T cell subsets
CD4+ T cellsStimulated byCytokines producedFunctionsRole in disease
Th1IL-12, IFN-γIFN-γ, TNF, IL-2
  • Activate macrophages
  • Activate cytotoxic T cells
  • Eradicate intracellular organisms
  • Proinflammatory
  • Autoimmunity
Th2IL-2, IL-4IL-4, IL-5, IL-6, IL-9, IL-10, IL-13
  • Activate eosinophils, ↑ IgE
  • Activate mast cells
  • Parasitic infections (e.g., helminths)
  • Allergic conditions
Th17IL-1, IL-6, IL-23, TGF-βIL-17, IL-21, IL-22Promote neutrophilic inflammation
  • Extracellular bacteria and fungi
  • Neutrophil predominant asthma
  • Autoimmunity
TfhIL-6IL-4, IL-21Facilitate B cell activation and maturationAntibody production
TregTGF-β, IL-2TGF-β, IL-10, IL-35
  • Suppress immune response
  • Promote self-tolerance
↓ Autoimmunity, allergy, inflammation
IL: interleukins
IFN: interferon
TNF: tumor necrosis factor
TGF: tumor growth factor

Other CD4+ T cell subsets

  • Th9 and Th22 were recently discovered.
  • Th9: 
    • Stimulated by IL-4, TGF-β
    • Important in antitumor immunity, allergies, and autoimmune diseases
  • Th22:
    • Produces IL-22 (like Th17 cells)
    • Involved in mucosal immunity
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, 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 that facilitate activation of other immune-cell partners.
IFN: interferon
TNF: tumor necrosis factor

Image by Lecturio. License: CC BY-NC-SA 4.0

CD8+ T cells

  • Cytotoxic or cytolytic T cells
  • Requires cytokine (interleukin-2 (IL-2)) stimulation (from Th1 cells) to be activated, then leaves the secondary lymphoid organ and circulates in search of targets
  • Produces cytokines interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and TNF-β
  • Transcription factor: RUNX3
  • Functions include killing of:
    • Pathogens
    • Infected cells
    • Tumor cells
    • Allografts
  • Cytotoxicity occurs via:
    • Granule exocytosis: Granule contents (including granzymes and perforins) enter the target cell and activate the caspase pathway, which leads to apoptosis.
    • Expression of Fas Ligand (FasL): Fas (receptor in the cell)-FasL (ligand in CD8+ T cell) interaction activates the caspase pathway, leading to cell death.
  • Clinical relevance:
    • Prominent role in intracellular pathogens (e.g., Listeria monocytogenes) as the pathogens spend little time in circulation (less susceptibility to antibodies)
    • Similar importance in the immune defense against viruses (e.g., HIV)

Memory T cells

  • Can be either CD4+ or CD8+
  • Mounts immune response years after initial exposure
  • Following initial exposure to antigens, some T cells develop into memory cells:
    • Cells initially reside in lymphoid tissues (central memory T cells)
    • T memory cells then reside in peripheral tissues (effector memory cells)
    • Become effector T cells following reinfection by the same antigen

T regulatory cells

  • Because unrestrained T cell response can become pathologic, Tregs are present to prevent excessive inflammation and tissue damage.
  • Can down regulate the activity of many immune cells including:
    • CD4+ T cells
    • CD8+ T cells
    • Dendritic cells (via cell surfaces of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and lymphocyte activation gene (LAG-3))
    • B cells
    • Natural killer cells
    • Eosinophils, basophils, and mast cells

Intraepithelial lymphocytes (IEL)

  • Associated with the protection of the mucosal surface (intestinal tract, respiratory tract, genitourinary tract epithelium, and skin) 
  • When pathogens invade the epithelial surface, IELs are the 1st immune cells to encounter the pathogens. 
  • Predominantly activated T cells: CD8+ > CD 4+ cells at most sites (not all)
  • TCR-αβ+ and TCR-γδ+ cells are found within IEL groups.
Intraepithelial lymphocytes

Intraepithelial lymphocytes (IEL) in the intestinal epithelium

Image by Lecturio.

Cytokines in Cell-mediated Immunity

Cytokines

  • Soluble proteins released by different cells in response to various inflammatory stimuli:
    • Play overlapping roles in both innate and adaptive immunity
    • Important in cell-mediated adaptive immunity: T-cell differentiation depends on cytokines, and T cells produce cytokines
  • According to function or cell of origin:
    • Lymphokines: cytokines made by lymphocytes 
    • Monokines: cytokines made by monocytes 
    • Chemokines: cytokines with chemotactic actions
  • Includes:
    • IL: cytokines made by a leukocyte and acting on other leukocytes
    • IFN: originally named for the function of “interfering” with viral infections:
      • Type I interferons (IFN-α and IFN-β): mainly function to prevent viral replication inside cells
      • Type II interferon (IFN-γ): activates macrophages
      • Type III (IFN-ƛ): antiviral activity 
    • TNF
    • Transforming growth factor (TGF)
    • Other growth or stimulating factors

Major cytokines produced by T cells

Table: Major cytokines
CytokineFunction and activity
IL-2
  • T cell activation and proliferation
  • NK cell proliferation and activation
IL-4
  • Th2 differentiation and proliferation
  • B cell maturation and class switch to IgE and IgG
IL-5
  • Eosinophil growth and differentiation
  • B cell growth, class switch to IgA
IL-10
  • Anti-inflammatory
  • Attenuation of immune response (↓ cytokines, inhibition of T cells and NK cells)
IL-13
  • IgE production
  • ↑ Mucus production
  • Collagen synthesis
IL-17Inflammatory cytokine release (including IL-6, IL-1, TNF, which mediate fever and sepsis)
IL-21B cell and T cell differentiation
IL-22
  • Tissue repair
  • ↑ Production of defensins and tight junction adhesion proteins in epithelial cells
IFN-ɣ
  • Regulates macrophage and NK cell activation
  • Activates macrophages → granuloma
TNF
  • Proinflammatory
  • Capillary leak
  • WBC recruitment and cytotoxicity
  • Cachexia in cancer
IL: interleukins
IFN: interferon
NK: natural killer
TNF: tumor necrosis factor

Cytokines and Clinical Applications

Cytokine inhibitors and applications

Table: Cytokine inhibitors and applications
Cytokine inhibitionDrug nameConditions treated
Anti-TNF
  • Infliximab
  • Etanercept
  • Adalimumab
  • Golimumab
  • Inflammatory bowel disease
  • Rheumatoid arthritis
  • Psoriasis
  • Psoriatic arthritis
Anti-interleukin-1AnakinraRheumatoid arthritis
Anti-interleukin-1bCanakinumab
  • Adult-onset Still disease
  • Hyper-IgD syndrome
  • Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
Anti-interleukin-6Tocilizumab
  • Rheumatoid arthritis
  • Giant cell arteritis
  • COVID-19 respiratory failure

Therapeutic cytokines and applications

Table: Therapeutic cytokines
Therapeutic cytokineConditions treated
Interferon-α
  • Hepatitis B and C
  • Papillomavirus (condylomata acuminata)
  • Hairy cell leukemia
  • Kaposi sarcoma
  • Recurrence of melanoma
  • Essential thrombocythemia
Interferon-βMultiple sclerosis
Interferon-γ
  • Chronic granulomatous disease
  • Osteopetrosis
Interleukin-2
  • Renal tumors
  • Melanoma
  • HIV infection

Clinical Relevance

  • Chronic mucocutaneous candidiasis (CMCC): an autoimmune syndrome with features including 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 and occurs in 30% of individuals. Adrenal insufficiency occurs in > 60% of cases by 15 years of age. Chronic mucocutaneous candidiasis is due to genetic defects in the immune system, including those affecting autoimmune regulator (AIRE), which is important in the negative selection of T cells, and the IL-17 pathway (among others).
  • Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: a disease caused by mutations in the gene from transcription factor FOXP3. The defining feature is Treg cell impairment, which manifests as an autoimmune disease with an allergic inflammation. The disease typically presents in male infants with a triad of enteropathy, dermatitis, and autoimmune endocrinopathy (usually type 1 diabetes or thyroiditis). Diarrhea can be profound and 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. The only curative therapy available is hematopoietic cell transplantation.
  • Adult T cell leukemia/lymphoma: a rare, but often aggressive, mature T cell malignancy caused by chronic infection of CD4+ cells with the human T-lymphotropic virus (HTLV)-I. The infection is endemic in Japan, the Caribbean, and Central Africa. General presentation is widespread involvement of lymph nodes, peripheral blood, and/or the skin. The known clinical variants are acute, lymphomatous, chronic, and smoldering. Each variant has a different clinical course. The characteristic feature seen in peripheral blood is “clover leaf” or “flower cells” (cells with bizarre, hyperlobulated nuclei). Diagnosis is based on clinical presentation, morphologic and immunophenotypic changes of the malignant cells, and confirmed HTLV-I infection. Treatment is tailored to the subtype, but options include antiviral agents, monoclonal antibody therapy, chemotherapy, and allogeneic stem cell transplantation. 

References

  1. Haynes, B.F., & Soderberg K.A., & Fauci A.S. (2018). Introduction to the immune system. Jameson J, Fauci A.S., Kasper D.L., Hauser S.L., Longo D.L., & Loscalzo J(Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192284326
  2. Heimall, J. (2021). The adaptive cellular immune response: T cells and cytokines. 2021. UpToDate. Retrieved June 19, 2021, from: https://www.uptodate.com/contents/the-adaptive-cellular-immune-response-t-cells-and-cytokines
  3. Kumar, B.V., Connors, T.J., Farber, D.L. (2018). Human T Cell Development, Localization, and Function throughout Life. Immunity, 48(2), 202–213.
  4. Levinson, W., Chin-Hong, P., Joyce, E.A., Nussbaum, J, & Schwartz, B. (Eds.), (2020). Adaptive immunity: lymphocyte antigen receptors. Review of Medical Microbiology & Immunology: A Guide to Clinical Infectious Diseases, 16e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2867&sectionid=242768234
  5. Levinson W., Chin-Hong P., & Joyce E.A., Nussbaum J., & Schwartz B. (Eds.), (2020). Overview of immunity. Review of Medical Microbiology & Immunology: A Guide to Clinical Infectious Diseases, 16e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2867&sectionid=242768067
  6. Levinson, W., Chin-Hong, P., Joyce, E.A., Nussbaum, J., & Schwartz, B. (Eds.), (2020). Adaptive immunity: T-cell–mediated immunity. Review of Medical Microbiology & Immunology: A Guide to Clinical Infectious Diseases, 16e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2867&sectionid=242768307
  7. Stephen, R., Holdsworth, S.R., Gan, P. (2015). Cytokines: Names and Numbers You Should Care About. Clin J Am Soc Nephrol, 10(12), 2243–54.

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