Adaptive Cell-mediated Immunity

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

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. 

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 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

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

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

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.

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

Cytokines and Clinical Applications

Cytokine inhibitors and applications

Therapeutic cytokines and applications

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.