Role of T Cells in Immune Responses

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Role of T Cells in Immune Responses

I T Cell Surface Molecules

A T cell receptor (TCR) complex

• Comprises an antigen-recognizing heterodimer associated with a multimeric activation unit (CD3) (Box 2-1; Fig. 2-1)

BOX 2-1 “Must-Knows” for each of the Immune Cell Receptors: CLAP

Ligand it binds

Action it causes

Purpose in immunity

2-1 T cell receptor (TCR) complex. The TCR consists of α and β subunits (most common) or γ and δ subunits, which recognize antigen in association with major histocompatibility complex molecules. Differences in the variable (V) regions of the TCR subunits account for the diversity of antigenic specificity among T cells. Activation of T cells requires the closely associated CD3, a complex of four different types of subunits. C, constant region; V, variable region.

TCR: associated with CD3 on T cells

TCRs resemble immunoglobulins but have to be presented with antigen by MHC.

1. All TCRs expressed by a single T cell are specific for the same antigen.

• The gene and protein structures of TCRs resemble those of immunoglobulins.

2. TCRs only recognize antigenic peptides bound to class I or II major histocompatibility complex (MHC) molecules.

• α,β TCR is present on most T cells.

a. Slightly different γ,δ TCR is present on different T cells.

• The CD3 activation unit consists of several subunits (γ, δ, ε, and ζ) that are noncovalently linked to TCR.

a. Binding of antigen to TCR activates a cascade of phosphorylation events, the first step in intracellular signaling leading to activation of T cells.

B Accessory molecules

• Promote adhesion of T cells and/or signal transduction leading to T cell activation

1. CD4 and CD8 coreceptors define two main functional subtypes of T cells.

CD4: binds to class II MHC

CD8: binds to class I MHC

• CD4, present on helper T (T_H) cells, binds to class II MHC molecules on the surface of antigen-presenting cells (APCs).

• CD8, present on cytolytic T (T_C) and suppressor T (T_S) cells, binds to class I MHC molecules on the surface of all nucleated cells.

2. Adhesion molecules (e.g., CD2, LFA-1) help bind T cells to APCs and target cells or direct T cells to sites of inflammation and lymph nodes.

3. Coreceptor activating molecules (e.g., CD28 and CTLA-4) transduce signals important in regulating functional responses of T cells.

II Development and Activation of T Cells

A Antigen-independent maturation

1. Begins in bone marrow and is completed in the thymus, generates immunocompetent, MHC-restricted, naive T cells

2. Diversity of antigenic specificity of TCRs results from rearrangement of V, D, and J gene segments during maturation (similar to rearrangement of immunoglobulin genes).

• Each T cell possesses only one functional TCR gene and thus recognizes a single antigen (or a small number of related cross-reacting antigens).

3. Thymic selection eliminates developing thymocytes that react with self-antigens (including self MHC molecules).

B Antigen-dependent activation

1. Leads to proliferation and differentiation of naive T cells (clonal expansion) into effector cells and memory T cells (Fig. 2-2)

2-2 Overview of T cell activation. The dendritic cell (DC) initiates an interaction with CD4 or CD8 T cell through an MHC-peptide interaction with the T cell receptor. The DC provides an 11–amino acid peptide on the class II MHC, B7 coreceptor, and cytokines to activate CD4 T cells. Activation of CD8 T cell is through the class I MHC and 8– to 9–amino acid peptide plus the B7 coreceptor and cytokines. Presentation of antigen to CD4 T cells and cross presentation to CD8 T cells is shown in the diagram. The cytokines produced by the DC determine the type of T helper cell. Activated CD8 T cells can interact with and lyse target cells through T cell receptor recognition of peptide in class I MHC molecules on target cell. APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte; Ig, immunoglobulin.

2. Effective stimulation requires primary and coactivating signals (fail-safe mechanism) that trigger intracellular signal transduction cascades, ultimately resulting in new gene expression (Fig. 2-3).

2-3 Cell-cell interactions that initiate and deliver T cell responses. A, Dendritic cells initiate specific immune responses by presenting antigenic peptides on class II MHC molecules to CD4 T cells with binding of coreceptors and release of cytokines. B, CD4 T cells activate B cells, macrophages, and dendritic cells (antigen-presenting cells [APCs]) by adding the CD40 ligand (CD40L) binding to CD40 and cytokines. C, CD8 cytotoxic lymphocytes (CTLs) recognize targets through T cell receptor and CD8 binding to antigenic peptides on class I major histocompatibility (MHC) molecules.

• Signal 1 (primary): specificity—dependent on antigen and MHC

a. Antigen-specific binding of TCR to antigenic peptide:MHC molecule on APC or target cell

b. Binding of CD4 or CD8 coreceptor to MHC molecule on APC or target cell

• Signal 2 (coactivating): permission—independent of antigen and MHC

a. Lack of signal 2 results in tolerance due to anergy or apoptosis.

b. Interaction between coreceptor activating molecules on T cell and APC or target cell (e.g., CD28-B7 interaction)

3. Signal 3 (determines nature of response): direction—cytokine from dendritic cell (DC) or APC

• Determines the cytokine response and function of the T cell (T_H1, T_H2, T_H17, regulatory T [Treg] cell)

4. Adhesion molecules: selectin (E-, L-, P-), ICAM (-1, -2, -3, LFA-3 CD2), and integrin (VLA, LFA-1, CR3)

• Strengthens cell-cell interactions; binds cells to epithelium in immune organs or facilitates migration and homing of cells.

Antigen specificity (TCR-MHC) + permission (CD28-B7) + direction (cytokine) = T cell activation

C Antigen processing and presentation by class I and II MHC molecules (Fig. 2-4)

2-4 Structures of class I and II major histocompatibility complex (MHC) molecules. Class I molecules comprise a large α chain and a much smaller β₂-microglobulin molecule (β₂m), which is encoded by a gene located outside of the MHC. The class I peptide binding site is a pocket-like cleft (like pita bread) that holds peptides of 8 to 10 residues. Class II molecules comprise α and β chains of about equal size. The class II peptide binding site is an open-ended cleft (like a hotdog roll) that holds peptides with 12 or more residues. Noncovalent interactions hold the subunits together in both class I and II molecules.

• Different pathways are used for degradation of intracellular and internalized extracellular protein trash. Peptides resulting from digestion of nonhost (foreign) protein trash are recognized by the T cell surveillance squad, which mounts an appropriate defense (Box 2-2).

BOX 2-2 Cellular Trash and T Cell Policemen

Extracellular, or exogenous, trash (e.g., dead cells, intact microbes, and soluble proteins) is picked up by APCs, the body’s garbage trucks. Once internalized, extracellular trash is degraded within lysosomes (garbage disposal), and the resulting peptides bind to class II MHC molecules, which then move to the cell surface. As the APCs circulate through lymph nodes, CD4 T_H cell police officers view the displayed peptide trash. The presence of foreign peptides activates the CD4 T cells to move, producing and secreting cytokines that alert other immune system cells to the presence of intruders within the lymph node and at the site of infection.

Cross-presented antigens (to activate CD8 T cells) from dead cells containing from dead cells containing viral, tumor, or intracellular bacterial antigens leak out into the cytoplasm and are processed for presentation on class I MHC molecules, as described for endogenous proteins. DCs use this process to initiate the CD8 T cell response.

Intracellular (endogenous) proteins are marked as trash by attachment of multiple ubiquitin molecules and then degraded in large, multifunctional protease complexes called proteasomes. These cytosolic garbage disposals, present in all cells, generate peptides that pass through TAP transporters into the rough endoplasmic reticulum, where they bind to class I MHC molecules, which act like garbage cans. Once an MHC garbage can is filled with a peptide, it moves to the cell surface. CD8 T_C cells, like neighborhood policemen searching for contraband, continually check the class I garbage cans for nonself peptides derived from viral intruders, foreign grafts, and tumor cells. Such antigenic peptides alert CD8 T cells to attack and kill the offending cells.

Both normal self proteins and foreign proteins are processed and presented in the endogenous and exogenous pathways. However, patrolling T cells normally recognize only foreign peptide–MHC complexes and ignore the large number of self peptide–MHC complexes on cells.

1. Endogenous antigen (class I MHC) pathway generates and presents antigenic peptides derived from intracellular viral, foreign graft, and tumor cell proteins (Fig. 2-5A).

2-5 Antigen processing and presentation. A, Endogenous. Cellular proteins that are targeted for degradation as trash by ubiquitination (u) are digested in the proteosome. Peptides of 8 or 9 amino acids pass through the transporter associated with processing (TAP) into the endoplasmic reticulum (ER). The peptide binds to a groove in the heavy chain of class I MHC molecules, the complex acquires β₂-microglobulin and is shuttled through the Golgi apparatus to the cell surface where the class I MHC molecule presents the peptide to CD8 T cells. B, Exogenous. Phagocytized proteins are degraded in endosomes, which fuse with vesicles that carry class II MHC molecules from the ER. The class II molecules acquire an invariant chain in the ER to prevent acquisition of a peptide in the ER. The class II molecules then acquire an 11– to 13–amino acid peptide, which is delivered to the cell surface for presentation to CD4 cells. C, Cross-presentation. Proteins phagocytized by antigen presenting cells (e.g., from viruses or tumor cells) are released into the cytoplasm and pass through the TAP to the ER, where they can fill class I MHC molecules to be presented to and activate CD8 T cells. (From Murray PR, Rosenthal KS, Pfaller MA: Medical Microbiology, 6th ed. Philadelphia, Mosby, 2009, Fig. 11-8.)

• Recognition of displayed antigenic peptides directs CD8 T cell activation and killing.

2. Exogenous antigen (class II MHC) pathway generates and presents antigenic peptides derived from internalized microbes and extracellular proteins (Fig. 2-5B).

• Recognition of displayed antigenic peptides triggers CD4 T cell activation.

3. Cross-presentation pathway in DCs allows extracellular proteins (e.g., virus, tumor) to activate CD8 T cells (Fig. 2-5C).

Class II MHC presents phagocytized protein trash to CD4 T cells.

Class I MHC presents intercellular protein trash to CD8 T cells.

III T Cell Effector Mechanisms

A Cytokine production by CD4 T cells

• DCs activate the naive T cells and determine the type of T cell.

• CD4 T cells differentiate into subsets of effector cells defined by the cytokines they secrete (Fig. 2-6; Table 2-1).

TABLE 2-1

Cytokine: STAT (Source, Trigger, Action, Target)

Ag, antigen; DC, dendritic cell; IFN-γ, interferon-γ; IL, interleukin; MHC, major histocompatibility complex; MP, macrophage; NK, natural killer; TCR, T cell receptor; TGF-β, transforming growth factor-β; TLR, toll-like receptor; TNF-α, tumor necrosis factor-α; Treg, regulatory T cell.

2-6 Characteristic features of T helper cell responses. CD4 T_H cells form subsets defined by the cytokines they produce. The T_H1 and T_H2 subsets and the responses they elicit are the best characterized. T_H17 responses are initiated by an acute phase response in a TGF-β tissue environment. Note that the responses control each other. CTL, cytotoxic T lymphocyte; IFN-γ, interferon-γ; Ig, immunoglobulin.

2. T_H0 cells: presumed precursor of T_H1 and T_H2 subsets

3. T_H1 cells: characteristic responses mediated by interferon-γ (IFN-γ), lymphotoxin (LT) (tumor necrosis factor-β [TNF-β]), and interleukin-2 (IL-2)

• IL-12 stimulates development and maintenance of T_H1 responses.

• Promote cell-mediated and IgG antibody responses

• Reinforce local, innate defense by activating macrophages and stimulating lymphocyte proliferation

• Mediate type IV (delayed-type) hypersensitivity (see Chapter 4)

• Important for intracellular infections (viral, tuberculosis), fungi, and tumors

4. T_H2 cells: characteristic responses mediated by IL-4, IL-5, IL-6, and IL-10

• Activate humoral (antibody) responses

• Promote allergic responses (type I hypersensitivity)

• Stimulate antiparasitic eosinophil response (immunoglobulin E [IgE])

5. T_H17 cells: characteristic responses mediated by IL-17

• Acute phase cytokines IL-6 and IL-1 in the presence of transforming growth factor-β (TGF-β) stimulate T_H17 response

• Important for anti-bacterial and anti-fungal infections responses

• Activates neutrophils

• Involved in autoimmune responses.

• Produce TGF-β and IL-10

• Suppress naive and inappropriate T cell responses

• Can be overridden by appropriate dendritic cell and cytokine action

T_H1-produced cytokines mediate “early (1st), local” cell-mediated responses; defense against viral infections and intracellular bacteria.

T_H2-produced cytokines mediate “later (2nd), systemic” responses; defense against extracellular bacteria and parasites.

T_H17-produced cytokines mediate antibacterial, antifungal, inflammatory, and autoimmune responses when TGF-β and acute phase cytokines are present.

B Cytotoxic T lymphocyte (CTL)-mediated killing of target cells

1. CD8 T_C cells are activated in lymph node by DCs, which cross-present phagocytosed or internal antigen on class I MHC molecules.

• CD8 T_C cells kill virus-infected cells, tumor cells, and transplanted cells expressing antigen on class I MHC molecules.

• Multiple interactions create an immune synapse between the CTL and target cell.

2. Cytotoxic substances released from granules in the CTL attack the target cell.

• Perforin pokes holes in the membrane (similar to complement component C9).

• Granzymes (serine esterases) and other toxic molecules that enter target cell through holes promote apoptosis.

3. Fas ligand on CTLs binds to Fas receptor on the target cell, stimulating apoptosis of target cell.

CTLs kill by apoptosis with perforin and granzymes or Fas ligand binding to Fas on target cell.

Apoptosis: “clean” cell death involving breakdown of DNA and release of small, apoptotic bodies.

Necrosis: “messy” cell death from injury in which cell swells and bursts; intracellular contents induce local inflammatory response.

IV MHC and the Immune Response to Transplanted Tissue (Box 2-3)

BOX 2-3 Major Histocompatibility Complex and Alloantigens

MHC molecules, also known as human leukocyte antigens (HLAs) in humans, are encoded by several highly polymorphic genes clustered together on chromosome 6. The α chain of class I MHC molecules is encoded by three separate genes—HLA-A, HLA-B, and HLA-C. (The gene for the β₂-microglobulin subunit of class I molecules is located outside the MHC complex.) Class II MHC molecules are encoded by the HLA-DP, HLA-DQ, and HLA-DR loci, each containing an α chain and β chain gene. Genes encoding TNF, some complement proteins, and several other proteins are also located within the MHC complex.

An individual inherits two sets of alleles (haplotypes), one from each parent. Each nucleated cell expresses both the maternal and the paternal alleles of all class I genes. Each APC also expresses all alleles of the class II genes. All nucleated cells thus express several HLA antigens on their surface. Given the numerous alleles of each HLA gene (>100), individuals can vary widely in their HLA haplotypes. The diversity of HLA molecules allows binding of diverse antigenic peptides for antigen presentation and activation of protective immune responses. HLA differences trigger host rejection of transplanted tissue, including allografts between individuals of the same species. Although red blood cells do not express HLA antigens, the ABO blood group glycoproteins function as alloantigens that can trigger antibody-mediated transfusion reactions.

A Clinical classification of allograft rejection

1. Hyperacute reaction is a rapid response (within hours) mediated by preexisting antibodies to transplanted alloantigens leading to complement-dependent damage to the graft.

• Preexisting antibodies can arise owing to exposure to alloantigens during previous blood transfusions, transplantation, or multiple pregnancies.

2. Acute reaction, mediated primarily by T cells, begins about 10 days after transplantation.

• Massive infiltration of host cells, especially CTLs, destroys graft cells bearing alloantigens.

3. Chronic reaction is marked by fibrosis and vascular injury developing months to years after transplantation.

• Both cell-mediated mechanisms (e.g., chronic type IV hypersensitivity) and antibody-dependent mechanisms (e.g., complement-mediated cell damage) contribute to chronic reaction.

B Graft-versus-host disease (GVHD)

1. Represents cell-mediated response mounted by lymphocytes in the graft against allogeneic host cells

2. Occurs when a graft containing many lymphocytes (e.g., bone marrow transplant) is transplanted into a host with a compromised immune system due to disease or treatment with immunosuppressive agents.

GVH reaction: jaundice, diarrhea, dermatitis

GVHD develops most commonly after allogeneic bone marrow transplantation.

C Determination of tissue compatibility

1. HLA typing with anti-HLA antibodies tests for the presence of specific HLA antigens on host and potential donor cells.

2. Mixed lymphocyte reaction is a laboratory test of the reaction of host T cells to donor cells or for GVHD.

V Cytokines

• Cytokines are low-molecular-weight proteins that induce characteristic cellular responses when they bind to specific receptors on their target cells.

A Cytokine functions and sources (Table 2-2)

TABLE 2-2

Selected Cytokines

Cytokine	Major Sources	Major Effects and Target Cells
IL-1	Macrophage, dendritic cell, B cell	Acts on various nonimmune cells to initiate acute phase responses, fever Coactivates T_H cells
IL-2	T_H1 cell	Promotes growth and activation of T and B cells
IL-3	T_H cell	Stimulates hematopoiesis in bone marrow
IL-4	T_H2 cell, mast cell	Promotes growth and differentiation of B cells Enhances IgG and IgE synthesis Stimulates T_H2 response
IL-5	T_H2 cell	Promotes growth and differentiation of B cells Enhances IgA synthesis Stimulates growth and activation of eosinophils
IL-6	T_H2 cell, macrophage, dendritic cell	Promotes formation of plasma cells from B cells and antibody production Induces synthesis of acute phase proteins by liver cells
IL-10	T_H2 cell	Reduces T_H1 response by inhibiting IL-12 production by macrophages Reduces class II MHC expression by APCs
IL-12	Macrophage, dendritic cell, B cell	Stimulates formation of T_H1 cells Acts with IL-2 to promote formation of CTLs, activates NK cells
IL-17	T_H17 cell	Promotes neutrophil activation and inflammatory responses
IL-23	Dendritic cell	Promotes T_H17 responses
IFN-γ	T_H1 cell, NK cell	Enhances macrophage activity Inhibits T_H2 response Mediates aspects of type IV hypersensitivity
TNF-α	Macrophage and other cells	Has effects similar to IL-1 Promotes cachexia associated with chronic inflammation Is cytotoxic for tumor cells
TNF-β (lymphotoxin)	T_H1 cell, T_C cell	Enhances phagocytic activity of macrophages and neutrophils Is cytotoxic for tumor cells
TGF-β	Macrophage, Treg cell, B cell	Generally limits inflammatory response, enhances IgA synthesis
CXC-type chemokines (e.g., IL-8)	Macrophage, neutrophil, endothelium, fibroblast	Attracts neutrophils and promotes their migration into tissues
CC-type chemokines (e.g., MIP, RANTES)	Macrophage, neutrophil, endothelium, T cell	Attracts macrophages, eosinophils, basophils, and lymphocytes

APC, antigen-presenting cell; CTL, cytotoxic T lymphocyte; IFN, interferon; Ig, immunoglobulin; IL, interleukin; MHC, major histocompatibility complex; TGF, transforming growth factor; TNF, tumor necrosis factor.

• The diverse functions of cytokines can be grouped into several broad classes, but many cytokines exert more than one class of effect.

1. Acute phase, innate, and inflammatory responses

• Include IL-1, TNF-α, IL-6, IL-8, and chemokines

• Secreted primarily by macrophages, DCs, and other nonlymphocytes

2. T_h17 antibacterial and inflammatory responses

• Activated by IL-6, IL-1, TGF-β, and mediated by IL-17, IL-23

3. T_h1-related local cell-mediated and antibody immune responses

• Activated by IL-12, TNF-α (secreted by DC and macrophage) and mediated by TNF-β, IFN-γ, IL-2

4. T_h2 humoral

• IL-4, IL-5, IL-6, and IL-10

5. Treg immunosuppressive responses

• TGF-β and IL-10 immunosuppressive cytokines

6. Stimulators of inducible hematopoiesis in response to infection

• Include IL-3, IL-5, IL-6, and colony-stimulating factors

• Produced by activated T_H cells, macrophages, and mesenchymal bone marrow cells

B Cytokine-related disorders

• Both the overexpression and underexpression of cytokines or their receptors can be pathogenic.

1. Overproduction of IL-1, IL-6, and TNF causes a drop in blood pressure, shock, fever, and widespread blood clotting.

• Endotoxin stimulation of dendritic cells and macrophages following infection by some gram-negative bacteria → bacterial septic shock

2. Massive release of cytokines can affect many systems.

• Superantigen stimulation of T cells by TSST-1 (a bacterial exotoxin) → toxic shock syndrome

3. Inappropriate cytokine production dysregulates the immune system.

• IL-6 secretion by cardiac myxoma (benign tumor) and other tumor cells leads to fever, weight loss, and increased antibody production.

Cardiac myxoma: IL-6 responsible for fever, weight loss, ↑ antibody synthesis

• Overproduction of IL-2 and the IL-2 receptor by T cells infected with the HTLV-1 retrovirus stimulates cell growth and contributes to development of adult T cell leukemia.

TAX protein product of the virus stimulates IL-2.

Cytokine storm can be due to excessive IL-1, TNF, and other cytokines adn lead to sepsis, and systemic failures.

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