Role of T Cells in Immune Responses

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Chapter 2

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

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

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