If these three interactions do not occur, the T cell becomes nonfunctional for an extended period. In some cases, nonresponsive T cells become apoptotic and die.

T cell activation is central to the elicitation of an immune response. T cells act as effector cells or direct the immune response by influencing the activity of macrophages in the inflammatory response and of B cells in the synthesis of antibodies.

Clonal Selection Hypothesis

In the late 1950s, MacFarland Burnet proposed the clonal selection theory, which states that antigens, rather than lymphocytes, direct the immune response. The five basic tenets of the theory are (1) each lymphocyte has a unique receptor that binds to only one antigen; (2) the receptor must react with the antigen for cellular activation; (3) only selected clones of lymphocytes activated by antigen will divide (clonal expansion); (4) all of the daughter cells will express antigen receptors identical to the parent cell and (5) some of the daughter cells act as effector cells, and others become memory cells.

T Cell Receptors

The unique antigen binding receptor on T cells is called the T cell receptor (TCR). It is expressed on all T cells and exists in either α/β or γ/δ forms. The α/β TCR is expressed on peripheral blood T cells. γ/δ expressing T cells are rare in peripheral blood but are found in abundance in mucosal tissue. Each T cell has a homogeneous TCR population that recognizes a single antigen or epitope.

α/β T Cell Receptors

The TCR is a dual chain α/β heterodimer that consists of variable (V) and constant (C) regions. The structure of an α/β TCR is shown in Figure 6-2.

Figure 6-2 Structure of the T cell receptor. The schematic diagram of the α/β T cell receptor (TCR) shows the domains of a typical TCR-specific for a peptide–major histocompatibility complex (MHC) complex. The antigen-binding portion of the TCR is formed by V_α and V_β domains. (From Abbas AK, Lichtman AH, Pillai S: Cellular and molecular immunology, ed 6 [updated edition], Philadelphia, 2010, Saunders. Adapted from Bjorkman PJ: MHC restriction in three dimensions: a view of T cell receptor/ligand interactions, Cell 89:167, 1997. Copyright Cell Press.)

The V regions of the α/β-chains determine antigenic specificity by creating a three-dimensional pocket that recognizes immunogenic epitopes. The dual-chain V region pocket is created through the association of several different genes. The V_α pocket is the result of V_α genes joining with a junctional (J_α) gene. In the β-chain, a functional V_β is created by linking V_β, diversity (D_β), and J_β-domains.

Complementarity determining regions (CDRs), which are hypervariable regions in the V_α/_β-chains have actual contact with antigens. Class II molecules have six CDRs (three on each chain). The role of CDRs in binding to major histocompatibility complex (MHC) class II molecules is shown in Figure 6-3.

Figure 6-3 Major histocompatibility complex (MHC) class II. Processed antigenic fragments (10–30 amino acids in length) interact with the α₁– and β₁-domains on the class II molecule within the peptide-binding groove, allowing presentation to CD4+ Th cells. Interactions with the T cell receptor (TCR) are stabilized by CD4 recognition of the conserved regions on the class II molecule. (From Actor JK: Elsevier’s integrated immunology and microbiology, Philadelphia, 2007, Mosby.)

In the α-chains, CDR1 interacts with the N-terminal portion of the epitope. β-chain CDR1 reacts with the C-terminal portion of the peptide. CDR2s interact with the class II molecules but are not involved in antigen recognition. CDR3s are responsible for binding to the epitope presented by class II molecules. Most of the sequence variability responsible for TCR diversity is found in CDR3.

In addition to V regions, each TCR has an invariant constant (C) region. The C region consists of 140 to 180 hydrophilic amino acids and continues to a short hinge region with cysteine residues that link the α-chain and the β-chain A transmembrane anchor unit, which consists of highly charged hydrophobic amino acids, is connected to a short cytoplasmic region.

γ/δ T Cell Receptors

The Tγ/δ TCR structure is similar to the α/β TCRs. These T cells are only found in the mucosa and function as a bridge between innate and adaptive immunity. CD4γ/δ T cells recognize microbial phosphorylated molecules such as isopentylpyrophosphate (IDP) and dimethylallylpyrophosphate (DMAP). Direct interaction between these molecules and the γ/δ TCR activates the T cell. Antigen processing by APCs or presentation by MHC molecules is not required for activation. A vigorous γ/δ T cell response localizes the microbe in the mucosa until an adaptive response is mounted.

Origin of T Cell Receptor Diversity

In the generation of TCR diversity, two factors must be considered. First, each lymphocyte has a TCR that recognizes a single epitope. Second, 10¹³ different epitopes must be recognized. If a single lymphocyte TCR recognizes only one epitope, it follows that 10¹³ lymphocyte clones are present in each of the CD4 (Th1 and Th2) and CD8 (Tc1 and Tc2) populations.

To create a repertoire of antigen-specific TCRs, alternative forms of genes present in somatic cells are rearranged in a process, called somatic cell recombination, by using RAG-1 and RAG-2 recombinase activating enzymes (Figure 6-4).

Figure 6-4 Gene rearrangement of T cell receptor genes. T cell receptor (TCR) diversity is generated by combinatorial joining of variable (V), joining (J), and diversity (D) genes and by N region diversification (nucleotides inserted by the enzyme deoxynucleotidyl transferase). The top and bottom rows show germ-line arrangement of the V, D, J, and constant (C) gene segments at the TCR-α and TCR-β loci. During T cell development, a V-region sequence for each chain is assembled by deoxyribonucleic acid (DNA) recombination. For the α-chain (top), a V_α gene segment rearranges to a J_α gene segment to create a functional gene encoding the V domain. For the β-chain (*bottom*), rearrangement of a Dβ, a Jβ, and a Vβ gene segment creates the functional V domain exon. (From Actor JK: Elsevier’s integrated immunology and microbiology, Philadelphia, 2007, Mosby.)

In the α-chain, 70 to 80 different V_α gene products can be linked to 61 different J-chains. Simple recombination in the α-chain can result in approximately 4.9 × 10³ antigen-specific TCRs. β-chains have 52 variable gene segments, two diversity gene segments, and 13 J region genes. Recombination in the β-chain results in 1.3 × 10³ unique TCRs.

Additional TCR diversity is created by alternate joining of D_β-chains, junctional flexibility, and N- and P-nucleotide additions. Alternate joining of D domains creates 5 × 10³ diverse TCRs. Adding six or more amino acids to the J domains (junctional diversity) creates more TCR diversity. Random insertion of palindromic sequences at single strand breaks (P-nucleotides) or nontemplated amino acids (N-nucleotides) into the TCR coding regions also occurs. Junctional diversity and P- and N-nucleotides generate an additional 10¹¹ possible TCRs. The sum of the gene re-arrangements (4.9 × 10³ + 1.3 × 10³ + 5.3 × 10 ³ + 1.0 × 10¹¹) allows the immune system to respond to all known antigens.

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