The TCR is a multimolecular complex with separate components able to bind ligand or to transduce an activating signal to the cell. The peptide–MHC binding regions of the TCR consist of an α/β heterodimer in the majority of T cells, and the related γ/δ heterodimer in a smaller subset of T cells. α and β as well as γ and δ consist of variable and constant regions. Similar to antibodies, the variable regions of the TCR antigen-binding proteins arise from rearranging gene segments that are imprecisely joined during T-cell development. This process allows for an extraordinarily diverse repertoire of potential antigen reactivity, although there are in total only several hundred genes that make up the α, β, γ, and δ loci. The germ line configurations of the α and β loci are different, such that the α-chain locus comprises about 70 variable (V) segments, 60 joining (J) segments, and 1 constant (C) segment, whereas the β-chain locus comprises 50 V regions, 2 diversity (D) segments, 13 J segments, and 2 C regions. Greater diversity is generated by the addition of nucleotides between the V and J gene segments on α chains and the V, D, and J segments in β chains during the formation of the mature TCR. In total, it has been calculated that approximately 1018 different TCRs can be created from these segments, although the functional population is much smaller because of the requirements for selection during maturation in the thymus (see T-Cell Development section later). Thus, once it has completed its developmental program, an individual T cell expresses a unique TCR encoded by a combination of gene segments that have been altered and rearranged (Fig.1). The T cells circulating through the lymphatics, lymph nodes (LNs), and spleen possess sufficient diversity for nearly all pathogens encountered to express an antigenic sequence recognized by a circulating T cell, which will then expand in number to combat that pathogen.

Fig1. GENERATION OF DIVERSITY OF THE T-CELL ANTIGEN RECEPTOR. To generate the diverse repertoire of antigen receptors needed for protective T-cell immunity, the genetic loci encoding the two proteins of the T-cell antigen receptor (TCR) undergo multiple rearrangements to form the mature α and β chains. The sequence of recombination and gene expression events is shown for the TCR β chain (A) and the TCR α chain (B). In the example shown in A, the variable (V) region of the rearranged TCR β chain includes the Vβ1 and Dβ1 gene segments and the third J segment in the Jβ1 cluster. The constant (C) region in this example is encoded by the exons of the Cβ1 gene, depicted for convenience as a single exon. Note that at the TCR β chain locus, rearrangement begins with D-to-J joining followed by V-to-DJ joining. In humans, 14 Jβ segments have been identified, and not all are shown in the figure. In the example shown in B, the V region of the TCR α chain includes the Vα1 gene and the second J segment in the Jα cluster. (This cluster is made up of at least 61 Jα segments in humans; not all are shown here.) (From Abbas AK, Lichtman AH, Pillai S, Baker DL, Baker A. Cellular and Molecular Immunology. 9th ed. Philadelphia: Elsevier; 2017.)

Soon after identification of the genes encoding TCR α and β, it became apparent that although they were sufficient to bind pep tide–MHC,1 the α/β heterodimer was not capable of transmitting an intracellular signal once ligand was bound. A series of studies demonstrated that the signal transduction function of the TCR complex resides in a protein complex that noncovalently associates with the α/β dimer. This complex, CD3, is required both for stable expression of the ligand-binding components of the TCR and for signal trans duction.2 CD3 is composed of three subunits, δ, ε, and γ, expressed as heterodimers (γ/ε and δ/ε) along with the ζ subunit, which is present as a homodimer. Each subunit contains immunoreceptor tyrosine based activation motifs (ITAMs), a stretch of amino acids with discretely placed tyrosine residues: one ITAM in δ, ε, and γ and three ITAMS in ζ. The ITAM tyrosines are inducibly phosphorylated upon engagement of the α/β TCR chains by peptide–MHC and become docking sites for other proteins that initiate the signaling cascade for T-cell activation. Notably, the CD4 or CD8 protein also plays a role in mediating signal transduction. These coreceptors bind both the appropriate MHC complex (MHC I for CD8, MHC II for CD4) and, via their cytoplasmic tails, the signaling molecule Lck, one of the kinases capable of phosphorylating the ITAMs (Fig. 2).

Fig3. PROXIMAL T-CELL RECEPTOR SIGNAL TRANSDUCTION. Upon antigen recognition, there is clustering of T-cell antigen receptor (TCR) complexes with coreceptors (CD4, in this case). CD4-associated Lck becomes active and phosphorylates tyrosines in the immunoreceptor tyrosine-based activation motifs (ITAMs) of CD3 and ζ chains (A). ζ-associated protein of 70 kDa (ZAP-70) binds to the phosphotyrosines of the ζ chains and is itself phosphorylated and activated. (The illustration shows one ZAP-70 molecule binding to two phosphotyrosines of one ITAM in the ζ chain, but it is likely that initiation of a T-cell response requires the assembly of multiple ZAP-70 molecules on each ζ chain.) Active ZAP-70 then phosphorylates tyrosines on various adaptor molecules, such as linker of activated T cells (LAT) (B). The adaptors become docking sites for cellular enzymes such as PLCγ1 and GDP-GTP exchange factors that activate Ras and other small G proteins upstream of MAP kinases (C), and these enzymes activate various cellular responses. MAPK, Mitogen activated protein kinase; PLC γ1, phospholipase C γ1. (From Abbas AK, Lichtman AH, Pillai S, Baker DL, Baker A. Cellular and Molecular Immunology. 9th ed. Philadelphia: Elsevier; 2017.)

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