The antigen receptor of the majority of T cells, including MHC-restricted CD4+ helper T cells and CD8+ cytotoxic T lymphocytes (CTLs), is a heterodimer consisting of two transmembrane polypeptide chains, designated TCR α and β, covalently linked to each other by a disulfide bridge between extracellular cysteine residues (Fig. 1). T cells expressing this form of TCR are called αβ T cells. A less common type of TCR is composed of TCR γ and δ chains, and the cells on which it is expressed are called γδ T cells. Each TCR α and β chain consists of one Ig-like N-terminal variable (V) domain, one Ig-like constant (C) domain, a hydrophobic transmembrane region, and a short cytoplasmic region. Thus, the extracellular portion of the TCR αβ heterodimer is structurally similar to the antigen-binding fragment (Fab) of an Ig molecule, which is made up of the V and C regions of a light chain and the V region and the first C region of a heavy chain.
Fig1. Structure of the T-cell receptor (TCR). The schematic diagram of the αβ TCR (left) 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 the Vβ and Vα domains. The ribbon diagram (right) shows the structure of the extracellular portion of a TCR as revealed by x-ray crystallography. The hypervariable segment loops that form the peptide-MHC binding site are at the top. Ig, Immunoglobulin. (Modified from Bjorkman PJ. MHC restriction in three dimensions: a view of T-cell receptor/ligand interactions. Cell. 1997;89:167–170.)
The V regions of the TCR α and β chains contain short stretches of amino acids where the variability between different TCRs is concentrated, and these form the hypervariable or complementarity-determining regions (CDRs). Three CDRs in the α chain and three CDRs in the β chain together form the part of the TCR that specifically recognizes peptide-MHC complexes (Fig.2). The β chain V domain contains a fourth hyper variable region that does not participate in antigen recognition; its function remains unclear. Each TCR chain, like Ig heavy and light chains, is encoded by multiple gene segments that are joined together during the maturation of T lymphocytes.
Fig2. Binding of a TCR to a peptide-MHC complex. The variable (V) domains of a TCR are shown interacting with a human class I MHC molecule, human leukocyte antigen A2 (HLA-A2), presenting a viral pep tide (in yellow). The figure represents a front view of the x-ray crystal structure of the trimolecular MHC-peptide-TCR complex. β2 m, Beta-2 microglobulin. (From Bjorkman PJ. MHC restriction in three dimensions: a view of T-cell receptor/ligand interactions. Cell. 1997;89:167–170.)
The C regions of both α and β chains continue into short hinge regions, which contain cysteine residues that contribute to a disulfide bond linking the two chains. Each hinge is followed by a hydrophobic transmembrane portion, an unusual feature of which is the presence of positively charged amino acids, including a lysine in the α chain and a lysine and an argi nine in the β chain. The positively charged residues of these amino acids interact with negatively charged residues present in the transmembrane portions of other polypeptides (those of the CD3 complex and ζ) that are part of the TCR complex. Both TCR α and β chains have carboxy-terminal cytoplasmic tails that are 5 to 12 amino acids long. Like membrane IgM on B cells (discussed later), the cytoplasmic regions are too short to transduce signals, and other proteins with ITAM motifs that are physically associated with the TCR serve the signal-transducing functions of this antigen receptor complex.
The CD3 and ζ proteins are noncovalently associated with the TCR αβ heterodimer to form the TCR complex, and when the TCR recognizes antigen, these associated proteins trans duce the signals that lead to T-cell activation. The components of the TCR complex are illustrated in Fig. 3. The CD3 proteins and the ζ chain are identical in all T cells in an individual regardless of specificity, which is consistent with their role in signaling and not in antigen recognition. The CD3 proteins are also required for surface expression of the complete receptor complex on T cells. Each TCR complex contains one TCR αβ heterodimer associated with one CD3 γε heterodimer, one CD3 δε heterodimer, and one disulfide-linked ζζ homodimer.
Fig3. Components of the TCR complex. The TCR complex of MHC-restricted T cells consists of the αβ TCR noncovalently linked to the CD3 and ζ proteins. The association of these proteins with one another is mediated by charged residues in their transmembrane regions (not shown).
The CD3 γ, δ, and ε proteins are homologous to one another. The N-terminal extracellular regions of these three proteins each contains a single Ig-like domain, and therefore, they are members of the Ig superfamily. The transmembrane segments of all three CD3 proteins contain a negatively charged aspartic acid residue that binds to positively charged residues in the transmembrane domains of the TCR α and β chains, thus keeping the TCR and CD3 associated as a complex. The cytoplasmic domains of CD3 γ, δ, and ε range from 44 to 81 amino acid residues in length, and each of these domains contains one ITAM.
The ζ chain has a short extracellular region of nine amino acids, a transmembrane region containing a negatively charged aspartic acid residue (similar to the CD3 chains), and a long cytoplasmic region (113 amino acids) that contains three ITAMs. The ζ chain is normally expressed as a homodimer, and it is also associated with signaling receptors on lymphocytes other than T cells, such as the Fcγ receptor (FcγRIIIA) of NK cells.
Ligation of the TCR by MHC-peptide ligands results in the phosphorylation of ITAM tyrosine residues in CD3 and ζ proteins. In addition, recognition of peptide-MHC complexes by the TCR may induce a conformational change in the TCR, making the ITAMs associated with the linked CD3 or ζ chains available for tyrosine phosphorylation by coreceptor-associated SRC family kinases.
In addition to the TCR complex, T cells express several other proteins that recognize ligands on APCs and play important roles in T-cell responses (Fig.4).
Fig4. Ligand-receptor pairs involved in T-cell activation. (A) The major surface molecules of CD4+ T cells involved in the activation of these cells (the receptors) and the molecules on APCs (the ligands) recognized by the receptors are shown. CD8+ T cells use most of the same molecules, except that the T-cell receptor (TCR) recognizes peptide–MHC-I (major histocompatibility complex I) complexes, and the coreceptor is CD8, which recognizes MHC-I. Immunoreceptor tyrosine-based activation motifs (ITAMs) are the regions of signaling proteins that are phosphorylated on tyrosine residues and become docking sites for other signaling molecules. CD3 is composed of three polypeptide chains, named γ, δ, and ε, arranged in two pairs (γε and δε), as shown in Fig. 3. Some inhibitory receptors, such as programmed death–1 (PD-1), contain cytoplasmic immunotyrosine-based inhibitory motifs (ITIMs) as well as “switch” motifs (ITSMs). (B) Important molecules of T cells that participate in activating or inhibiting responses to antigens, but are not the receptors for antigen, are summarized. CTLA-4, Cytotoxic T-lymphocyte antigen–4; ICAM-1, intercellular adhesion molecule 1; LFA-1, leukocyte function-associated antigen 1; PDL-1/2, programmed death ligands 1 and 2.
