Antigen Recognition by Lymphocytes aB T-cell Receptors While B cells rec nize native antigen T cells MHC molecuk)CD cells antigen in the contricts the in class II molecules,while CD8 restricts the interaction to class I molecules. class II molecules present exogenous antigens and cla MHC sent endo .The interaction of MHC-bound superantigens with VB of TCRs results in VyoaTcellactivao f Structure of T-cell receptors and T-cell receptor-ligand complexes XnacteepctndiecrCCRiandTGgReg 996.1998 showed that TCRs have an immunoglobulin-like struc ture.with some unique features:(i)the hinge region of the B chain is veryriid:()TCR Bchains have a solvent cks a B2 there isastrand switch in V which resultsina flatteningo onrieac the e complexes in a orientation implies conserved atomic interactions between TCR V regions(mainly Va)and residues of the MHCclass s(mainly 2) 9 dimensional view of the Ab T-cell receptor (TCR)-HLA D chains,one 8 chain,one y chain and twochains,which e.Produced from the form three disulfide-linked dimers an E-Y and an E- MHC class I/ll-peptide complexes (Daviser strong an e cyto These tecl ents in TCR participati (e.g.CD8 which contain ITA Ms (i.e.sequences expressing repeats of and CD3).TCR-ligand interactions have also been TCR triggering are tyro analysed on purified recombinant molecules using surface orylate n kin snd CD d cytoplas c po protein of 70kDa(ZAP-70)and Syk. molecules (Fremont et al.1996). TCRs typically exhibit low affinity with equilibrium Affinities and kinetics of T-cell receptor ligand interactions counted for Physical properties of TCR-ligand interactions have been oineuc conants the range of on intac ether by TC ding assay with those observed for ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net 3 ab T-cell Receptors While B cells recognize native antigen, T cells recognize processed antigen (i.e. antigen-derived peptides bound to MHC molecules). CD4 1 T cells recognize antigen in the context of MHC class II molecules and CD8 1 cytotoxic T lymphocytes (CTLs) in the context of MHC class I molecules. The CD4 molecule restricts the interaction to class II molecules, while CD8 restricts the interaction to class I molecules. MHC class II molecules present exogenous antigens and class I molecules present endo￾genous antigens. Moreover, MHC class II, but not class I, molecules can bind superantigens. The interaction of MHC-bound superantigens with Vb of TCRs results in polyclonal T-cell activation of T cells expressing particular Vb. Structure of T-cell receptors and T-cell receptor–ligand complexes X-ray crystallographic studies of TCRs and TCR–ligand complexes (Garboczi et al., 1996; Garcia et al., 1996, 1998) showed that TCRs have an immunoglobulin-like struc￾ture, with some unique features: (i) the hinge region of the b chain is very rigid; (ii) TCR b chains have a solvent￾exposed loop of 13 residues in Cb; (iii) TCR Ca lacks a b￾pleated sheet and thus has a poorly ordered structure; (iv) there is a strand switch in Va, which results in a flattening of the outer surface of Va. TCRs bind MHC class I–peptide complexes in a ‘diagonal’ orientation, in which the peptide runs diagonally between the two CDR3 loops, extending from CDR1a to CDR1b (Figure 2). This canonical orientation implies conserved atomic interactions between TCR V regions (mainly Va) and residues of the MHC class I helices (mainly a2). TCRs are expressed on the surface only as associated with CD3 and z chains. The CD3 complex consists of two e chains, one d chain, one g chain and two z chains, which form three disulfide-linked dimers, an e–g and an e–d heterodimer and a z-chain homodimer. This association is strong and TCR–CD3 complexes can be isolated from cell membranes. CD3 and z chains have cytoplasmic tails, which contain ITAMs (i.e. sequences expressing repeats of Y-x-x-L/I, which upon TCR triggering are tyrosine phosphorylated, mainly by the src tyrosine kinase p56lck, which in part is associated with CD8 and CD4. Phos￾phorylated ITAMs bind the tyrosine kinases, z-associated protein of 70 kDa (ZAP-70) and Syk. Affinities and kinetics of T-cell receptor– ligand interactions Physical properties of TCR–ligand interactions have been studied on intact cells, either by TCR photoaffinity labelling or by a direct binding assay with radiolabelled soluble MHC class I/II–peptide complexes (Davis et al., 1998). These techniques detect the participation of other cellular components in TCR–ligand interactions (e.g. CD8 and CD3). TCR–ligand interactions have also been analysed on purified recombinant molecules using surface plasmon resonance. These studies require purified recom￾binant TCR and MHC molecules that are rendered soluble by deletion of the spanning and cytoplasmic portions of the molecules (Fremont et al., 1996). TCRs typically exhibit low affinity with equilibrium dissociation constants in the range of 10 2 4 to 10 2 7 mol L 2 1 (Davis et al., 1998). This is accounted for by very rapid dissociation of TCR–ligand complexes, with dis￾sociation kinetic constants in the range of 0.02–5 s 2 1 . The association rate constants are comparable with those observed for low-affinity antibodies. The rapid Figure 2 Three-dimensional view of the Ab T-cell receptor (TCR)–HLA￾A2–Tax peptide complex (Garboczi et al., 1996). The TCR b-chain is shown in grey, Va/Ja in dark blue, the peptide in green, the HLA-A2 heavy chain in yellow and b2-microglobulin (b2m) in light blue. Produced from the Brookhaven PDB file using the MOLMOL program. Antigen Recognition by Lymphocytes ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 3