Antigymphye dissociation of TCR-ligand complexes permits dynamic y&T-cell receptors scanning of MHC-peptide complexes by TCRs on presenting cells. TCRsare many may the Bchai T-cell activation and effector functions n composition and structure.T cells constitute only I- The principal function of CD4+ effector T cells is to 3%of CD3+T cells.However,in epithelial tissue, pro anes an ited di TNFa.CD40 ligand or Fas ligand.Upon activation naive CD4+T cells proliferate and differentiate first into espond to the same antigens.Although the pre function of these cells is enigmatic,it s ems that their contrib NGM-CSF infe H Fo daptivei ce h activating cvtokin but also various amounts of unrelated patho ens,rather than distinct epitopes char- acteristic for individual organisms or species(Welshetal -10and TGFB.CD 1997). 3.GM-CS cing apoptos Activated CD8+CTLs kill target cells primarily by Structure of y&T-cell receptors CTL TCRs are formed d by rearrangement of V binds to Fas on target 1006 the cells and induces an Activated CTLs also release cytokines such as TNF encoding the 6 chain is located between the ones of Va N)and varous interleukins. and Ja segments,so that rearrangements at the and loci usive.A rea receptor ce apoptos rangedδchain com few hours)and can be elicited by a few MHC-peptide fewer V complexes on target cells.By contrast,cytokine production and V8 gene segments than at the TCR Va and VB loci.In and FasL synthesis umans there are only four V8,three J,three D and one e gene transcription. dependent evtolysis ()and TNF-mediated killing is inin Jyand Cysegments.The main diversity of TCRsisin the of pr mainly because duringchain rearran surface or release of Fas segme the can be use ah:same gene, V&TCR ed on the and ar Altered peptide ligands associated with CD3and mediate TCR signalling in much the same way as TCRs. hains are often,bu ctiona ulndcod ge alter the pattern of lymnhokines produced (partial () agonists)or antagonize T-cell responses to agonists this structure shows that the framework structure of V (antagonists).For CD8+T cells some partial resembles that of IgV H more closely than that of Va,V an elic cyto icity.which may e p ons and t T-cell function two basi TCRs seem to he structurally distinet fro been put forward:(1)the kinetic proofreading concept, Together with the observation that the CDR3 length ngagem results in TCR 6 chains signa ng and (2)th ormat nti onformational changes in the TCR that qualitati vely alte TCR signalling. ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nadissociation of TCR–ligand complexes permits dynamic scanning of MHC–peptide complexes by TCRs on presenting cells. T-cell activation and effector functions The principal function of CD4 1 effector T cells is to produce cytokines and to express surface effector mole￾cules that belong to the tumour necrosis family, such as TNFa, CD40 ligand or Fas ligand. Upon activation naive CD4 1 T cells proliferate and differentiate first into immature effector T cells (TH0) and then either into inflammatory or TH1 cells, or TH2 cells. TH1 cells mainly secrete IFNg, GM-CSF and TNFa, which are macro￾phage-activating cytokines, but also various amounts of IL-3, leucotriene and IL-2. TH2 cells mainly provide help to B cells and secrete the B-cell activation cytokines IL-4, IL-5 and IL-6, IL-3, GM-CSF, IL-10 and TGFb. CD4 1 T cells can also be cytotoxic by inducing apoptosis via Fas ligand expression. Activated CD8 1 CTLs kill target cells primarily by releasing perforin and granzymes, which in a synergistic manner induce target cell death. CTLs can also kill by expression of Fas ligand (FasL) on their surface, which binds to Fas on target cells and induces apoptosis. Activated CTLs also release cytokines, such as TNFa, interferon g (IFNg) and various interleukins. By binding to CD40 receptor on cells, TNFa can also induce apoptosis. Perforin-dependent killing is rapid (from a few minutes to a few hours) and can be elicited by a few MHC–peptide complexes on target cells. By contrast, cytokine production and FasL synthesis involve gene transcription, which requires sustained TCR signalling for extended periods of time. Fas-dependent cytolysis is slower than perforin￾dependent cytolysis (6–18 h) and TNFa-mediated killing is slower still (after 16 h). In some cases Fas–FasL-dependent killing involves translocation of preformed, intracellular FasL to the cell surface or release of soluble FasL. Altered peptide ligands Modifications of antigenic peptides can affect functional T-cell responses in a diverse manner, for example they can alter the pattern of lymphokines produced (partial agonists) or antagonize T-cell responses to agonists (antagonists). For CD8 1 T cells some partial agonists can elicit selective Fas-dependent cytotoxicity, which may play a role in maintaining homeostasis of lymphocytes. To explain aberrant T-cell function two basic concepts have been put forward: (1) the kinetic proofreading concept, which suggests that a short TCR engagement results in incomplete TCR signalling; and (2) the conformational model, which suggests that epitope modifications induce conformational changes in the TCR that qualitatively alter TCR signalling. cd T-cell receptors gd TCRs are in many respects similar to ab TCRs and may by derived from a common progenitor. The d chain resembles the a chain, and the g chain resembles the b chain in composition and structure. gd T cells constitute only 1– 3% of CD3 1 T cells. However, in epithelial tissue, especially in the small intestine and the epidermis, most of the T cells belong to the gd lineage. The TCRs of these epithelial gd T cells exhibit limited diversity, and most respond to the same antigens. Although the precise function of these cells is enigmatic, it seems that their contribution to host defence against infection consists more of innate than of adaptive immunity. Thus gd T cells seem to recognize antigens common to a large number of unrelated pathogens, rather than distinct epitopes char￾acteristic for individual organisms or species (Welsh et al., 1997). Structure of cd T-cell receptors gd TCRs are formed by rearrangement of V, (D), J and C gene elements, which precedes the one of ab TCR genes (Chien et al., 1996). Remarkably, the gene complex encoding the d chain is located between the ones of Va and Ja segments, so that rearrangements at the a and d loci are mutually exclusive. A rearranged d chain comprises the Vd, Dd, Jd and Cd regions, and a rearranged g chain the Vg, Jg and Cg segments. Importantly, there are many fewer Vg and Vd gene segments than at the TCR Va and Vb loci. In humans there are only four Vd, three Jd, three Dd and one Cd, and 12 Vg and two Cg, each with its own Jg segment. In the mouse the organization of the g genes is more complex and there are three clusters of g genes, each containing Vg, Jg and Cg segments. The main diversity of gdTCRs is in the junctional region, mainly because during d chain rearran￾gement both D segments can be used in the same gene, which greatly increases the junctional variability. gd TCRs are expressed on the cell surface and are associated with CD3 and mediate TCR signalling in much the same way as ab TCRs. The two chains are often, but not always, linked by a disulfide bridge between Cg and Cd. At present the three-dimensional structure of only one human Vd domain is known (Li et al., 1998). Interestingly, this structure shows that the framework structure of Vd resembles that of IgVH more closely than that of Va, Vb or VL, whereas the relative positions and conformations of its CDR1 and CDR2 share features of both Va and VH. Thus gd TCRs seem to be structurally distinct from ab TCRs. Together with the observation that the CDR3 length distribution of TCR d chains is similar to that of immunoglobulin heavy chains, this suggests that gd TCRs may bind antigen similarly to antibodies. Antigen Recognition by Lymphocytes 4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net