TCR diversity is also generated by gene rearrangements

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3 TCR diversity is also generated by gene rearrangements In T cells the mechanisms that generate diversity before antigen stimulation are essentially the same as those in B cells After antigen encounter, things are different: whereas Ig genes continue to diversify, the genes encoding T-cell receptors remain unchanged. The TCR α chain locus (chromosome 14) resembles an Ig light-chain locus, containing sets of V and J gene segments only (except there is only one C α gene segment). The β-chain locus resembles an Ig H-chain locus, since it contains D gene segments in addition to V and J segments. (Again, D and J are joined, then DJ is joined to V. As is the case with Ig genes, segments are flanked by RSS sequences, and the same enzymes that act to recombine Ig gene segments are used for TCR genes. Also, additional diversity again comes from insertion of additional, non-templated) P and N nucleotides are inserted in the junctions between recombined V, D, and J segments. Evolutionarily related to Ig Light Chain (V, J segments Evolutionarily related to Ig Heavy Chain (V, D, J segments 57

4 The T-cell receptorcomplex The firnctional antigenreceptor on the surfaceof T ceils consistsof 8 polypeptides. The G,and p chainsbind antigenand form the core T-cell receptor. Tleeyassociatewith two copies of a protein called the q (zeta) chain, and the CD3 complex, which consistsof one copy each of the y (gamma)and 6 (delta) proteins, and two copies each of the e (epsilon) protein. The u,and P TCR chainsmust associatewitir the CD3 compiex in order to leave the ER.and be expressedat the cell surface. Tlre CD3 proteins and the zetachainsrecruit signai-ransducingproteins after the TCR binds antigen. reffi*4.e TSH l_j_--_--r pqpryfilian nnligen 'd. f,'^:^ / d? aai: F : f I os.ug t\-\'t ;;, "\ co'*q\sr ffbs +-1 e(5'\6$ t z 4.eTo' rbr$*l l;**bt Gnhrd'fuHlldt1lElnhr HErs The transrnembranedomains of the fi and p chains contain positively charged amino acids (+), which forrr qtrongelectrostaticinteractionswith negativeiy chargedamino acids in the transmembraneregions of the CD3 T, 6, and e proteins. F ffi )

5 γ:δ T-cell receptors There is a second type of T-cell receptor which is similar in overall structure to the α:β TCR, but which is formed by two different proteins, termed γ and δ. T-cells with γ:δ receptors arise early in embryonic development, and play a role early after birth, but are eventually largely replaced by cells expressing the more versatile repertoire of α:β receptors. The γ:δ T-cells are thought to represent an evolutionarily older, more primitive and somewhat less diverse component of the adaptive immune system, with aspects of innate immunity. They comprise a small subset (1-5%) of T-cells in circulation in adult animals, but they are much more abundant in epithelial tissues. The identification of γ:δ TCR ligands has been difficult and confusing. Unlike α:β T-cells, γ:δ T-cells do not recognize peptide antigens presented by classic MHC molecules; many instead recognize non-peptide antigens such as bacterial lipopolysaccharides or certain bacterial organopyrophosphate compounds presented by special, MHC-related proteins. In some cases, certain γ:δ T-cell receptors apparently even bind to and are activated by whole proteins (of bacterial origin), without the involvement of any MHC-like presenting molecule. Like α:β TCRs, the γ:δ TCRs associate with CD3 protein complex to initiates signaltransduction. 59a

6 The organization of the human T-cell receptor γ-chain and δ-chain loci The γ-chain and δ-chain loci, like the α and β loci, contain sets of V, D, J, and C gene segments. The δ locus is located within the α-chain locus on chromosome 14, lying between clusters of V α and J α segments, but resembles the β locus in having V, D, and J segments. The γ locus is located on chromosome 7, and resembles an α locus in having only V and J segments. Analogous to the β-chain locus Analogous to the α-chain locus γ corresponds to α (and is related evolutionarily to the Ig light chain) δ corresponds to β (and is related evolutionarily to the Ig heavy chain) 59b

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13 MHC-I molecules bind short peptides by both ends $ ' In an MHC-I molecule, the peptide is bound in an extended conformation with both Tqt Ril.9 in pockets at the end of the binding grooye. Because of this gecmetry oi tlre bmcltng groove, the size of the peptide that binds to an MHC-I molecule is limited in size to 8-10 aminotcids in tength. The differences in peptide length are accommodated bf the extended conformation of the bound peptide. (Tr?r"nnj r^^*t;g;i, Li * a.r b,ar io rrii;":f?- \ Peptides binding to a given allelic variant of an MHC molecule have been shown to have the,same or very similar amino acid residues at two or three specific positions along the peptide sequence. The amino acid side chains at these positions insert into pockets in the MHC molecule that are lined by the polymorphic u-irro acids. These peptide residues are called anchor residues, because they ptuv " a bie part in anchoring the peptide to the MHC binding groove _ fo&l, f, f Gtfiriql A'?) L r?"'j*" F- L II il r"n^.^*t \- _ t.7 t I I S"W$f-1f-1$*1{-.T -.dfr :{-f ffihhffim#ffih-$ffi dbc.)tl \..1, I[ffiutrruuffiruu,ffiffi?'?rrl..lr t{^.t Ll.l It a.j c t. tr., Jv.i.Q t;fr f't /4''A l, j i v I r l r ' t i i3!.'+,3...-t f: \ -5''\ l s 4 R ' n. i {..-,.,,.,-(11e;";l r l I n,r fi,i u Science"ffi arlard Fublishins (f,.*.q) rr orcf.. rcj, J".l )) Gtto bti.l.* ;r$d gckch) A Jt$*rJ.t:ttiJ., r3\ ).. \*l rj'f;gb ] ;{ lsr\rr n11q'l rr'l3.rle ' I*..-{*',*,,t a.\$.nq. l* 6r,',.,o. nf t''.;a wtil*es.-l L6

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