TCR78 protein

The sequence relatedness of y8 genes to each other and to Ig genes is low. A y cDNA is -18-23% (depending on the regions being compared) similar to either TCR(3 cDNA or IgH cDNA; 8 genes are only -10-20% similar to other TCR and Ig genes, although parts of Cfi are claimed to be over 30% similar to IgG C regions. Despite these limited sequence similarities, the antigen receptor genes share high organizational similarities. Hence, based on the observation that within multigene families, protein folding is better conserved than primary amino acid sequence, TCR and Ig sequences have been intensively compared, in order to assess the likely resemblance of TCR protein structures to Ig structures that have been resolved by X-ray crystallography. The data suggest that y8 TCR V and C regions can assume the characteristic structure of an Ig domain, termed the 'Ig fold' - seven 3 strands arranged in two antiparallel 3 sheets packed face to face. Furthermore, the Ig folds of V7 and VB should associate, presenting at their surface a rather flat antigen-combining surface, perhaps of similar geometry to that of Ig.

When sequence data are used to create 'divergence trees', the human ADV regions (i.e. those rearranged as either V„ or VB genes) differ from other V„ regions in occupying their own branch, one that in mouse is occupied solely by V6 regions. Such comparisons pinpoint structural signatures of TCRy8, particularly in regions implicated in yS chain-pairing and in the putative complementarity-determining regions (CDR1, CDR2 and CDR3) that most likely bind antigen. For example, in all human and mouse V„, residue 14 is glutamic acid, and residue 37 is gluta-mine, whereas neither is the case in any mouse or human V8. Residue 37 may be critical in restricting chain-pairing of Va with VB, and V6 with Vr Indeed, residue 37 in human DV102 (VB2) is positively charged, while the only y chain that is negatively charged in the equivalent position is GV2 (V72/V79) with which DV102 pairs almost exclusively.

Compared to most Va regions, DV102 (Vs2) is two amino acids longer in CDR1, while DV103 (Vh3) is two amino acids longer in CDR2. Likewise, the ADV genes have longer N-terminal sequences, that may extend the exposed, antigen-binding face occupied by the CDR loops. Interestingly, V7 and Vp chain genes are similar in many respects (e.g. both have CDR2 regions four amino acids larger than V„), but compared to Vp, GV2 is two amino acids longer in CDR1, just as DV102, the 8 chain commonly paired with GV2, is longer in CDR1. Similarly, GV1 has a two amino acid extension in CDR2, as does DV103, with which it commonly pairs.

CDR3 regions largely comprise amino acids encoded at the V(D)J join. Their diversity stems from variability in the joins and is heightened by the capacity of TCR D segments to be read in all three reading frames. CDR3 lengths are predicted to profoundly affect CDR shape and hence ligand specificity. Comparison of many sequences showed that murine and human CDR38 lengths are both highly variable and commonly longer than those in other TCR or Ig chains. This is in part because of Ds-Dft joining. CDR3y lengths are shorter, but more variable than CDR3a or CDR33- The constraint on CDR3ot and CDR33 may be imposed by the requirement of TCRa3 to 'fit' on to major histocompatibility complex (MHC) molecules. Conversely, the IgH-like variability in CDR38, and the imbalance between CDR3y and CDR38 (akin to that between IgH and IgL) indicates that y8 TCRs are not restricted to recognition of a single class of antigen presentation molecule (e.g. MHC), and may recognize diverse antigens, as does Ig. Consistent with this is the high divergence of y8 V gene segments. For example, two murine y genes <1 kb apart are only -30% similar. Hence, CDR1 and CDR2 would be very different in y5 TCRs using these two V7s, predicting that the TCRs might bind dissimilar antigens.

Nonetheless, there are constraints on TCRy8. Unlike Ig, there is no evidence that diversity is increased by somatic hypermutation, and the small size of y8 gene families limits combinatorial diversity, obtained by recombination of any one of many V segments with any one of many D and/or J segments. There is also limited chain-pairing, and remarkably, certain epithelial y8 populations show virtually no diversity; e.g. a single TCR (V75-J71:VB1-DB2-J81 (GV1-GJ1:DV101-DD2-DJ1)) is expressed by >95% of murine skin T cells; another TCR (V76-J71:VB1-D82-J81 (GV2-GJ1:DV101-DD2-DJ1)) is expressed by most murine uterine T cells. Taken together, the data suggest that y8 T cell repertoires may recognize a small number of highly diverse antigens.

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