IN A SMALL MULTIDETERMINANT PEPTIDE, EACH DETERMINANT IS RECOGNIZED BY A DIFFERENT V-BETA-GENE SEGMENT

Given the vast potential for diversification of the T cell receptor (TCR) repertoire and the fact that V(beta)a mice exist in the wild, it would have been predicted that in spite of the absence of 10 TCR V(beta) gene segments, V(beta)a mice would still have been able to produce an antigen-specific T cell response to all determinants. We have recently shown that V(beta)b mice, with a wild-type TCR V(beta) repertoire, respond to peptide 110-121 of sperm whale myoglobin, with a majority of T cells expressing TCR V(beta)8.2 and restricted to a hybrid I-A(d)/I-E(d) major histocompatibility complex molecule, and a smaller number of T cells expressing TCR V(beta)8.1 and restricted to the I-A(d) molecule. However, V(beta)a mice, lacking members of the TCR V(beta)8 gene family, responded only with I-A(d)-restricted T cells. Thus, it appeared that the I-A(d)-restricted response was less constrained, or more plastic. We now show that the two separate panels of I-A(d)-restricted T cell hybrids derived from V(beta)a or V(beta)b mice in fact recognize distinct determinants within the same peptide 110-121. The determinant recognized by V(beta)a T cells is NH2 terminal (core: 110-118) with an absolute requirement for the residue Ala-110 for a successful interaction with TCRs. On the other hand, V(beta)b T cells recognize the COOH-terminal region (core:112-118) on the same peptide with an absolute requirement for COOH-terminal residue 118. In the dominance hierarchy displayed by the three distinct determinants of peptide 110-121, V(beta)a mice cannot recognize the two most dominant: the hybrid I-A(d)/I-E(d)-restricted determinant and the COOH-terminal, I-A(d)-restricted determinant. They instead respond with T cells specific for a third, distinctly NH2-terminal determinant. Our results show a strict association between recognition of a particular specificity and TCR V(beta) usage. This evidence suggests that even when a small peptide induces a heterogenous group of TCR V(beta)s, this need not be considered evidence for plasticity. Rather, at the level of individual determinants within the peptide, the results can point in the opposite direction, towards serious constraints in recognition at the level of V(beta) expression.