DEGENERATE MHC RESTRICTION REVEALS THE CONTRIBUTION OF CLASS-I MHC MOLECULES IN DETERMINING THE FINE SPECIFICITY OF CTL RECOGNITION OF AN IMMUNODOMINANT DETERMINANT OF HIV-1 GP160 V3 LOOP

The novel allogeneic presentation of an immunodominant determinant wit hin the HIV-1 gp160 V3 loop by three different class I MHC molecules t o the same CD8(+) CTL is used to study the influence of the MHC molecu le on the fine specificity of CTL recognition. We previously reported that four distinct class I molecules of H-2(d,u,p,q) presented the V3 decapeptide P18-I10 (RGPGRAFVTI) to CTL. Surprisingly, we found that H -2(d,u,p) cells mutually cross-present the P18-I10 peptide to allogene ic CTL clones of each of the other haplotypes, whereas none of these c ross-presents to H-2(q) CTL, nor do H-2(q) targets present to CTL of t he other haplotypes. Here, we explore the critical amino acid residues for the cross-presentation using 10 variant peptides with single amin o acid substitutions. The fine specificity examined using these mutant peptides presented by the same MHC class I molecule showed striking s imilarity among the CTL of each haplotype, expressing either V beta 8. 1 or V beta 14. In contrast, the fine specificity is different between the distinct MHC class I molecules even for the lysis by the same CTL , as shown by reciprocal effects of the same substitutions. Thus, pept ide fine specificity of a single TCR is influenced by changes in the c lass I MHC molecules presenting the Ag.