DEGENERATE AND PROMISCUOUS RECOGNITION BY CTL OF PEPTIDES PRESENTED BY THE MHC CLASS-I A3-LIKE SUPERFAMILY - IMPLICATIONS FOR VACCINE DEVELOPMENT

Recent data demonstrate that HLA class I alleles can be grouped into s uperfamilies based on similarities of their peptide-binding motifs, In this study, we have tested the immunogenicity and antigenicity of pep tides capable of degenerate binding to multiple HLA class I molecules of the A3-like superfamily, The assay systems utilized included both p rimary in vitro cultures of lymphocytes from healthy donors, as well a s in vitro restimulation of lymphocytes from HIV-infected individuals, Several of the peptides capable of binding more than one HLA AS-like class I molecule were also found to be immunogenic in the context of t his same group of AS-like molecules (degenerate CTL recognition), Furt hermore, some of the CTL lines thus generated demonstrated promiscuous recognition of the cognate epitope in the context of MHC molecules fr om more than one member of the superfamily. The fine Ag specificity of this phenomenon was further analyzed using two promiscuous CTL clones derived from A3 and All individuals, respectively, and specific for a n epitope in the HIV-1 reverse transcriptase, By the use of single-ami no acid-substitution analogues, it was demonstrated that the fine spec ificity of the TCR is largely maintained between MHC-matched and MHC-m ismatched presentation of peptide within the AS-like superfamily, Thes e results indicate that the similar peptide-binding specificities amon g different members of the AS-like superfamily can be reflected in a r emarkable similarity in the peptide-MHC complex structures engaged by the TCR and responsible for T cell activation.