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 superfamilies based on similarities of their peptide-binding motifs. In this study, we have tested the immunogenicity and antigenicity of peptides capable of degenerate binding to multiple HLA class I molecules of the A3-like superfamily. The assay systems utilized included both primary in vitro cultures of lymphocytes from healthy donors, as well as in vitro restimulation of lymphocytes from HIV-infected individuals. Several of the peptides capable of binding more than one HLA A3-like class I molecule were also found to be immunogenic in the context of this same group of A3-like molecules (degenerate CTL recognition). Furthermore, some of the CTL lines thus generated demonstrated promiscuous recognition of the cognate epitope in the context of MHC molecules from 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 A11 individuals, respectively, and specific for an epitope in the HIV-1 reverse transcriptase. By the use of single-amino acid-substitution analogues, it was demonstrated that the fine specificity of the TCR is largely maintained between MHC-matched and MHC-mismatched presentation of peptide within the A3-like superfamily. These results indicate that the similar peptide-binding specificities among different members of the A3-like superfamily can be reflected in a remarkable similarity in the peptide-MHC complex structures engaged by the TCR and responsible for T cell activation.
Threlkeld
S C
SC
Department of Immunology, Cytel Corporation, San Diego, CA 92121, USA.
Wentworth
P A
PA
Kalams
S A
SA
Wilkes
B M
BM
Ruhl
D J
DJ
Keogh
E
E
Sidney
J
J
Southwood
S
S
Walker
B D
BD
Sette
A
A
D016915:AIDS Vaccines / Q000276:immunology*; D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology; D000939:Epitopes; D054303:HIV Reverse Transcriptase / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015234:HLA-A Antigens / Q000276:immunology; D059870:HLA-A11 Antigen; D015791:HLA-A3 Antigen / Q000276:immunology*; D006801:Humans; D010446:Peptide Fragments / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D016915:AIDS Vaccines; D000939:Epitopes; D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D015791:HLA-A3 Antigen; D010446:Peptide Fragments; D054303:HIV Reverse Transcriptase