Promiscuous CTL Recognition of Viral Epitopes on Multiple Human Leukocyte Antigens: Biological Validation of the Proposed HLA A24 Supertype

Abstract

Multiple HLA class I alleles can bind peptides with common sequence motifs due to structural similarities in the peptide binding cleft, and these groups of alleles have been classified into supertypes. Nine major HLA supertypes have been proposed, including an A24 supertype that includes A*2301, A*2402, and A*3001. Evidence for this A24 supertype is limited to HLA sequence homology and/or similarity in peptide binding motifs for the alleles. To investigate the immunological relevance of this proposed supertype, we have examined two viral epitopes (from EBV and CMV) initially defined as HLA-A*2301-binding peptides. The data clearly demonstrate that each peptide could be recognized by CTL clones in the context of A*2301 or A*2402; thus validating the inclusion of these three alleles within an A24 supertype. Furthermore, CTL responses to the EBV epitope were detectable in both A*2301+ and A*2402+ individuals who had been previously exposed to this virus. These data substantiate the biological relevance of the A24 supertype, and the identification of viral epitopes with the capacity to bind promiscuously across this supertype could aid efforts to develop CTL-based vaccines or immunotherapy. The degeneracy in HLA restriction displayed by some T cells in this study also suggests that the dogma of self-MHC restriction needs some refinement to accommodate foreign peptide recognition in the context of multiple supertype alleles.

Novel and Promiscuous CTL Epitopes in Conserved Regions of Gag Targeted by Individuals with Early Subtype C HIV Type 1 Infection from Southern Africa

“…B cells were washed four times with RPMI 1640 supplemented with 1% FCS (R1), and the B cells were mixed with Ag-specific cells (effectors) at a ratio of 5:1 T cells to B cells in 1 ml of R10 and incubated with anti-CD28/CD49d mAbs, and the assay continued as described for ICS. 51 Cr release assay PBMC at 1 ϫ 10 6 were stimulated with 10 g of peptide and 330 U/ml IL-7 (Roche, Basel, Switzerland), and cells were transferred to a 24-well plate and incubated at 37°C and 5% CO 2 . Following 1 wk in culture, 25 U/ml IL-2 was added, and after 14 -21 days in culture, PBMC (effectors) were harvested for use in a standard 51 chromium release assay.…”

Essential differences in ligand presentation and T cell epitope recognition among HLA molecules of the HLA‐B44 supertype

“…One peptide could be used for the vaccination of a large number of patients all expressing HLA antigens that are different but belong to the same supertype. Hence, many studies have investigated such cross-binding peptides by using binding assays, by T-cell stimulations, or by the prediction of promiscuous peptides [5,7,8].…”

“…One peptide could be used for the vaccination of a large number of patients all expressing HLA antigens that are different but belong to the same supertype. Hence, many studies have investigated such cross-binding peptides by using binding assays, by T-cell stimulations, or by the prediction of promiscuous peptides [5,7,8].The first supertypes, namely A2, B7 and A3, were defined in 1995 and 1996. Based on peptide binding motifs, the HLA-B44 supertype comprising HLA-B37, B41, B44, B45, B47, B49, B50, B60 and B61 was first proposed in 1996 [9].…”

Extensive HLA class I allele promiscuity among viral CTL epitopes

“…Yet, some similarities between different binding motifs exist, and promiscuous presentation of epitopes to a certain degree could be expected [11][12][13]. Indeed, a number of individual CTL epitopes have been shown to be presented in the context of more than one HLA class I allele [22][23][24][25][26][27][28][29][30]. However, the described instances have largely been limited to epitopes shared by alleles that are assigned to the same HLA supertype which, by definition, share similar binding motifs.…”