The polymorphism at residue 156 determines the HLA-B*35 restricted peptide repertoire during HCMV infection

Abstract

Peptide selection in infected cells is not fully understood yet, but several indications point to the fact that there are differences to uninfected cells, especially in productive HCMV infection, since HCMV evolved various strategies to disable the hosts immune system, including presentation of peptide-HLA complexes to immune effector cells. Therefore, peptide predictions for specific HLA alleles are limited in these cases and the naturally presented peptide repertoire of HCMV-infected cells is of major interest to optimize adoptive T cell therapies. The allotypes HLA-B*35:01 and B*35:08 differ at a single amino acid at position 156 and have been described to differ in their peptide features and in their association with the peptide loading complex. Virus specific T cells recognizing the allelic pHLA-B*35 complexes could be detected, indicating a significant role of this HLA subtypes in viral immunity. However, naturally selected and presented viral peptides have not been described so far. In this study, we analyzed the peptide binding repertoire for HLA-B*35:01 and HLA-B*35:08 in HCMV-infected cells. The isolated peptides from both allelic subtypes were of extraordinary length, however differed in their features, origin, and sequence. For these HCMV-originated peptides, no overlap in the peptide repertoire could be observed between the two allelic subtypes. These findings reveal the discrepancies between predicted and naturally presented immunogenic epitopes and support the need of comprehensive peptide recruitment data for personalized and effective cellular therapies.

Peptidomes and Structures Illustrate Two Distinguishing Mechanisms of Alternating the Peptide Plasticity Caused by Swine MHC Class I Micropolymorphism

“…The first manner has always been a concern, that is, the key amino acid changes the nature of the pocket, resulting in a change in the preference of amino acids accommodated in the pocket (Figure 7A). The impacts of micropolymorphism at residue 156 on peptide presentation and CTL immunity were found during comparative studies of HLA-B*35:01/08 (156 Leu/Arg ) (19,52) and HAL-B*44:02/03 (156 Asp/Leu ) (23,53,54). The 156 Arg in HLA-B*35:08 was shown to prefer P5 E/D as the secondary anchor residues outside the primary peptide anchor pockets (B and F pocket) (23).…”