P028 Immunogenicity of minor histocompatibility antigens may be dependent on the frequencies of naive precursor cells in the donor repertoire

Abstract

Aim Out of 60+ minor histocompatibility antigens (MiHA) discovered so far some are immunodominant, i.e. almost universally cause allogeneic response when mismatched, while others are much less immunogenic. Before transplantation MiHA specific T cells reside in naive T cell (TN) subpopulation of the donor. One potential explanation for unequal MiHA immunogenicity is the variation in frequencies of TN specific to different antigens in the donor T cell repertoires. To test this hypothesis we compared the frequencies of naive T cells, specific for highly immunogenic minor antigen HA-2 and less immunogenic ACC-1Y in individuals negative for these antigens. Methods We genotyped a panel of healthy volunteers for HA-2 and ACC-1Y polymorphisms and selected donors negative for these minor antigens, but bearing restricting HLA alleles (HLA-A∗02:01 and HLA-A∗24:02 respectively). Donor naive T cells were magnetically purified and stimulated by autologous monocyte derived dendritic cells, loaded with appropriate peptides. Expanding MiHA-specific lymphocytes were detected using MHC-multimers and flow cytometry. Frequencies of HA-2 and ACC-1Y-specific TN cells were calculated by extreme limiting dilution analysis. Results Frequency of specific TN was found to be substantially higher for HA-2 than for ACC-1Y (5 × 10−6 vs. 2 × 10−7, p = 3 × 10−9), which correlates with HA-2 immunodominance and confirms the initial hypothesis. Conclusions Further studies are needed to elucidate the reason for major differences in TN frequencies between various MiHA. It is possible that the variation could be explained by the peptide properties or by the influence of the negative selection on initial T cell repertoire. In contrast with HA-2, ACC-1Y has alternative allelic variant (ACC-1C) presented in the thymus, which leads to elimination of all cross-reactive clones. Creating a model of MiHA immunogenicity would be very useful for predicting allogeneic immune response after transplantation. Funding: Russian Science Foundation grant 17-15-01512.