Identification of the Immunodominant HY H2-Dk Epitope and Evaluation of the Role of Direct and Indirect Antigen Presentation in HY Responses

Abstract

Minor histocompatibility Ags derive from self-proteins and provoke allograft rejection and graft-vs-host disease in MHC-matched donor-recipient combinations. In this study, we define the HYDk epitope of the HY minor histocompatibility Ag as the 8mer peptide RRLRKTLL derived from the Smcy gene. Using HY tetramers, the response to this peptide was found to be immunodominant among the four characterized MHC class I-restricted HY epitopes (HYDkSmcy (defined here), HYKkSmcy, HYDbUty, and HYDbSmcy). Indirect presentation stimulated a robust primary HYDkSmcy response. Indirect presentation and priming of HY-specific CD8+ T cells is also operative in the presence of a full MHC mismatch. To determine whether the indirect route of Ag presentation is required for HY priming, female parent into F1 (H2bxk) female recipient bone marrow chimeras were immunized with male cells of the other parental haplotype, limiting presentation to the direct pathway. The dominant H2b HY response (HYDbUty) was dependent on indirect presentation. However, the dominant H2k HY response (HYDkSmcy) could be stimulated efficiently by the direct pathway. In contrast, secondary expansion of both HYDkSmcy and HYDbUty-specific CD8+ T cells was effective only when Ag was presented by the direct route. Transgenic overproduction of Smcy mRNA within the immunizing cells resulted in a corresponding increase in the HYDkSmcy, HYDbSmcy, and HYKkSmcy-specific CD8+ T cell responses when presented via the direct pathway but did not enhance indirect presentation demonstrating the independent regulation of MHC class I-peptide occupancy in the two Ag-processing pathways.

CD31 signals confer immune privilege to the vascular endothelium

“…In cytotoxicity assays T cells were incubated with IFN-γ-treated ECs derived from WT and CD31-deficient female mice (H-2 b background) pulsed with the HY-derived Uty peptide (52). As a control non-peptide-pulsed ECs were used.…”

Local immunostimulation leading to rejection of accepted male skin grafts by female mice as a model for cancer immunotherapy

“…They have identified HY antigenic peptides encoded by the Smcy gene, including the dominant peptide RRLRKTLL presented by the H2-D k class I molecule and the peptide TENSGKDI presented by H2-K k (19,20). We observed that female CBA mice produce CTL against male target cells expressing both peptides after grafting with syngeneic male, but not female, skin.…”

Natural Regulation of Immunity to Minor Histocompatibility Antigens

“…For individual minor histocompatibility Ags, relative tissue susceptibility is likely to differ and be controlled by multiple factors including epitope density and properties of the T cell repertoire. For example, although the H2 krestricted CD8 T cell response to HY is immunodominant over the H2 b response (19) and both reject hemopoietic cell grafts, H2 brestricted CD8 T cells are more effective at eliciting skin graft rejection. The most attractive targets for promoting the graft-vsleukemia effect without GvH disease are, however, those minor histocompatibility Ags whose expression is restricted to hemopoietic lineages (42).…”

“…To explore the mechanism(s) limiting the response, we first characterized the immunodominant HYD k -specific CD8 T response (19) in the H2 k strains CBA and B10.BR. Females were immunized with male spleen cells and peripheral blood analyzed using HYD k Smcy tetramer.…”

“…The HY minor histocompatibility Ag is particularly amenable to analysis because the epitopes are encoded by genes on the Y chromosome and, in mice, these map to the ⌬Sxr deletion interval (15) (19). Here, the basis for the weak immune response to HY in the context of the H2 k haplotype has been dissected and found to be multifactorial.…”