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Identification of the Immunodominant HY H2-D^k Epitope and Evaluation of the Role of Direct and Indirect Antigen Presentation in HY Responses¹

Maggie Millrain^3,*, Diane Scott^3,*, Caroline Addey^*, Hamlata Dewchand^*, Pamela Ellis^4,*, Ingrid Ehrmann^5,*, Michael Mitchell, Paul Burgoyne, Elizabeth Simpson^* and Julian Dyson^2,*

^* Transplantation Biology Group, Department of Immunology, Imperial College London, Hammersmith Hospital, London, United Kingdom; Institut National de la Sante et de la Recherche Medicale Unite 491, Faculté de Médecine, Marseille, France; and National Institute for Medical Research, London, United Kingdom

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 HYD^k 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 (HYD^kSmcy (defined here), HYK^kSmcy, HYD^bUty, and HYD^bSmcy). Indirect presentation stimulated a robust primary HYD^kSmcy 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 (H2^bxk) female recipient bone marrow chimeras were immunized with male cells of the other parental haplotype, limiting presentation to the direct pathway. The dominant H2^b HY response (HYD^bUty) was dependent on indirect presentation. However, the dominant H2^k HY response (HYD^kSmcy) could be stimulated efficiently by the direct pathway. In contrast, secondary expansion of both HYD^kSmcy and HYD^bUty-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 HYD^kSmcy, HYD^bSmcy, and HYK^kSmcy-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.

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