On the mechanisms of immunodominance in cytotoxic T lymphocyte responses to minor histocompatibility antigens.

Although there are numerous minor histocompatibility antigens (MiHA), T cell responses leading to graft-versus-host (GVH) and graft-versus-tumor effects involve only a small number of immunodominant MiHA. The goal of the present study was to analyze at the cellular and molecular levels the mechanisms responsible for MiHA immunodominance. Cytotoxic T lymphocytes (CTL) generated in eight combinations of H2b strains of mice were tested against syngeneic targets sensitized with HPLC-fractionated peptides eluted from immunizing cells. The number of dominant MiHA was found to range from as little as two up to ten depending on the strain combination used. The nature of dominant MiHA was influenced by both the antigen profile of the antigen-presenting cells (APC) and the repertoire of responding CTL. When C57BL/6 dominant MiHA (B6dom) and H-Y were presented on separate APC, they showed similar immunogenicity. In contrast, when they were presented on the same APC, B6dom MiHA totally dominated H-Y. B6dom MiHA did not suppress anti-H-Y responses by acting as T cell receptor antagonists for anti-H-Y CTL, nor were anti-B6dom CTL precursors more abundant than anti-H-Y CTL precursors. Dominance resulted from competition for the APC surface between anti-B6dom and anti-H-Y CTL; the crucial difference between the dominant and the dominated MiHA appears to depend on the differential avidity of their respective CTL for APC. The only B6dom epitope thus far identified is the nonapeptide AAPDNRETF presented by H2-D(b). We found that compared with other known D(b)-binding peptides, AAPDNRETF is expressed at very high levels on the cell surface, binds to the D(b) molecule with very high affinity, and dissociates very slowly from its presenting class I molecule. These data indicate that one cannot predict which MiHA will be dominant or dominated based simply on their respective immunogenicity when presented on separate APC. Indeed, the avidity of T cell/APC interactions appears to determine which antigen(s) will trigger T cell responses when numerous epitopes are presented by the same APC.