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-t umor effects involve only a small number of immunodominant MiHA. The g oal 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 H2(b) strains o f mice were tested against syngeneic targets sensitized with HPLC-frac tionated 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 influence d by both the antigen profile of the antigen-presenting cells (APC) an d the repertoire of responding CTL. When C57BL/6 dominant MiHA (B6(dom )) and H-Y were presented on separate APC, they showed similar immunog enicity. In contrast, when they were presented on the same APC, B6(dom ) MiHA totally dominated H-Y. B6(dom) MiHA did not suppress anti-H-Y r esponses by acting as T cell receptor antagonists for anti-H-Y CTL, no r were anti-B6(dom) CTL precursors more abundant than anti-H-Y CTL pre cursors. Dominance resulted from competition for the APC surface betwe en anti-B6(dom) and anti-H-Y CTL; the crucial difference between the d ominant and the dominated MiHA appears to depend on the differential a vidity of their respective CTL for APC. The only B6(dom) epitope thus far identified is the nonapeptide AAPDNRETF presented by H2-D-b. We fo und 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 mo lecule with very high affinity, and dissociates very slowly from its p resenting class I molecule. These data indicate that one cannot predic t which MiHA will be dominant or dominated based simply on their respe ctive immunogenicity when presented on separate APC. Indeed, the avidi ty of T cell/APC interactions appears to determine which antigen(s) wi ll trigger T cell responses when numerous epitopes are presented by th e same APC.