Immune response (Ir) genes mapping in the I region of the mouse H-2 complex appear to regulate specifically the presentation of a number of antigens by macrophages to proliferating T cells. We have investigated the possibility that similar Ir genes mapping in the H-2K and H-2D regions specifically regulate the presentation of target antigens to cytotoxic effector T cells. We report that the susceptibility of targets expressing specific non-H-2 H alloantigens to lysis by H-2-compatible, H-antigen-specific cytotoxic effector T cells is controlled by polymorphic H-2K/D genes. This control of susceptibility to lysis is accomplished through what we have defined operationally as antigen-specific regulation of non-H-2 H antigen immunogenicity. High immunogenicity of the H-4.2 alloantigen is determined by a gene mapping in the H-2K region of H-2b. However, high immunogenicity of H-7.1 is determined by a gene mapping in the H-2D region of H-2b. High immunogenicity of the H-3.1 alloantigen is determined by genes mapping in both the H-2K and H-2D regions of H-2b. Therefore, genes mapping in the H-2K and H-2D regions serve a function in presenting antigen to cytotoxic effector T cells. This function is analogous to that played by I-region Ir genes expressed in macrophages which present antigen to proliferating T cells. We present arguments for classification of these H-2K/D genes as a second system of Ir genes and discuss the implications of two H-2-linked Ir-gene systems, their possible functions, and their evolution.
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