Absence of Ir gene control of T cells recognizing foreign antigen in the context of allogeneic MHC molecules

The major histocompatibility complex (MHC)-linked immune response (Ir) genes confer high responsiveness on some MHC haplotypes and low or no responsiveness to certain antigens on other haplotypes (for review see ref. 1). The cause of nonresponsiveness is thought to be a failure of T cells to be stimulated by a given combination of antigen and MHC molecules, which can, in principle, arise in two ways: either the antigen-presenting cells (APCs or macrophages) of the nonresponder haplotypes are incapable of presenting the foreign antigen to T cells in an immunogenic form^2,3 or the T-cell repertoire of nonresponder haplotypes lacks clones recognizing the antigen in the context of a given MHC⁴. We have recently shown that APCs from nonresponder strains can in fact present antigen to allogeneic responder T cells, depleted of alloreactivity against the APCs themselves⁵, which indicates that the mechanism of nonresponsiveness is not a failure of APC function. Using the same experimental system, we show here that responses of T cells to antigen presented on allogeneic APCs do not depend on the Ir phenotype of either the T cell or the APC: Ir gene control is completely absent from these responses. The results strongly suggest that Ir gene-controlled nonresponsiveness is associated with the adjustment of the T-cell repertoire to self-MHC antigens.