The major histocompatibility complex (MHC) includes a number of genes which control or regulate the immune response. Several genes mapping in the I-region of the MHC appear to control the interaction of immunocompetent cells including the interaction of thymus-derived (T) lymphocytes with bone marrow-derived (B) lymphocytes or macrophages. In the guinea pig there seems to be a close association between I-region-associated (Ia)antigens of the MHC and immune response (Ir) genes controlling the T cell-dependent response to certain antigens. The objective of this proposal is to further define the role of MHC antigens in immunocompetent cell interactions and their involvement in the immunogenic interaction with antigens. The primary approach to this objective will involve in vitro sensitization and challenge of guinea pig T cells with antigen-pulsed syngeneic or allogeneic macrophages. By this procedure we will investigate the requirement for macrophage and/or T cell Ia antigen expression in antigen-specific responses, and the expression of Ir genes by macrophages and/or T cells. The role of the MHC in the antigenic signal recognized by T cells will be investigated by using alloantisera directed against guinea pig macrophage MHC antigens which we have shown induces an immunogenic modification that sensitizes guinea pig T cells using the in vitro technique. Approaches to determine the mechanisms by which macrophages activate T cells will involve defining the role of macrophages in the macrophage-dependent activation of guinea pig T cells by B cell-like guinea pig leukemia cells, and attempts to identify an antigen-specific factor released from macrophages that directly sensitizes T cells.