This project deals with the function of immune response (Ir) genes in the activation of thymus-derived (T) lymphocytes. We have shown that antigen-presenting cells from low responder mice specifically fail to stimulate proliferation to the antigen under Ir gene control in primed (responder x non-responder) F1 T lymphocytes, suggesting that one site of expression for Ir gene products is in the antigen-presenting cell. This cell type in the spleen bears Ia determinants, lacks immunoglobulin and Thy 1 determinants and is radio-resistant and adherent. The most likely candidate for this cell is one in the monocyte-macrophage lineage. The T-cell proliferative response to defined protein antigens was investigated and for Staphylococcal nuclease and pigeon cytochrome c was found to be under the control of more than one Ir gene. In the case of pigeon cytochrome c, the antigenic determinant was localized to two amino acid substitutions at the C-terminal end of the molecule. These comprised a single antigenic site whose recognition was under the control of two complementing Ir-genes. Furthermore, a functional heteroclitic response was demonstrated for the first time at the T cell level.