When tested in the in vitro T-cell proliferation assay, H-2a cells are nonresponders to lactate dehydrogenase B (LDH-B; L-lactate:NAD+ oxidoreductase, EC 126.96.36.199) and to IgG2a myeloma protein. However, the cells can be converted into responders either by the addition to the culture of monoclonal anti-Ia.m7 antibody or by the removal from the culture of Lyt-2+ [T-lymphocyte-associated alloantigen (Lyt)-2 positive] lymphocytes. In both instances, the responsiveness can be suppressed again by the addition to the culture of monoclonal antibodies to I region-associated (Ia) molecules controlled by the I-A subregion. These data suggest that, in some H-2 haplotypes, the response to LDH-B and IgG2a is the result of interaction between the I-A and I-E subregions. The H-2a haplotype carries a responder allele at the I-A subregion but the responsiveness of H-2a cells is normally suppressed by T cells recognizing the antigen in the context of the I-E molecules. When the recognition of I-E molecules is blocked by an antiserum or when the cells capable of this recognition are removed, the H-2a cells become responders. These experiments demonstrate a nonresponder turned responder by antibody inhibition. They also demonstrate that the postulate of the I-B subregion is no longer necessary and provide additional evidence that the Ia molecules are the products of the immune response (Ir) genes.