AbstractThe major histocompatibility complex (MHC) control of T cell‐mediated response to drug‐derived determinants is not well understood. As a first step in studying the MHC control of drug hypersensitivity, semisynthetic penicillin, sulbenicillin (SBPC), was used as an antigen to establish anin vitroproliferative assay for mouse T cell response to this drug. The lymph node cells taken 7–9 days after immunization with 10 mg SBPC in complete adjuvant were tested for SBPC‐specific response in a standard 3 day proliferation assay. SBPC‐induced proliferation of the primed lymph node cells was mediated by the Thy‐1+, Lyt‐1+2–cells,i.e., helper type T (Th) cells. The Lyt‐1+2–, T cell proliferative responsiveness to SBPC was mapped on the I‐A locus within the H‐2 MHC regions. The proliferation was inhibited by the monoclonal antibody against Aβmolecules, product of the I‐A locus, but not by the monoclonal antibody against Eαmolecules, product of the I‐E locus. These results indicate that the SBPC response of Lyt‐1+2–, Th cells is controlled by the I‐A locus, the products of which, the MHC class II A (AβAα) molecules, function as restriction molecules in the Th cell recognition of SBPC.The removal of the Lyt‐2+suppressor type T (Ts) subset from the SBPC nonresponder cultures by a positive Lyt‐separation did not reverse the I‐A allele‐related nonresponsiveness. This result suggests that the nonresponsiveness is not due to the presence of the Lyt‐2+Ts subset, but rather to the absence of the Lyt‐1+Th subset, which recognizes SBPC together with self A molecules on the antigen presenting cell a