The possible functional involvement of the T4 molecule in T-cell recognition of and/or activation by the class II HLA antigens SB was investigated. SB antigens are encoded by the SB gene that (1) maps between GLO and HLA-DR; and (2) codes for Ia-like molecules that are similar to but distinct from HLA-DR molecules. Both cytotoxic T lymphocyte (CTL) and proliferative responses to SB antigens were found to be mediated by OKT4+, OKT8- cells. SB-specific cytotoxicity and proliferation were analyzed in the presence of a series of monoclonal antibodies (OKT4, 4A, 4B, 4C, and 4D) that react with distinct epitopes on the OKT4 molecule. SB1-, SB3-, and SB4-specific CTL were partially inhibited by OKT4A and 4B, but not by OKT4, 4C, and 4D. SB2-specific CTL were not substantially inhibited by any of the OKT4-related antibodies. SB-specific proliferative responses to SB1, 2, 3, and 4 were strongly blocked by OKT4A and 4B but not by OKT4, 4C, and 4D. Proliferative responses of SB-primed cells stimulated with TCGF-containing supernatants alone were not inhibited by any of the OKT4-related antibodies, but were completely inhibited by the anti-Tac monoclonal, which reacts with the TCGF receptor. These results indicate that: (1) the T4 marker may be expressed on most T cells, regardless of their function, that recognize allogeneic Ia or self-Ia plus foreign antigens; and (2) the T4 molecule may be involved in T-cell recognition of and/or activation by class II HLA antigens.