We have studied the mechanism of T-cell activation by antigen, and the MHC-linked genetic control thereof. In contrast to antibodies, the T-cell response is dominated by a few immunodominant antigenic sites, which represent regions on which a polyclonal T-cell response is focused. We found that the immunodominance of a site can be determined both by extrinsic factors, such as the major histocompatibility (MHC) antigens of the responder, and by intrinsic factors in the antigen structure. The two immunodominant sites of myoglobin we found around residues 109 and 140 were recognized with different MHC antigens, I-Ad and I-Ed, respectively. With synthetic peptides, we narrowed these sites to 106-118 and 133-146, respectively. Both of these are amphipathic alpha helices. We examined the 23 known immunodominant sites from 12 different proteins, and found that 18 of these have a periodicity of hydrophobicity that would make them amphipathic if they fold as an alpha helix. We have developed an algorithm to search for such sequences and are using this to predict T-cell sites from AIDS and malaria proteins, for purposes of developing synthetic vaccines. Corresponding peptides are being prepared and tested. Using a biotinylated immunodominant peptide, we showed that the peptide was on the surface of the presenting cell, accessible to macromolecules such as avidin. We found that the cloned, antigen-specific, Ia-restricted, L3T4+ T cells also killed tumor but not normal presenting cells. The induction was antigen-specific, but the effector phase was not, although it was preferentially inhibited by specific cold targets. This may represent a novel type of tumor surveillance. We also found that on antigen stimulation, the T-cell clones release soluble IL-2 receptor, secrete a new lymphokine that stimulates IL-1 secretion by macrophages, and increase their expression of Fc receptors for IgD (also induced by IgD itself). We also found a novel population of L3T4+, IL-2 receptor-bearing T cells in unstimulated normal spleen cells, whose level is controlled by several genes including one mapped to chromosome 7.