Antigen-induced activation of a chicken gamma-globulin (CGG)-specific Lyt-1+ T cell clone measured both as a function of proliferation and immune interferon (IFN-gamma) production is restricted by a class II determinant of the major histocompatibility complex (MHC) mapped to the I-A subregion, as determined by studies with both recombinant inbred lines and monoclonal antibodies. Activation of Lyt-2+ picryl chloride (PC1)-specific cloned T cell lines by trinitrophenyl (TNP)-coupled spleen cells results in proliferation and the production of at least two lymphokines: lymphotoxin (LT) and IFN-gamma. This antigen-specific activation is restricted to a class I determinant of the MHC complex encoded in the K region. Thus, the common intracellular pathway leading to production of IFN-gamma by Lyt-1+ and Lyt-2+ T cells is mediated and restricted through different surface recognition units. The LT that is produced by antigen-specific activation of T cells not only kills fibroblasts, but it inhibits interleukin 2 (IL 2)-maintained T cells as well. Activation of T cells by concanavalin A (Con A) results in suicidal inhibition of proliferation and cell death by those clones that make LT, but not by those that produce only IFN-gamma under such induction conditions. These results indicate that it is neither Con A nor IFN-gamma that kills T cells, but LT. These results strongly suggest a self-regulatory role of LT in limiting continuing unrestricted T cell response to antigen activation.