Signaling pathways in T lymphocytes have been incompletely charac terized. It is evident that differences exist among the T cell subsets. We have defined several distinct mechanisms that affect differentially the activities of murine T lymphocyte clones representing various CD4+ and CD8+ sub sets: Interferon-y (IFN-y) inhibits proliferation of but not lymphokine production by T H2 cells. IL-lO inhibits antigen-presenting cell (APC) induced lymphokine production by T HI cells but not by T H2 cells. Murine THI and T H2 clones proliferate optimally in response to distinct APC populations. T HI and T H2 clones utilize different TCR-associated signaling pathways. High concentrations of antigen (or anti-TCR mAb) inhibit IL-2-induced proliferation (but not lymphokine production) by T HI and cytolytic T lymphocyte (CTL) clones only. Exposure of T HI clones (but not TH2 clones or CD8+ CTL clones) to IL-2 induces unresponsiveness to antigen. THI and T H2 clones as well as CD8+ clones can be cytolytic, but not all T cells use the same cytolytic mechanisms. CD4+ clones from some mouse strains are not cytolytic if they do not secrete IFN-y. Under standing the mechanisms that differentially regulate the various kinds of T cells, in addition to providing insights into the molecular events associ ated with activation of those subsets, should facilitate modulation of their activities in vivo, making it possible to influence favorably the outcome of disease processes.