A subset of human T lymphocytes expresses the natural killer (NK) cell-associated receptor CD56 and is capable of major histocompatibility complex (MHC)-unrestricted cytotoxicity against a variety of autologous and allogeneic tumor cells. CD56+T cells have shown potential for immunotherapy as antitumor cytotoxic effectors, but their capacity to control adaptive immune responses via cytokine secretion is unclear. We have examined the inducibility of CD56+T cells from human blood in vitro and compared the kinetics of Th1, Th2, and regulatory cytokine secretion by CD56+T cells with those of conventional CD56¯ T cells. CD56 was induced on CD8+ and CD4¯CD8¯ T cells by CD3/T-cell receptor (TCR)- mediated activation, particularly when grown in the presence of interleukin (IL)-2. Activation induced CD56+ T cells proliferated less vigorously but displayed enhanced natural cytotoxicity compared with CD56¯ T cells. CD56+ T cells released interferon-y )IFN-y) and interleukin-13(IL-13), but not IL-10, upon TCR stimulation. Flow cytometric analysis demonstrated that, compared with CD56¯ T cells, elevated proportions of CD56+ T cells expressed IFN-y, IL-4, and IL-13 within hours of activation. These acquired cytolytic and cytokine secretion activities of CD56+ T cells make them potential targets for immunotherapy for infectious and immune-mediated disease.