INHIBITION OF IL-2 PRODUCTION BY NITRIC-OXIDE - A NOVEL SELF-REGULATORY MECHANISM FOR TH1 CELL-PROLIFERATION

Cloned Th1 cells, but not Th2 cells, specific for malaria antigen, pro duce nitric oxide (NO) when activated with specific antigen or Con A. Furthermore, NO inhibits proliferation of, and production of IL-2 and IFN-gamma by, Th1 but not Th2 cells. Here, it is demonstrated that the inhibition of Th1 cell proliferation by the NO donor S-nitroso-N-acet yl penicillamine (SNAP) can be reversed by the addition of rIL-2 but n ot of rIFN-gamma, suggesting that the inhibition of Th1 cells by NO ma y be preventing the production of IL-2. Dose-response studies showed t hat Th1 cells produce optimal levels of IL-2 and a proliferative respo nse, and no detectable NO, when stimulated with relatively low concent rations of antigen or mitogen in vitro. As the antigen/mitogen increas ed, however, high levels of NO were produced, accompanied by a concomi tant reduction in IL-2 secretion and T cell proliferation. The prolife ration of, and IL-2-IFN-gamma production by, naive CD4(+) T cells from normal spleens activated with Con A in vitro can be similarly inhibit ed by SNAP. These results suggest that NO may serve as a self-regulato ry molecule preventing the over-expansion of Th1 cells. Unrestricted T h1 cell activity has been implicated in a range of immunopathologies a nd autoimmune diseases. The proposed mechanism for down-regulation of Th1 cell function may also account for the suppression of lymphocyte p roliferation observed in malaria infections.