COUNTERREGULATION OF T-HELPER-1 CELL-PROLIFERATION BY NITRIC-OXIDE AND INTERLEUKIN-2

It was reported previously that cloned Th1 cells, but not Th2 cells, r aised to malaria antigens, produce nitric oxide (NO) when activated wi th specific antigen or mitogen. Furthermore, NO inhibits the prolifera tion of, and production of interleukin-2 (IL-2) and interferon-gamma b y, Th1 but not Th2 cells. By dose-response analysis, I demonstrate her e that Th1 cells produce optimal levels of IL-2 and a proliferative re sponse, and no detectable NO, when stimulated with relatively low conc entrations of antigen or mitogen in vitro. As the antigen/mitogen incr eased, however, high levels of NO were produced, accompanied by a conc omitant reduction in IL-2 secretion anal T cell proliferation. At the highest concentrations of antigen/mitogen examined, addition of recomb inant IL-2 reversed the NO-mediated downregulation of T cell prolifera tion, These results suggest that NO may serve as a self-regulatory mol ecule preventing the over-expansion of Th1 cells. At the other extreme , exogenous IL-2 may act to counter-regulate the suppressive effect of high concentrations of NO on Th1 cen proliferation, thereby maintaini ng homeostasis. (C) 1997 Academic Press.