A DIRECT ROLE FOR IFN-GAMMA IN REGULATION OF TH1 CELL-DEVELOPMENT

IL-12 has been identified as a major cytokine influencing the differen tiation of CD4 cells to a Th1 phenotype, whereas a role for IFN-gamma is controversial. We investigated the interrelationship between IL-12 and IFN-gamma in promoting Th1 responses using naive CD4 cells reactiv e with pigeon cytochrome c from TCR transgenics and memory CD4 cells d erived by in vivo priming with KLH. Without exogenous rIL-12 or rIFN-g amma, primary and memory effecters induced by Ag or anti-CD3 and anti- CD28 secreted variable levels of IL-2 and IFN-gamma. The level of IFN- gamma secreted by effectors correlated with endogenous IFN-gamma produ ced in primary cultures, and anti-IFN-gamma largely inhibited the deve lopment of effectors producing IFN-gamma. With optimal TCR stimulation and costimulation, endogenous IFN-gamma, without IL-12, was sufficien t to elicit Th1 cells via an autocrine mechanism, whereas with subopti mal stimulation, exogenous rIFN-gamma or rIL-12 was required for Th1 d evelopment. However, rIL-12 was more effective than rIFN-gamma, partia lly because rlL-12 greatly enhanced autocrine production of IFN-gamma, and optimal development of the Th1 phenotype was mediated by the syne rgistic actions of both cytokines. Thus, both IFN-gamma and IL-12 can independently regulate Th1 development, but because of IFN-gamma-media ted feedback, their relative contributions are determined by the condi tions of T cell stimulation. The extent of differentiation to a Th1 ph enotype may, therefore, depend on the availability of both APC-derived IL-12 and autocrine IFN-gamma consequent to the overall strength of T cell stimulation.