A direct role for IFN-γ in regulation of Th1 cell development

Abstract

IL-12 has been identified as a major cytokine influencing the differentiation of CD4 cells to a Th1 phenotype, whereas a role for IFN-γ is controversial. We investigated the interrelationship between IL-12 and IFN-γ in promoting Th1 responses using naive CD4 cells reactive with pigeon cytochrome c from TCR transgenics and memory CD4 cells derived by in vivo priming with KLH. Without exogenous rIL-12 or rIFN-γ, primary and memory effectors induced by Ag or anti-CD3 and anti-CD28 secreted variable levels of IL-2 and IFN-γ. The level of IFN-γ secreted by effectors correlated with endogenous IFN-γ produced in primary cultures, and anti-IFN-γ largely inhibited the development of effectors producing IFN-γ. With optimal TCR stimulation and costimulation, endogenous IFN-γ, without IL-12, was sufficient to elicit Th1 cells via an autocrine mechanism, whereas with suboptimal stimulation, exogenous rIFN-γ or rIL-12 was required for Th1 development. However, rIL-12 was more effective than rIFN-γ, partially because rIL-12 greatly enhanced autocrine production of IFN-γ, and optimal development of the Th1 phenotype was mediated by the synergistic actions of both cytokines. Thus, both IFN-γ and IL-12 can independently regulate Th1 development, but because of IFN-γ-mediated feedback, their relative contributions are determined by the conditions of T cell stimulation. The extent of differentiation to a Th1 phenotype may, therefore, depend on the availability of both APC-derived IL-12 and autocrine IFN-γ consequent to the overall strength of T cell stimulation.