T helper type 1 development of naive CD4+ T cells requires the coordinate action of interleukin42 and interferon-y and is inhibited by transforming growth factor+* Institut fur Immunologie, Maim
It was observed in vitro and in vivo that both interferon (1FN)y and interleukin (1L)-12 can promote the development of T helper type 1 ( T H ~) cells. Since IL-12 was shown to be a costimulator for the production of IFNy by Tor natural killer (NK) cells, IL-12 might play only an indirect role in T H ~ differentiation by providing IFN-y which represents the essential differentiation factor. Using anti-CD3 monoclonal antibody (mAb) for activation of naive CD4+ T cells in the absence of accessory cells we could demonstrate that costimulation by IFNy alone results only in marginal T H ~ development. Similarly, IL-12 in the absence of IFN-y is only a poor costimulator for inducing differentiation towards the T H ~ phenotype. Our data indicate that both cytokines are required to allow optimal T H ~ development and that IL-12 has a dual role, it promotes differentiation by direct costimulation of the T cells and also enhances the production of IFN-y which serves as a second costimulator by an autocrine mechanism. Another cytokine that was reported to favor T H ~ differentiation in certain experimental systems is transforming growth factor (TGF)-P. With naive CD4+ T cells employed in this study TGF-f3 strongly inhibited the production of IFNy triggered by IL-12 as well as the IL-12-induced T H ~ development. When TGF-p was combined with anti-IFN-y mAb for neutralization of endogenous IFNy the TH1-inducing capacity of IL-12 was completetly suppressed.