T helper type 1 development of naive CD4+ T cells requires the coordinate action of interleukin‐12 and interferon‐γ and is inhibited by transforming growth factor‐β

It was observed in vitro and in vivo that both interferon (IFN)‐γ and interleukin (IL)‐12 can promote the development of T helper type 1 (TH1) cells. Since IL‐12 was shown to be a costimulator for the production of IFN‐γ by T or natural killer (NK) cells, IL‐12 might play only an indirect role in TH1 differentiation by providing IFN‐γ 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 IFN‐γ alone results only in marginal TH1 development. Similarly, IL‐12 in the absence of IFN‐γ is only a poor costimulator for inducing differentiation towards the TH1 phenotype. Our data indicate that both cytokines are required to allow optimal TH1 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‐γ which serves as a second costimulator by an autocrine mechanism. Another cytokine that was reported to favor TH1 differentiation in certain experimental systems is transforming growth factor (TGF)‐β. With naive CD4+ T cells employed in this study TGF‐β strongly inhibited the production of IFN‐γ triggered by IL‐12 as well as the IL‐12‐induced TH1 development. When TGF‐β was combined with anti‐IFN‐γ mAb for neutralization of endogenous IFN‐γ the TH1‐inducing capacity of IL‐12 was completetly suppressed.