T-HELPER TYPE-1 DEVELOPMENT OF NAIVE CD4(+) T-CELLS REQUIRES THE COORDINATE ACTION OF INTERLEUKIN-12 AND INTERFERON-GAMMA AND IS INHIBITED BY TRANSFORMING GROWTH-FACTOR-BETA

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