TGF-β1 prevents the development of autoimmune disease by restraining the development of autoreactive Th1 cells. TGF-β1 inhibits Th1 development in part by suppressing the expression of T-bet, an IFN-γ-induced transcription factor that promotes Th1 differentiation, but how TGF-β1 suppresses T-bet is not known. In this study we show that TGF-β1 suppresses IFN-γ-induced T-bet expression through the hemopoietic protein tyrosine phosphatase (PTP) Src homology region 2 domain-containing phosphatase-1 (Shp-1). In murine CD4+ T cells, IFN-γ rapidly induced the expression of T-bet as well as of IFN regulatory factor-1, another transcription factor important for Th1 development. TGF-β1 antagonized the effects of IFN-γ, inhibiting IFN-γ’s induction of both Th1 transcription factors. In the presence of IFN-γ, TGF-β1 rapidly induced in Th cells the synthesis of the PTP Shp-1, but did not induce Shp-2 or several members of the suppressor of cytokine signaling family of Jak-Stat inhibitors. We tested the requirement for Shp-1 by using T cells from the Shp-1-deficient mev/mev mouse strain. Shp-1 was required for TGF-β1’s suppressive effects, because its suppression of T-bet and IFN regulatory factor-1 was completely abrogated in mev/mev CD4+ T cells. Receptor-proximal responses to IFN-γ, such as the induction of Jak-Stat phosphorylation, were inhibited by TGF-β1 in wild-type T cells, but not in mev/mev T cells. Consistent with a direct role for Shp-1, TGF-β1’s inhibition of IFN-γ-induced Stat1 phosphorylation was sensitive to the general PTP inhibitor pervanadate. Together, these data show that TGF-β1 suppresses IFN-γ signaling and transcriptional responses in CD4+ T cells through the PTP Shp-1.

In addition to classic Smad signaling pathways, the pleiotropic immunoregulatory cytokine TGF-β1 can activate MAP kinases, but a role for TGF-β1-MAP kinase pathways in T cells has not been defined heretofore. We have shown previously that TGF-β1 inhibits Th1 development by inhibiting IFN-γ's induction of T-bet and other Th1 differentiation genes, and that TGF-β1 inhibits receptorproximal IFN-γ-Jak-Stat signaling responses. We now show that these effects of TGF-β1 are independent of the canonical TGF-β1 signaling module Smad3, but involve a specific MAP kinase pathway. In primary T cells, TGF-β1 activated the MEK/ERK and p38 MAP kinase pathways, but not the JNK pathway. Inhibition of the MEK/ERK pathway completely eliminated the inhibitory effects of TGF-β1 on IFN-γ responses in T cells, whereas inhibition of the p38 pathway had no effect. Thus, TGF-β1's inhibition of IFN-γ signaling in T cells is mediated through a highly specific Smad3-independent, MEK/ERK-dependent signaling pathway.