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1 Inhibits T-bet Induction by IFN-
in Murine CD4+ T Cells through the Protein Tyrosine Phosphatase Src Homology Region 2 Domain-Containing Phosphatase-11
* Departments of Pathology and Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756;
The Jackson Laboratory, Bar Harbor, ME 04609; and
Laboratory of Cell Regulation and Carcinogenesis and Laboratory of Molecular Biology, Center for Cancer Research, National Institutes of Health, Bethesda, MD 20892
TGF-
1 prevents the development of autoimmune disease by restraining the development of autoreactive Th1 cells. TGF-1 inhibits Th1 development in part by suppressing the expression of T-bet, an IFN-
-induced transcription factor that promotes Th1 differentiation, but how TGF-1 suppresses T-bet is not known. In this study we show that TGF-1 suppresses IFN--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- rapidly induced the expression of T-bet as well as of IFN regulatory factor-1, another transcription factor important for Th1 development. TGF-1 antagonized the effects of IFN-, inhibiting IFN-’s induction of both Th1 transcription factors. In the presence of IFN-, TGF-1 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-1’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-, such as the induction of Jak-Stat phosphorylation, were inhibited by TGF-1 in wild-type T cells, but not in mev/mev T cells. Consistent with a direct role for Shp-1, TGF-1’s inhibition of IFN--induced Stat1 phosphorylation was sensitive to the general PTP inhibitor pervanadate. Together, these data show that TGF-1 suppresses IFN- signaling and transcriptional responses in CD4+ T cells through the PTP Shp-1.
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