title: TGF-beta1 inhibits T-bet induction by IFN-gamma in murine CD4+ T cells through the protein tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1.
abstract: TGF-beta1 prevents the development of autoimmune disease by restraining the development of autoreactive Th1 cells. TGF-beta1 inhibits Th1 development in part by suppressing the expression of T-bet, an IFN-gamma-induced transcription factor that promotes Th1 differentiation, but how TGF-beta1 suppresses T-bet is not known. In this study we show that TGF-beta1 suppresses IFN-gamma-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-gamma rapidly induced the expression of T-bet as well as of IFN regulatory factor-1, another transcription factor important for Th1 development. TGF-beta1 antagonized the effects of IFN-gamma, inhibiting IFN-gamma's induction of both Th1 transcription factors. In the presence of IFN-gamma, TGF-beta1 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 me(v)/me(v) mouse strain. Shp-1 was required for TGF-beta1's suppressive effects, because its suppression of T-bet and IFN regulatory factor-1 was completely abrogated in me(v)/me(v) CD4+ T cells. Receptor-proximal responses to IFN-gamma, such as the induction of Jak-Stat phosphorylation, were inhibited by TGF-beta1 in wild-type T cells, but not in me(v)/me(v) T cells. Consistent with a direct role for Shp-1, TGF-beta1's inhibition of IFN-gamma-induced Stat1 phosphorylation was sensitive to the general PTP inhibitor pervanadate. Together, these data show that TGF-beta1 suppresses IFN-gamma signaling and transcriptional responses in CD4+ T cells through the PTP Shp-1.
authors.affiliation: Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756, USA.
authors.forename: Il-Kyoo
authors.initials: IK
authors.lastname: Park
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: John J
authors.initials: JJ
authors.lastname: Letterio
authors.forename: James D
authors.initials: JD
authors.lastname: Gorham
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D000098815:T-bet Transcription Factor
chemical_list: D050856:Interferon Regulatory Factor-1; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C508961:Tgfb1 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D007371:Interferon-gamma; D003513:Cycloheximide; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse