title: The tyrosine phosphatase SHP-1 dampens murine Th17 development.
abstract: Th17 cells represent a subset of CD4+ T helper cells that secrete the proinflammatory cytokine IL-17. Th17 cells have been ascribed both a beneficial role in promoting clearance of pathogenic fungi and bacteria, and a pathogenic role in autoimmune diseases. Here we identify the tyrosine phosphatase SHP-1 as a critical regulator of Th17 development, using 3 complementary approaches. Impaired SHP-1 activity through genetic deletion of SHP-1, transgenic expression of an inducible dominant negative SHP-1, or pharmacologic inhibition of SHP-1 strongly promotes the development of Th17. Ex vivo Th17 skewing assays demonstrate that genetic or pharmacologic disruption of SHP-1 activity in T cells results in a hyper-response to stimulation via IL-6 and IL-21, 2 cytokines that promote Th17 development. Mechanistically, we find that SHP-1 decreases the overall cytokine-induced phosphorylation of STAT3 in primary CD4+ T cells. These data identify SHP-1 as a key modifier of IL-6-and IL-21-driven Th17 development via regulation of STAT3 signaling and suggest SHP-1 as a potential new therapeutic target for manipulating Th17 differentiation in vivo.
authors.affiliation: Beirne Carter Center for Immunology Research and Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Ileana S
authors.initials: IS
authors.lastname: Mauldin
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Tung
authors.forename: Ulrike M
authors.initials: UM
authors.lastname: Lorenz
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000378:metabolism / Q000502:physiology*; D000098546:Interleukin-21
chemical_list: D015850:Interleukin-6; D007378:Interleukins; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; D000098546:Interleukin-21