title: SHIP regulates the reciprocal development of T regulatory and Th17 cells.
abstract: Maintaining an appropriate balance between subsets of CD4(+) Th and T regulatory cells (Tregs) is critical to maintain immune homeostasis and prevent autoimmunity. Through a common requirement for TGF-beta, the development of peripherally induced Tregs is intimately linked to that of Th17 cells, with the resulting lineages depending on the presence of proinflammatory cytokines such as IL-6. Currently very little is known about the molecular signaling pathways that control the development of Tregs vs Th17 cells. Reduced activity of the PI3K pathway is required for TGF-beta-mediated induction of Foxp3 expression and the suppressive activity of Tregs. To investigate how negative regulators of the PI3K pathway impact Treg development, we investigated whether SHIP, a lipid phosphatase that regulates PI3K activity, also plays a role in the development and function of Tregs. SHIP-deficient Tregs maintained suppressive capacity in vitro and in a T cell transfer model of colitis. Surprisingly, SHIP-deficient Th cells were significantly less able to cause colitis than were wild-type Th cells due to a profound deficiency in Th17 cell differentiation, both in vitro and in vivo. The inability of SHIP-deficient T cells to develop into Th17 cells was accompanied by decreased IL-6-stimulated phosphorylation of STAT3 and an increased capacity to differentiate into Treg cells under the influence of TGF-beta and retinoic acid. These data indicate that SHIP is essential for normal Th17 cell development and that this lipid phosphatase plays a key role in the reciprocal regulation of Tregs and Th17 cells.
authors: Department of Surgery, University of British Columbia and Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada.
authors: Natasha R
authors: NR
authors: Locke
authors: Scott J
authors: SJ
authors: Patterson
authors: Melisa J
authors: MJ
authors: Hamilton
authors: Laura M
authors: LM
authors: Sly
authors: Gerald
authors: G
authors: Krystal
authors: Megan K
authors: MK
authors: Levings
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003092:Colitis / Q000209:etiology; D006706:Homeostasis / Q000276:immunology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D020381:Interleukin-17; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000637:transplantation; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000637:transplantation
chemical_list: D020381:Interleukin-17; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases