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* Department of Surgery, University of British Columbia and Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada; and
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
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-β, 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-β-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-β 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Canadian Institutes for Health Research (MOP57834), National Cancer Institute of Canada, Terry Fox Foundation, and StemCell Technologies. Core support was funded by the Immunity and Infection Research Centre Michael Smith Foundation for Health Research Unit, British Columbia Cancer Foundation, and British Columbia Cancer Agency. M.K.L. holds a Canada Research Chair in Transplantation and is a Michael Smith Foundation for Health Research Scholar. N.R.L. and S.J.P. are recipients of Canadian Institutes for Health Research Transplantation Training Program awards. M.J.H. holds a Michael Smith Foundation for Health Research Trainee award and a Canadian Institutes for Health Research studentship.
2 Address correspondence and reprint requests to Dr. Megan K. Levings, Department of Surgery, University of British Columbia and Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, 2660 Oak Street, Vancouver, British Columbia V6H 3Z6, Canada. E-mail address: megan.levings{at}ubc.ca
3 Abbreviations used in this paper: Treg, regulatory T cell; IBD, inflammatory bowel disease; iTreg, peripherally induced regulatory T cell; MLN, mesenteric lymph node; Teff, effector T; RA, retinoic acid; ROR, retinoic acid-related orphan receptor; WT, wild type.
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