HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: jimmunol.0803749v1 183/2/975    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Locke, N. R. Articles by Levings, M. K. PubMed PubMed Citation Articles by Locke, N. R. Articles by Levings, M. K. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Substance via MeSH

SHIP Regulates the Reciprocal Development of T Regulatory and Th17 Cells

Natasha R. Locke^*, Scott J. Patterson^*, Melisa J. Hamilton, Laura M. Sly, Gerald Krystal and Megan K. Levings^*

^*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.

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

This article has been cited by other articles:

				M. Pierau, S. Engelmann, D. Reinhold, T. Lapp, B. Schraven, and U. H. Bommhardt Protein Kinase B/Akt Signals Impair Th17 Differentiation and Support Natural Regulatory T Cell Function and Induced Regulatory T Cell Formation J. Immunol., November 15, 2009; 183(10): 6124 - 6134. [Abstract] [Full Text] [PDF]

				G. Lal and J. S. Bromberg Epigenetic mechanisms of regulation of Foxp3 expression Blood, October 29, 2009; 114(18): 3727 - 3735. [Abstract] [Full Text] [PDF]