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SHIP regulates the reciprocal development of T regulatory and Th17 cells.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2009 Jul 15; Vol. 183 (2), pp. 975-83. Date of Electronic Publication: 2009 Jun 19. - Publication Year :
- 2009
-
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.
- Subjects :
- Animals
Cell Differentiation
Colitis etiology
Inositol Polyphosphate 5-Phosphatases
Interleukin-6 pharmacology
Mice
Mice, Knockout
Phosphatidylinositol 3-Kinases metabolism
Phosphoric Monoester Hydrolases deficiency
STAT3 Transcription Factor metabolism
Signal Transduction
T-Lymphocyte Subsets transplantation
T-Lymphocytes, Regulatory transplantation
Homeostasis immunology
Interleukin-17
Phosphoric Monoester Hydrolases physiology
T-Lymphocyte Subsets cytology
T-Lymphocytes, Regulatory cytology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 183
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 19542365
- Full Text :
- https://doi.org/10.4049/jimmunol.0803749