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J Immunol. 2012 Feb 1;188(3):968-75. doi: 10.4049/jimmunol.1102840. Epub 2011 Dec 16.

STAT6-dependent regulation of Th9 development.

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  • 1Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.


Th cell effector subsets develop in response to specific cytokine environments. The development of a particular cytokine-secreting pattern requires an integration of signals that may promote the development of opposing pathways. A recent example of this paradigm is the IL-9-secreting Th9 cell that develops in response to TGF-β and IL-4, cytokines that, in isolation, promote the development of inducible regulatory T cells and Th2 cells, respectively. To determine how the balance of these factors results in priming for IL-9 secretion, we examined the effects of each pathway on transcription factors that regulate Th cell differentiation. We demonstrated that TGF-β induces the PU.1-encoding Sfpi1 locus and that this is independent of IL-4-induced STAT6 activation. IL-4-activated STAT6 is required for repressing the expression of T-bet and Foxp3 in Th9 cells, transcription factors that inhibit IL-9 production, and STAT6 is required for the induction of IRF4, which promotes Th9 development. These data established a transcription factor network that regulates IL-9 and demonstrated how combinations of cytokine signals generate cytokine-secreting potential by altering the expression of a panel of transcription factors.

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