4.7 Article

The tyrosine phosphatase SHP-1 dampens murine Th17 development

Journal

BLOOD
Volume 119, Issue 19, Pages 4419-4429

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-09-377069

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Funding

  1. National Institutes of Health [RO1 AI48672, AI 41236, AI 51420]

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Th17 cells represent a subset of CD4(+) T helper cells that secrete the proinflammatory cytokine IL-17. Th17 cells have been ascribed both a beneficial role in promoting clearance of pathogenic fungi and bacteria, and a pathogenic role in autoimmune diseases. Here we identify the tyrosine phosphatase SHP-1 as a critical regulator of Th17 development, using 3 complementary approaches. Impaired SHP-1 activity through genetic deletion of SHP-1, transgenic expression of an inducible dominant negative SHP-1, or pharmacologic inhibition of SHP-1 strongly promotes the development of Th17. Ex vivo Th17 skewing assays demonstrate that genetic or pharmacologic disruption of SHP-1 activity in T cells results in a hyper-response to stimulation via IL-6 and IL-21, 2 cytokines that promote Th17 development. Mechanistically, we find that SHP-1 decreases the overall cytokine-induced phosphorylation of STAT3 in primary CD4(+) T cells. These data identify SHP-1 as a key modifier of IL-6-and IL-21-driven Th17 development via regulation of STAT3 signaling and suggest SHP-1 as a potential new therapeutic target for manipulating Th17 differentiation in vivo. (Blood. 2012;119(19):4419-4429)

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