The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation

Deregulation of the T(H)17 subset of helper T cells is closely linked with immunological disorders and inflammatory diseases. However, the mechanism by which T(H)17 cells are regulated remains elusive. Here we found that the phosphatase DUSP2 (PAC1) negatively regulated the development of T(H)17 cells. DUSP2 was directly associated with the signal transducer and transcription activator STAT3 and attenuated its activity through dephosphorylation of STAT3 at Tyr705 and Ser727. DUSP2-deficient mice exhibited severe susceptibility to experimental colitis, with enhanced differentiation of T(H)17 cells and secretion of proinflammatory cytokines. In clinical patients with ulcerative colitis, DUSP2 was downregulated by DNA methylation and was not induced during T cell activation. Our data demonstrate that DUSP2 is a true STAT3 phosphatase that modulates the development of T(H)17 cells in the autoimmune response and inflammation.