Dual Specificity Phosphatase 6 (DUSP6) regulates CD4+ T cell functions and restrains the spontaneous colitis in IL-10 deficient mice

Mitogen-activated protein kinase (MAPK) phosphatases are dual-specificity phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs. DUSP6 preferentially dephosphorylates extracellular signal-regulated kinase 1 and 2 (ERK1/2) rendering them inactive. Here, we study the role of DUSP6 in CD4(+) T cell function, differentiation, and inflammatory profile in the colon. Upon T cell receptor (TCR) stimulation, DUSP6 knock out (Dusp6(−/−)) CD4(+) T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation and IFN-γ production, as well as a marked decrease in survival, IL-17A secretion, and regulatory T cell function. To analyze the role of DUSP6 in vivo, we employed the Il10(−/−) model of colitis and generated Il10(−/−)/Dusp6(−/−) double knockout mice. Il10(−/−)/Dusp6(−/−) mice suffered from accelerated and exacerbated spontaneous colitis, which was prevented by ERK1/2 inhibition. ERK1/2 inhibition also augmented regulatory T cell differentiation in vitro and in vivo in both C57Bl/6 and Dusp6(−/−)mice. In summary, DUSP6 regulates CD4(+) T cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation. DUSP6 might therefore be a potential intervention target for limiting aberrant T cell responses in T cell mediated diseases such as inflammatory bowel disease.