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.

Although cancers arise from genetic mutations enabling cells to proliferate uncontrollably, they cannot thrive without failure of the anticancer immunity due in a large part to the tumor environment's influence on effector and regulatory T cells. The field of immune checkpoint inhibitor (ICI) therapy for cancer was born out of the fact that tumor environments paralyze the immune cells that are supposed to clear them by activating the immune checkpoint molecules such as PD-1. While various subsets of effector T cells work collaboratively to eliminate cancers, Tregs enriched in the tumor environment can suppress not only the native anticancer immunity but also diminish the efficacy of ICI therapies. Because of their essential role in suppressing autoimmunity, various attempts to specifically deplete tumor-associated Tregs are currently underway to boost the efficacy of ICI therapies without causing systemic autoimmune responses. A better understanding the roles of Tregs in the anti-cancer immunity and ICI therapies should provide more specific targets to deplete intratumoral Tregs. Here, we review the current understanding on how Tregs inhibit the anti-cancer immunity and ICI therapies as well as the advances in the targeted depletion of intratumoral Tregs.