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Abstract
The serine-threonine kinase, tumor progression locus 2 (Tpl2, also known as Map3k8/Cot), is a potent inflammatory mediator that drives the production of TNF, IL-1, and IFN. We previously demonstrated that Tpl2 regulates TCR signaling and modulates T helper cell differentiation. However, very little is known about how Tpl2 modulates the development of regulatory T cells (Tregs). Tregs are a specialized subset of T cells that express FoxP3 and possess immunosuppressive properties to limit excess inflammation. Because of the documented role of Tpl2 in promoting inflammation, we hypothesized that Tpl2 antagonizes Treg development and immunosuppressive function. Herein, we demonstrate that Tpl2 constrains the development of inducible Tregs (iTregs). Tpl2-/- nave CD4+ T cells preferentially develop into FoxP3+ iTregs in vitro as well as in vivo in a murine model of OVA-induced systemic tolerance. Treg biasing of Tpl2-/- T cells depended upon the TCR signal strength and corresponded with reduced activation of the mammalian target of rapamycin (mTOR) pathway. Importantly, Tpl2-/- Tregs have basally increased expression of FoxP3 and immunosuppressive molecules, IL-10 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Furthermore, they were more immunosuppressive in vivo in a T cell transfer model of colitis, as evidenced by reducing effector T cell accumulation, systemic production of inflammatory cytokines, and colonic inflammation. These results demonstrate that Tpl2 promotes inflammation in part by constraining FoxP3 expression and Treg immunosuppressive functions. Overall these findings suggest that Tpl2 inhibition could be used to preferentially drive Treg induction and thereby limit inflammation in a variety of autoimmune diseases.