The MAP kinase, tumor progression locus 2 (Tpl2), activates the Akt/mTOR/S6 ribosomal protein pathway, inhibits Foxp3 expression and limits Treg immunosuppressive functions.

Abstract

Abstract The serine-threonine kinase, tumor progression locus 2 (Tpl2 or Map3k8/Cot), is a potent inflammatory mediator that drives the production of TNF alpha, IL-1 beta, and IFN gamma. We previously demonstrated that Tpl2 modulates TCR signaling and T helper cell differentiation. However, little is known about how Tpl2 alters the development or function of regulatory T cells (Tregs). Tregs are a specialized subset of T cells that express Foxp3 and possess immunosuppressive properties. Because of Tpl2’s role in promoting inflammation, we hypothesized that Tpl2 inhibits Treg development and immunosuppressive functions. Tpl2−/− naïve CD4 T+ cells preferentially differentiated into Foxp3+ inducible Tregs in vitro as well as in vivo in a murine model of OVA-induced systemic tolerance. Treg biasing in Tpl2−/− T cells depended upon the TCR signal strength and correlated with reduced activation of the Akt/mTOR/S6 pathway. Importantly, freshly isolated Tpl2−/− Tregs had increased expression of Foxp3 and immunosupressive cytokines IL-10 and IL-35 and were more suppressive in a T cell transfer model of colitis, as evidenced by reduced accumulation of inflammatory T effectors, systemic inflammatory cytokines TNF, IL-6 and IFN gamma, and colonic inflammation. Therefore, Tpl2 promotes inflammation in part by limiting Foxp3 expression, iTreg differentiation and immunosuppressive functions. These findings suggest that Tpl2 inhibition may be used to preferentially drive Treg induction and limit inflammation in autoimmune diseases.