Tpl2 differentially regulates IFNγ and IL-17 production by CD4+ T cells in a T cell transfer model of colitis. (LYM8P.636)

Abstract

Abstract Autoimmune diseases are approaching epidemic levels, estimated to affect 5-8% of the population. A number of autoimmune diseases are driven by autoreactive T cells, specifically T helper 1 (Th1) and T helper 17 (Th17) cells. One molecule gaining interest as a therapeutic target is the serine-threonine kinase, Tpl2, which promotes expression of proinflammatory mediators. We previously demonstrated that Tpl2 regulates Th1 differentiation, secretion of the inflammatory cytokine IFNγ, and host defense against the intracellular parasite Toxoplasma gondii. The goal of this study was to determine whether Tpl2 also regulates Th1 or Th17 differentiation in vivo in a T cell transfer model of colitis associated with mixed Th1/Th17 pathology. In vitro, Tpl2-/- naïve CD4+ T cells were impaired in IL-17A secretion under traditional Th17 inducing conditions of IL-6+TGF-β. Reduced IL-17A secretion correlated with increased expression of FoxP3, a transcription factor known to antagonize RORγt function. In vivo, transfer of Tpl2-/- T cells resulted in reduced proportions of CD4+ T cells expressing IFNγ, but not IL-17A, compared to that induced by wild type T cells. Further studies revealed that Th17 cells alternatively induced by IL-6+IL-23 was unaffected by Tpl2 deficiency. Collectively, these results implicate Tpl2 in TGF-β-induced FoxP3 expression. Additionally, they underscore the contribution of Tpl2 to Th1-dependent responses, including Th1-mediated immunopathology during autoimmunity.