Abstract
Autoimmune diseases are approaching epidemic levels, estimated to affect 5–8% of the population. A number of autoimmune diseases are believed to be driven by autoreactive T cells, specifically by T helper 1 (Th1) cells 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 model of colitis associated with mixed Th1/Th17 pathology. In vitro, Tpl2−/− naïve CD4 T cells were significantly impaired in IL-17A secretion under traditional Th17 inducing conditions. Reduced IL-17A secretion correlated with increased expression of FoxP3, a transcription factor known to antagonize RORγt function. In a murine T cell transfer model of colitis, 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 IL-17A differentiation induced by IL-6 and IL-23, cytokines implicated in driving Th17 differentiation in vivo, 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 immunopathology specifically, which suggests that Tpl2 inhibitors may selectively target Th1-based inflammation.
Highlights
Tumor progression locus 2, Tpl2, is a serine-threonine protein kinase originally described as an oncogene, because its C-terminal truncation promoted tumor growth [1]
The nearly normal circulating IFNγ levels and colitis pathology were surprising. Since both T helper 1 (Th1) and T helper 17 (Th17) cells are associated with colitis, we investigated whether Tpl2 altered the proportions of IFNγ or IL-17A positive CD4 T cells within the spleen and mesenteric lymph nodes (MLN)
We describe a T cell-intrinsic defect in IL-17A production by Tpl2−/− Th17 cells driven by IL-6 and TGF-β
Summary
Tumor progression locus 2, Tpl ( known as MAP3K8), is a serine-threonine protein kinase originally described as an oncogene, because its C-terminal truncation promoted tumor growth [1]. Activated by toll-like receptors, cytokines, antigen receptors and G protein-coupled receptors [2, 4,5,6,7,8,9,10], Tpl enhances inflammation by PLOS ONE | DOI:10.1371/journal.pone.0119885. Initial characterization of Tpl2−/− mice identified major defects in the induction of proinflammatory cytokines, TNFα, by antigen presenting cells that conveyed resistance to endotoxin-induced shock [5]. Because it promotes inflammatory mediators, Tpl is being investigated as a therapeutic target for treating autoimmune diseases [15,16,17]
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