Tumor Progression Locus 2 Differentially Regulates IFNγ and IL-17 Production by Effector CD4+ T Cells in a T Cell Transfer Model of Colitis

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.

Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

“…In contrast, Tpl2 did not influence CD4 T cell expression of the Th17-associated cytokine IL-22 during infection. These findings are similar to those observed for Th17 cells cultured in vitro, in which IL-17A expression was significantly reduced but the expression of IL-22 or the Th17-associated transcription factors ROR␣, ROR␥t, and interferon regulatory factor 4 (IRF4) was unaffected (38), suggesting a specific defect in IL-17A expression rather than a global defect in Th17 cell differentiation.…”

“…Tpl2 has previously been shown to promote Th1 cell differentiation and the production of IFN-␥ in vitro and in vivo (22), as well as Th17 cell differentiation and the secretion of IL-17A but not the secretion of IL-22 in vitro (38). Accordingly, Tpl2 Ϫ/Ϫ mice are more susceptible than wild-type mice to the Th1-inducing intracellular pathogens Toxoplasma gondii (22), Listeria monocytogenes (21), and Mycobacterium tuberculosis (23).…”

“…Claudin 2 and claudin 5 require signaling through the MEK/ERK pathway for protein expression on epithelial cell lines (42,43), and expression of the genes for claudin 1 and 2 can be upregulated by IL-17A stimulation (42). Because Tpl2 signals upstream of the MEK/ERK pathway (41) and contributes to IL-17A production in vitro (38) and in vivo (this study), we tested the possibility that Tpl2 regulates intestinal barrier integrity by regulating the expression of claudin 2 and/or 5 on the surface of epithelial cells. Indeed, the expression of claudin 2 was significantly reduced and the expression of claudin 5 trended toward a reduction in Tpl2 Ϫ/Ϫ mouse colon tissue at 8 dpi.…”

“…We have recently shown that Tpl2 promotes Th17 cell differentiation and the secretion of IL-17A but not the secretion of IL-22 in vitro (38). However, Tpl2 has little impact on Th17 cell production of IL-17A in vivo during myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (39) or in a T cell transfer model of colitis (38). It has yet to be investigated whether Tpl2 influences Th17 cell differentiation, IL-17A production, or neutrophil accumulation during extracellular bacterial or fungal infections.…”

“…Together, Th17 effector cytokines are required for the clearance of extracellular bacterial and fungal infections, including those caused by Citrobacter rodentium, Klebsiella pneumoniae, Staphylococcus aureus, and Candida albicans, while they also contribute to the inflammation associated with autoimmune diseases (reviewed in reference 37). We have recently shown that Tpl2 promotes Th17 cell differentiation and the secretion of IL-17A but not the secretion of IL-22 in vitro (38). However, Tpl2 has little impact on Th17 cell production of IL-17A in vivo during myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (39) or in a T cell transfer model of colitis (38).…”