title: 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.
authors.affiliation: Department of Infectious Diseases, University of Georgia, 501 DW Brooks Drive, Athens, GA, United States of America.
authors.forename: Nicole V
authors.initials: NV
authors.lastname: Acuff
authors.affiliation: Department of Infectious Diseases, University of Georgia, 501 DW Brooks Drive, Athens, GA, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, University of Georgia, 501 DW Brooks Drive, Athens, GA, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Kirkland
authors.affiliation: Department of Pathology, University of Georgia, Athens, GA, United States of America.
authors.forename: Tamas
authors.initials: T
authors.lastname: Nagy
authors.affiliation: Department of Infectious Diseases, University of Georgia, 501 DW Brooks Drive, Athens, GA, United States of America.
authors.forename: Wendy T
authors.initials: WT
authors.lastname: Watford
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D002454:Cell Differentiation; D002478:Cells, Cultured; D003092:Colitis / Q000209:etiology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011518:Proto-Oncogene Proteins; D007371:Interferon-gamma; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse