Inflammatory bowel diseases (IBD) are diseases of immune dysregulation. Animal models and human genetic data support a central role for unrestrained Th17 responses in the pathogenesis of at least some forms of IBD. Cytokine reporter mice that we have generated led to the discovery that Th17 cells are flexible in their late program of differentiation, such that cytokine signals received after Th17 commitment impact the stability and phenotype of mature Th17 cells so as to influence their ability to cause colitis. While it has been known for some time that IL-6 is indispensable for initiation of Th17 lineage commitment, its function late in the Th17 pathway is ill-defined. We have recently identified an unanticipated role for IL-6 in the maintenance and pathogenicity of mature Th17 cells. Unlike wildtype Th17 cells, IL-6-deficient Th17 cells are unable to sustain a pathogenic phenotype and do not induce colitis. Although early commitment to the Th17 lineage is mediated via binding of IL-6 to membrane-bound IL-6Ra (mIL-6R), which associates with gp130 for signal transduction ("classical" IL-6 signaling), developing Th17 cells rapidly cleave mIL-6R from their surface and do not re-express detectable mIL-6R. Thus, IL-6 appears to act on mature Th17 cells via trans signaling, in which gp130 is activated by binding of shed, soluble IL-6R (sIL-6R) in complex with IL-6. Accordingly, our data suggest that mature Th17 cells must both produce IL-6 and respond to IL-6 via trans signaling to induce colitis. This identifies an autocrine/paracrine loop by which IL-6 might act on Th17 cells to promote colitis. Here, we will define mechanisms by which IL-6 contributes to late Th17 development and how this impacts IBD initiation and perpetuation. We hypothesize that IL-6 produced by a subset of mature Th17 cells contributes to the maintenance of pathogenic Th17 and Th1-like cells that mediate colitis. Further, we posit that whereas classical IL-6 signaling is essential for Th17 lineage specification, trans IL-6 signaling is essential for the maintenance of mature Th17 and Th1-like effectors that develop from a common Th17 precursor;in the absence of IL-6 trans signaling, pathogenic effector T cells are not sustained and colitis is attenuated. To test this hypothesis, we have generated novel reporter knock-in and knockout models with which to identify and track IL-6 producing cells and dissect specific mechanisms by which IL-6 acts late in the Th17 pathway to regulate its potential for pathogenesis. These transgenic models are complemented by new blocking antibodies and recombinant proteins that we have acquired through collaboration. We anticipate that these studies will elucidate new features of the Th17 pathway that contribute to chronic immune-mediated disease and will facilitate the design of more rational therapeutics that target Th17-mediated disease.
Factors Controlling Effector T Cell Maintenance in the Pathogenesis of Colitis. Inflammatory bowel diseases are diseases of immune dysregulation mediated by CD4 T cells that have poorly restrained reactivity to components of the enteric bacterial flora. This proposal will address mechanisms by which cytokines control the maintenance and pathogenic potential of effector CD4 T that contribute to IBD pathogenesis. We expect that results from these studies will provide a basis for new interventions to curb pathogenic immunity to the intestinal microbiota in the treatment of human IBD.
|Basu, Rajatava; Whitley, Sarah K; Bhaumik, Suniti et al. (2015) IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell-iTreg cell balance. Nat Immunol 16:286-95|
|Singer, Jeffrey R; Weaver, Casey T (2015) Daughter's Tolerance of Mom Matters in Mate Choice. Cell 162:467-9|
|Basu, Rajatava; Hatton, Robin D; Weaver, Casey T (2013) The Th17 family: flexibility follows function. Immunol Rev 252:89-103|
|Zindl, Carlene L; Lai, Jen-Feng; Lee, Yun Kyung et al. (2013) IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc Natl Acad Sci U S A 110:12768-73|
|Palmer, Matthew T; Weaver, Casey T (2013) Linking vitamin d deficiency to inflammatory bowel disease. Inflamm Bowel Dis 19:2245-56|
|Weaver, Casey T; Elson, Charles O; Fouser, Lynette A et al. (2013) The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu Rev Pathol 8:477-512|
|Basu, Rajatava; O'Quinn, Darrell B; Silberger, Daniel J et al. (2012) Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37:1061-75|
|Luckey, C John; Weaver, Casey T (2012) Stem-cell-like qualities of immune memory; CD4+ T cells join the party. Cell Stem Cell 10:107-8|
|Maynard, Craig L; Elson, Charles O; Hatton, Robin D et al. (2012) Reciprocal interactions of the intestinal microbiota and immune system. Nature 489:231-41|