The aetiology of the inflammatory bowel diseases ulcerative colitis and Crohn’s disease remains uncertain. Genetic studies and model systems strongly implicate components of the IL-23/type-17 axis in the pathogenesis of disease, but the cellular and molecular mediators are uncertain. Using an IL-23R<sup>gfp</sup> reporter mouse we analysed the cellular expression of IL-23R in homeostasis and disease. Whereas steady state expression in the intestine was dominated by a collection of unconventional lymphoid cells including ;gamma& ;delta& T-cells, we found rapid accumulation of IL-23R<sup>+</sup>CD4<sup>+</sup T-cells occurred in evolving colitis, and demonstrate an important role for IL-10 in the regulation of IL-23R specifically upon intestinal CD4+ T-cells. Examining the role of ;gamma& ;delta& T-cells in a model of IL-23-dependent colitis, we demonstrate apparent redundancy of such cells for the development of the adaptive CD4+ Th17 response. Furthermore, treatment with FTY720 which is known to inhibit lymphocyte recirculation did not attenuate disease nor reduce intestinal Th17 cell accumulation, suggesting the mechanisms of accumulation of Th17 cells in the intestine may differ from other anatomical sites. Next, we addressed the role of IL-21, a cytokine implicated in the development and effector functions of the IL-23/Th17 axis. Remarkably, we found that although IL-21 was pathogenic in models of chronic colitis, its effects on effector T-cell subsets were model-specific and included Th17 and Th1 cells. However, increased regulatory T-cell populations and reduced Ccl5 expression were common effects between models. Paradoxically, in a model of enteric infection, IL-21 was required for host defence, with IL-21R<sup>-/-</sup> mice developing increased bacterial colonisation and severe colitis, shown to be driven by increased Th1/IFN-;gamma& responses. These studies provide novel insights into aspects of IL-23 driven cellular and molecular pathways in homeostasis and inflammation in the intestine, with implications for future therapeutic approaches to IBD.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:639963 |
| Date | January 2013 |
| Creators | Shale, Matthew |
| Contributors | Powrie, Fiona |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:90aa31d4-a216-44b4-8a0b-7964886b3583 |
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