IL-23 is an essential mediator of chronic intestinal inflammation in experimental models of colitis. Polymorphisms in the IL23R locus are associated with IBD susceptibility in humans. The biological activity of IL-23 has been linked to Th17 cells but little is known about the cellular and molecular mechanism by which IL-23 drives intestinal inflammation. The work presented herein has identified that direct IL-23 signalling into CD4+ T cells was not only required for the accumulation of Th17 cells in the intestine but also modulated their phenotype. Through direct cell intrinsic effects on T cells, IL-23 drove the emergence of an IL-17A+IFN-γ+ population of T cells that co-expressed RORγ and T-bet. Interestingly, we found that expression of RORγ but not T-bet by T cells was required for the development of intestinal inflammation. Furthermore, colitis induced by T-bet deficient T cells was dependent on IL-17A, and showed a unique inflammatory phenotype, thus demonstrating that pathogenic intestinal Th17 responses can develop independently of T-bet. In addition, using transcriptional profiling we identified a core set of genes that is regulated by direct cell-intrinsic IL-23 signals into intestinal CD4+ T cells. This revealed a previously unrecognised role for IL-23 in suppressing Th2 associated genes, such as GATA3 and IL-33R. Functional experiments demonstrated that expression of GATA3 in CD4+ T cells limited their colitogenic potential, suggesting that IL-23-mediated inhibition of GATA3 might contribute to the development of intestinal inflammation. Finally, we described a novel function for IL-33 as a factor that promotes Foxp3+ iTreg differentiation in vitro and in vivo through direct effects on T cells. This activity of IL-33 was inhibited in the presence of IL-23, providing a mechanistic link for the known role of IL-23 in restraining iTreg generation. Collectively, these data suggest that IL-23 promotes acquisition of a pathogenic effector T cell phenotype through multiple mechanisms. This indicates that therapeutic blockade of IL-23 is likely to reduce pro-inflammatory mediators while also facilitating the expansion of regulatory pathways that might help to re-establish intestinal homeostasis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:588435 |
| Date | January 2013 |
| Creators | Schiering, Chris |
| 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:b33533f6-c7e1-4c77-9fd2-a3b174fb9bde |
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