Mice lacking the transcription factor T-bet in the innate immune system (Tbx21-/- x Rag2-/- Ulcerative Colitis, or TRUC) develop microbiota-dependent inflammatory bowel disease (IBD). The innate immune mechanisms responsible for causing disease are still to be resolved, yet potentially offer novel insights into the pathogenesis of IBD, and how T-bet might influence inflammation in the gut. In this thesis it was shown that chronic IBD in TRUC mice was dependent on interleukin-17A (IL-17A) producing IL-7R+ CD90+ innate lymphoid cells (ILCs). Depletion of ILCs or IL-17A neutralization cured disease. Cytokines responsible for driving innate IL-17A included IL-23, IL-6 and TL1A. IL-23 and IL-6 played functionally important roles in TRUC disease, since neutralisation reduced innate IL-17A production and attenuated disease. TNFα, predominantly produced by CD11chigh class II+ CD11b+ CD103- dendritic cells (DCs), synergised with IL-23 to drive IL-17A production by ILCs. Helicobacter typhlonius (HT) was identified as the key colitigenic bacterium driving TRUC disease. Four-five-four ribosomal RNA gene sequencing demonstrated that HT was consistently present in the faeces of all TRUC mice, but absent from a newly-derived colony of disease-free Tbx21-/- x Rag2-/- mice. Inoculation of pure HT cultures was sufficient to reinstate disease into this new colony of healthy mice. T-bet impacted on colitis in several ways. In the absence of T-bet, ILCs selectively produced IL-17A and were poor producers of interferon-γ. Second, T-bet deficient DCs produced excess TNFα in comparison with T-bet sufficient DCs. Finally, T-bet was a transcriptional repressor of the Il7ra locus. IL-7R was expressed by ILCs and signalling through this receptor was critical for TRUC disease. Selective IL-7R blockade attenuated disease. Together these data provide new insights into TRUC disease and demonstrate at least some of the mechanisms by which T-bet regulates the interplay between mucosal innate immune cells and the intestinal microbiota.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:628475 |
| Date | January 2014 |
| Creators | Powell, Nicholas |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/defining-the-role-of-the-transcription-factor-tbet-in-the-innate-immune-system-in-intestinal-inflammation(d78ff348-ac4f-4ef6-b1a9-7e527226bf04).html |
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