Communicable Ulcerative Colitis Induced by T-bet Deficiency in the Innate Immune System
Abstract
Inflammatory bowel disease (IBD) has been attributed to overexuberant host immunity or the emergence of harmful intestinal flora. The transcription factor T-bet orchestrates inflammatory genetic programs in both adaptive and innate immunity. We describe a profound and unexpected function for T-bet in influencing the behavior of host inflammatory activity and commensal bacteria. T-bet deficiency in the innate immune system results in spontaneous and communicable ulcerative colitis in the absence of adaptive immunity and increased susceptibility to colitis in immunologically intact hosts. T-bet controls the response of the mucosal immune system to commensal bacteria by regulating TNF-α production in colonic dendritic cells, critical for colonic epithelial barrier maintenance. Loss of T-bet influences bacterial populations to become colitogenic, and this colitis is communicable to genetically intact hosts. These findings reveal a novel function for T-bet as a peacekeeper of host-commensal relationships and provide new perspectives on the pathophysiology of IBD.
Additional Information
© 2007 Elsevier Under an Elsevier user license. Received 23 April 2007, Revised 9 July 2007, Accepted 13 August 2007, Available online 4 October 2007. We thank D. Hu for expertise in histology and IHC; I. Jackson for assistance in phenotyping and FC; J. Ramirez for his care of our mice; Dr. J. Shim for advice and constructs for luciferase assays; Drs. S. Turley, T. Staton, M. Wein, A. Zullo, A. Kaser, and R. Blumberg for critical reading of the manuscript; Drs. W. Lencer, J. Gordon, D. Peterson, and T. Yatsunenko and members of the Glimcher and Grusby laboratories for helpful discussion. This work was supported by grants from the NIH (CA112663 and AI56296) and an Ellison Scholar Award to L.H.G. W.S.G. is a postdoctoral fellow of the Damon Runyon Cancer Research Foundation and received funding from the Irving Janock Fellowship. G.M.L. was supported by an MRC Clinician Scientist Grant (G108/380) and funding from the Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London, UK. L.H.G. is a member of the Board of Directors of the Bristol-Myers Squib Corporation.Attached Files
Accepted Version - nihms32124.pdf
Supplemental Material - 1-s2.0-S009286740701080X-mmc1.pdf
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Additional details
- PMCID
- PMC2169385
- Eprint ID
- 101806
- DOI
- 10.1016/j.cell.2007.08.017
- Resolver ID
- CaltechAUTHORS:20200309-164448458
- NIH
- CA112663
- NIH
- AI56296
- Ellison Medical Foundation
- Damon Runyon Cancer Research Foundation
- Irving Janock Fellowship
- Medical Research Council (UK)
- G108/380
- Guy's & St Thomas' NHS Foundation Trust
- King's College London
- Created
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2020-03-10Created from EPrint's datestamp field
- Updated
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2021-11-16Created from EPrint's last_modified field