Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 22, Pages 7061-7066Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1415675112
Keywords
Th17; Th1; colitis
Categories
Funding
- National Institutes of Health
- Crohn's and Colitis Foundation of America
- Daiichi-Sankyo, Co. Ltd.
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Th17 cells reactive to the enteric microbiota are central to the pathogenesis of certain types of inflammatory bowel disease. However, Th17 cells display substantial developmental plasticity, such that some progeny of Th17 cell precursors retain a predominantly IL-17A(+) phenotype, whereas others extinguish IL-17 expression and acquire expression of IFN-gamma, giving rise to Th1-like cells. It remains unclear what role these subsets play in inflammatory bowel disease. Using a Th17 transfer model of colitis, we found that IFN-gamma-deficient Th17 cells retained an IL-17A(+) phenotype and were unable to induce colitis in recipients. Development of disease required the transition of a subset of Th17 precursors to Th1-like cells and was contingent on the expression of both Stat4 and T-bet, but not the IL-12 or IFN-gamma receptors. Moreover, Th17 cells could provide help for the development of pathogenic Th1 cells from naive precursors. These results indicate that Th17 cells are potent mediators of colitis pathogenesis by dual mechanisms: by directly transitioning to Th1-like cells and by supporting the development of classic Th1 cells.
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