T-bet is a key modulator of IL-23-driven pathogenic CD4(+) T cell responses in the intestine

IL-23 is a key driver of pathogenic Th17 cell responses. It has been suggested that the transcription factor T-bet is required to facilitate IL-23-driven pathogenic effector functions; however, the precise role of T-bet in intestinal T cell responses remains elusive. Here, we show that T-bet express...

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Published inNature communications Vol. 7; no. 1; p. 11627
Main Authors Krausgruber, Thomas, Schiering, Chris, Adelmann, Krista, Harrison, Oliver J, Chomka, Agnieszka, Pearson, Claire, Ahern, Philip P, Shale, Matthew, Oukka, Mohamed, Powrie, Fiona
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 19.05.2016
Nature Portfolio
Subjects
Animals
CD4-Positive T-Lymphocytes - physiology
Cells
Colitis - immunology
Disease Models, Animal
Female
Infections
Inflammatory bowel disease
Interleukin-17 - metabolism
Interleukin-22
Interleukin-23 - metabolism
Interleukins - metabolism
Intestines - immunology
Lymphocytes
Male
Medicine
Mice, Inbred C57BL
Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism
Pathology
Receptors, Interleukin - metabolism
T-Box Domain Proteins - metabolism
Transcription factors
United Kingdom > UK
United States > US
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Summary:IL-23 is a key driver of pathogenic Th17 cell responses. It has been suggested that the transcription factor T-bet is required to facilitate IL-23-driven pathogenic effector functions; however, the precise role of T-bet in intestinal T cell responses remains elusive. Here, we show that T-bet expression by T cells is not required for the induction of colitis or the differentiation of pathogenic Th17 cells but modifies qualitative features of the IL-23-driven colitogenic response by negatively regulating IL-23R expression. Consequently, absence of T-bet leads to unrestrained Th17 cell differentiation and activation characterized by high amounts of IL-17A and IL-22. The combined increase in IL-17A/IL-22 results in enhanced epithelial cell activation and inhibition of either IL-17A or IL-22 leads to disease amelioration. Our study identifies T-bet as a key modulator of IL-23-driven colitogenic responses in the intestine and has important implications for understanding of heterogeneity among inflammatory bowel disease patients.
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Present address: The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, UK
These authors contributed equally to this work.
Present address: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri 63108, USA
Present address: Program in Barrier Immunity and Repair, Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892-0485, USA
Present address: Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California 94305, USA.
Present address: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090 Vienna, Austria
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms11627