Expression of αvβ8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice
Andrew C. Melton, … , Jeffrey A. Bluestone, Dean Sheppard
Andrew C. Melton, … , Jeffrey A. Bluestone, Dean Sheppard
Published November 22, 2010
Citation Information: J Clin Invest. 2010;120(12):4436-4444. https://doi.org/10.1172/JCI43786.
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Research Article

Expression of αvβ8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice

Abstract

Th17 cells promote a variety of autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. TGF-β is required for conversion of naive T cells to Th17 cells, but the mechanisms regulating this process are unknown. Integrin αvβ8 on DCs can activate TGF-β, and this process contributes to the development of induced Tregs. Here, we have now shown that integrin αvβ8 expression on DCs plays a critical role in the differentiation of Th17 cells. Th17 cells were nearly absent in the colons of mice lacking αvβ8 expression on DCs. In addition, these mice and the DCs harvested from them had an impaired ability to convert naive T cells into Th17 cells in vivo and in vitro, respectively. Importantly, mice lacking αvβ8 on DCs showed near-complete protection from experimental autoimmune encephalomyelitis. Our results therefore suggest that the integrin αvβ8 pathway is biologically important and that αvβ8 expression on DCs could be a therapeutic target for the treatment of Th17-driven autoimmune disease.

Authors

Andrew C. Melton, Samantha L. Bailey-Bucktrout, Mark A. Travis, Brian T. Fife, Jeffrey A. Bluestone, Dean Sheppard

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Figure 5

DCs from β8fl/fl × CD11c-cre mice fail to drive Th17 development through a defect in TGF-β activation.

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DCs from β8fl/fl × CD11c-cre mice fail to drive Th17 development through...
(A) Flow cytometry plots of naive CD4+ 2D2 TCR transgenic T cells after culture with DCs from control or β8fl/fl × CD11c-cre mice for 5 days. Cells were activated with PMA/ionomycin for 4 hours and then stained for IL-17 and IFN-γ. Cultures were grown under the following conditions: no treatment, Th17 (see Methods), Th17 without TGF-β, and Th17 with TGF-β–neutralizing antibody. (B) Percentage of IL-17–producing CD4+ 2D2 T cells after cultured as described in A. (C) Measurement of IL-17A in the supernatants of the cultures described in A using ELISA. (D) Measurement of IL-17F in the supernatant of the Th17 without the TGF-β condition described in A. (E) qRT-PCR analysis of the Rorc and Il23r genes from T cells after culture under the Th17 without the TGF-β condition described in A. Data represent the means ± SEM of at least 3 independent experiments with 8 mice in each group. *P < 0.01.