Article

Expression of αVβ8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice

Lung Biology Center, Department of Medicine, University of California, San Francisco, California, USA.
The Journal of clinical investigation (Impact Factor: 13.77). 12/2010; 120(12):4436-44. DOI: 10.1172/JCI43786
Source: PubMed

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.

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Available from: Jeffrey Bluestone, Dec 26, 2013
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    • "There are increasing evidences that αv integrins are involved in the differential regulation of T h 1 vs. T h 17 cells and their cytokine production during EAE by regulating TGF-β activation. Furthermore there are reports that lack of αv integrins resulted in loss of T h 17 cells in the intestine and lymphoid tissues and also led to protection from EAE (Acharya et al., 2010; Melton et al., 2010). Here, we have demonstrated for the first time that blocking the αv integrins by using anti-αv integrin mAb in the effector phase markedly suppresses the development of TMEV-IDD and decreases the number of infiltrating cells, suggesting that αv integrins play a critical role in deteriorating TMEV-IDD. "
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    • "With the aid of transforming growth factor-b (TGF-b),inter- leukin-6 (IL-6), and other cytokines, antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages, trigger development of Th17 cells (Bettelli et al., 2006). Recent studies revealed that TGF-b signaling is mediated by integrin molecules on APCs, which enables direct delivery of biologically active TGF-b into naive T cells (Acharya et al., 2010; Melton et al., 2010). Integrin-triggered TGF-b signaling results in activation of ROR family transcription factors that direct Th17 cell differentiation and production of the signature cytokine IL-17 (Ivanov et al., 2006; Yang et al., 2008). "
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    • "DCs that lack integrin ␣v␤8 expression have a reduced ability to induce Th17 cells in vitro, and this defect can be rescued by the addition of active TGF␤ (Melton et al. 2010). Mice lacking integrin ␣v␤8 expression on DCs also have reduced numbers of Th17 cells in vivo, and are protected from symptoms during EAE, a model of autoimmunity known to involve Th17 cells (Melton et al. 2010). Similar results are observed in mice lacking all ␣v integrins on myeloid cells, and when integrin-latent TGF␤ interactions were blocked by administration of an RGD peptide (Acharya et al. 2010). "
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