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.
Full-textDOI: · Available from: Jeffrey Bluestone, Dec 26, 2013
- SourceAvailable from: Byung S Kim
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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. "
ABSTRACT: We examined the regulatory role of αv integrins in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a model of multiple sclerosis (MS). Blockade of αv integrins by anti-αv integrin monoclonal antibody (mAb) in the effector phase significantly suppressed the development of TMEV-IDD both clinically and histologically. The number of infiltrating mononuclear cells (MNCs) in the CNS was significantly decreased in mice treated with anti-αv integrin mAb. Flow cytometric analysis of cytokine staining revealed that absolute numbers of IFN-γ- and IL-17-producing CD4 + and IFN-γ-producing CD8 + T cells were significantly decreased in the CNS of mice treated with anti-αv integrin mAb. These data suggest that αv integrins may play important roles in the development of TMEV-IDD.Journal of Neuroimmunology 03/2014; DOI:10.1016/j.jneuroim.2013.12.013 · 2.79 Impact Factor
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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). "
ABSTRACT: Recent epidemiological studies have identified interferon regulatory factor 8 (IRF8) as a susceptibility factor for multiple sclerosis (MS). However, how IRF8 influences the neuroinflammatory disease has remained unknown. By studying the role of IRF8 in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we found that Irf8(-/-) mice are resistant to EAE. Furthermore, expression of IRF8 in antigen-presenting cells (APCs, such as macrophages, dendritic cells, and microglia), but not in T cells, facilitated disease onset and progression through multiple pathways. IRF8 enhanced αvβ8 integrin expression in APCs and activated TGF-β signaling leading to T helper 17 (Th17) cell differentiation. IRF8 induced a cytokine milieu that favored growth and maintenance of Th1 and Th17 cells, by stimulating interleukin-12 (IL-12) and IL-23 production, but inhibiting IL-27 during EAE. Finally, IRF8 activated microglia and exacerbated neuroinflammation. Together, this work provides mechanistic bases by which IRF8 contributes to the pathogenesis of MS.Immunity 01/2014; 40(2):187-98. DOI:10.1016/j.immuni.2013.11.022 · 19.75 Impact Factor
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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). "
ABSTRACT: Regulation of an immune response requires complex crosstalk between cells of the innate and adaptive immune systems, via both cell-cell contact and secretion of cytokines. An important cytokine with a broad regulatory role in the immune system is transforming growth factor-β (TGF-β). TGF-β is produced by and has effects on many different cells of the immune system, and plays fundamental roles in the regulation of immune responses during homeostasis, infection and disease. Although many cells can produce TGFβ, it is always produced as an inactive complex that must be activated to bind to the TGFβ receptor complex and promote downstream signalling. Thus, regulation of TGFβ activation is a crucial step in controlling TGFβ function. This review will discuss how TGFβ controls diverse immune responses and how TGFβ function is regulated, with a focus on recent work highlighting a critical role for the integrin αvβ8 expressed by dendritic cells in activating TGFβ.Immunobiology 07/2012; 217(12). DOI:10.1016/j.imbio.2012.06.009 · 3.18 Impact Factor