In summary, our data demonstrate a critical role for DC αv integrins in generating Th17 cells in normal homeostatic immunity or in pathological settings. We propose that this is due to the failure of αv-deficient DCs to activate latent TGF-β, which is required for T cell differentiation into Th17 cells and aTregs. Consequently, mice in which αv is deleted from myeloid cells did not develop Th17 cells in the intestine or in the periphery following immunization and were protected from Th17-mediated inflammatory disease. Furthermore, pharmacological inhibition of αv integrins impaired Th17 differentiation in vivo and ameliorated Th17-mediated pathology in a mouse model.
These studies complement and build on the work of others (23
) and on our previous work (21
), in which we demonstrated that αv integrins were required for generation of aTregs in the intestine. We previously postulated that αv integrins on myeloid cells are essential for T cell responses to TGF-β by facilitating activation of latent TGF-β. Here we provide direct in vitro evidence for this hypothesis and demonstrate that this mechanism underlies DC control of generation of both Tregs and Th17 cells. Th17 cells and aTregs appear to share a common precursor and a requirement for TGF-β signaling during early development, and the loss of both populations of cells in αv-deficient mice is consistent with this. However, our data show that αv deletion causes a greater reduction in Th17 cells than in FoxP3+
Tregs (Figures and ), which are only depleted in the intestine and are actually found at higher numbers in mesenteric LNs (MLNs) of αv-tie2 mice (21
). This probably reflects the existence of a separate population of FoxP3+
Tregs (innate or natural Tregs) that develop independently of TGF-β signaling (27
). However, it is also possible that aTregs are less dependent on DC-mediated TGF-β activation than Th17 cells due to greater sensitivity to TGF-β, as was proposed by Littman and colleagues (17
), or to alternative mechanisms of TGF-β activation.
Th17 cells are increasingly implicated as pathogenic effectors in inflammatory disorders in humans, including rheumatoid arthritis, psoriasis, and multiple sclerosis, and our data support such a role, as αv-tie2 mice lacking Th17 cells are protected in an auto-inflammatory disease model, EAE. Th17 cells have also been implicated in inflammatory bowel disease (28
), and high levels of IL-17A and other Th17-derived cytokines are found in inflamed mucosa of patients with either Crohn disease or ulcerative colitis (30
). Genome-wide association studies have also highlighted Th17-conditioning cytokine IL-23 and other genes in the Th17 pathway as potential contributors to inflammatory bowel disease (12
). However, αv-tie2 mice develop spontaneous colitis, as we described previously (21
), and our data therefore show that Th17 cells are not required for intestinal inflammation in mice. Furthermore, a number of recent studies in mouse models suggest that Th17 cells may actually be protective against colitis and act to maintain epithelial integrity during infection and immunity (7
). It is possible, therefore, that the loss of Th17 cells in αv-deficient mice contributes to the development of spontaneous colitis, which we had previously attributed principally to the loss of aTregs. In this regard, it is important to recognize that despite the lack of Th17 cells in αv-tie2 mice, other lymphocyte sources of IL-17 were largely unaffected by αv deletion, and IL-17A expression in the colon was not significantly changed. Hence, associations of inflammatory bowel disease with increased IL-17 do not necessarily implicate Th17 cells, and further studies with mice such as αv-tie2, which lack Th17 cells rather than Th17-derived cytokines, will be important to understand the function of this complex T cell subset in disease.
In this study, we have identified αv integrin as a new component of the mechanism by which DCs generate Th17 cells. Although we have not directly addressed the identity of the β subunit that is required for generation of Th17 cells, conditional deletion of β8 in DCs similarly is associated with colitis and loss of intestinal Tregs (23
), strongly implicating αvβ8 in activation of TGF-β and associated Th17 cell generation by DCs. Our data further suggest that pharmacological disruption of this DC/αvβ8/TGF-β dialogue is a potential therapeutic option in Th17-mediated diseases.