Sullivan, J. A.Jankowska-Gan, E.Shi, L.Roenneburg, D.Hegde, S.Greenspan, D. S.Wilkes, D. S.Denlinger, L. C.Burlingham, W. J.2016-04-082016-04-082014-07Sullivan, J., Jankowska-Gan, E., Shi, L., Roenneburg, D., Hegde, S., Greenspan, D., … Burlingham, W. (2014). Differential Requirement for P2X7R Function in IL-17 Dependent vs IL-17 Independent Cellular Immune Responses. American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 14(7), 1512–1522. http://doi.org/10.1111/ajt.127411600-6143https://hdl.handle.net/1805/9231IL17-dependent autoimmunity to collagen type V (Col V) has been associated with lung transplant obliterative bronchiolitis. Unlike the T helper 1 (Th1)-dependent immune responses to Tetanus Toxoid (TT), the Th17 response to Col V in lung transplant patients and its Th1/17 variant observed in coronary artery disease patients requires IL-1β, tumor necrosis factor α and CD14(+) cells. Given the involvement of the P2X7 receptor (P2X7R) in monocyte IL-1β responses, we investigated its role in Th17-, Th1/17- and Th1-mediated proinflammatory responses. Transfer of antigen-pulsed peripheral blood mononucleated cells (PBMCs) from Col V-reactive patients into SCID mouse footpads along with P2X7R antagonists revealed a selective inhibition of Col V-, but not TT-specific swelling responses. P2X7R inhibitors blocked IL-1β induction from monocytes, including both Col V-α1 peptide-induced (T-dependent), as well as native Col V-induced (T-independent) responses. Significantly higher P2X7R expression was found on CXCR3(neg) CCR4(+)/6(+) CD4(+) [Th17] versus CXCR3(+)CCR4/6(neg) CD4(+) [Th1] subsets in PBMCs, suggesting that the paradigm of selective dependence on P2X7R might extend beyond Col V autoimmunity. Indeed, P2X7R inhibitors suppressed not only anti-Col V, but also Th1/17-mediated alloimmunity, in a heart transplant patient without affecting anti-viral Epstein-Barr virus responses. These results suggest that agents targeting the P2X7R might effectively treat Th17-related transplant pathologies, while maintaining Th1-immunity to infection.en-USPublisher PolicyHeart TransplantationImmunity, CellularimmunologyInterleukin-17Lung TransplantationMonocytesReceptors, Purinergic P2X7metabolismTh1 CellsArticle