title: Differential requirement for P2X7R function in IL-17 dependent vs. IL-17 independent cellular immune responses.
abstract: IL17-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.
authors.affiliation: Department of Surgery, University of Wisconsin, Madison, WI.
authors.forename: J A
authors.initials: JA
authors.lastname: Sullivan
authors.forename: E
authors.initials: E
authors.lastname: Jankowska-Gan
authors.forename: L
authors.initials: L
authors.lastname: Shi
authors.forename: D
authors.initials: D
authors.lastname: Roenneburg
authors.forename: S
authors.initials: S
authors.lastname: Hegde
authors.forename: D S
authors.initials: DS
authors.lastname: Greenspan
authors.forename: D S
authors.initials: DS
authors.lastname: Wilkes
authors.forename: L C
authors.initials: LC
authors.lastname: Denlinger
authors.forename: W J
authors.initials: WJ
authors.lastname: Burlingham
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015551:Autoimmunity / Q000276:immunology; D024062:Collagen Type V / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation; D006801:Humans; D006968:Hypersensitivity, Delayed; D007111:Immunity, Cellular / Q000276:immunology*; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D016040:Lung Transplantation; D051379:Mice; D016513:Mice, SCID; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D058486:Receptors, Purinergic P2X7 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D013498:Suramin / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D024062:Collagen Type V; D020381:Interleukin-17; D058486:Receptors, Purinergic P2X7; D013498:Suramin; D007371:Interferon-gamma
keywords: Chronic rejection; Col V; IL-1β; P2X7R; Th17