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Differential Requirement for P2X7R Function in IL‐17 Dependent vs. IL‐17 Independent Cellular Immune Responses
Author(s) -
Sullivan J. A.,
JankowskaGan E.,
Shi L.,
Roenneburg D.,
Hegde S.,
Greenspan D. S.,
Wilkes D. S.,
Denlinger L. C.,
Burlingham W. J.
Publication year - 2014
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.12741
Subject(s) - alloimmunity , immunology , autoimmunity , medicine , immune system , proinflammatory cytokine , inflammation
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.