Differential requirement for P2X7R function in IL-17 dependent vs. IL-17 independent cellular immune responses

J. A. Sullivan, E. Jankowska-Gan, L. Shi, D. Roenneburg, S. Hegde, D. S. Greenspan, D. S. Wilkes, L. C. Denlinger, W. J. Burlingham

Research output: Contribution to journalArticle

12 Scopus citations

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 CXCR3negCCR4 +/6+ CD4+ [Th17] versus CXCR3 +CCR4/6neg 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. The authors report that IL-17 dependent cellular immune responses require P2X7R function whereas Th1 responses to viral or bacterial antigens do not.

Original languageEnglish (US)
Pages (from-to)1512-1522
Number of pages11
JournalAmerican Journal of Transplantation
Volume14
Issue number7
DOIs
StatePublished - Jul 2014

Keywords

  • Chronic rejection
  • Col V
  • IL-1β
  • P2X7R
  • Th17

ASJC Scopus subject areas

  • Transplantation
  • Immunology and Allergy
  • Pharmacology (medical)

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    Sullivan, J. A., Jankowska-Gan, E., Shi, L., Roenneburg, D., Hegde, S., Greenspan, D. S., Wilkes, D. S., Denlinger, L. C., & Burlingham, W. J. (2014). Differential requirement for P2X7R function in IL-17 dependent vs. IL-17 independent cellular immune responses. American Journal of Transplantation, 14(7), 1512-1522. https://doi.org/10.1111/ajt.12741