P2X7 Receptor Activity Mediates Th17-Specific Self- and Alloreactivity in Non-Human Primates
Department of Surgery, University of Wisconsin, Madison, WI
Meeting: 2021 American Transplant Congress
Abstract number: 563
Keywords: Lymphocyte activation, Primates, Rejection, T cell activation
Topic: Basic Science » Lymphocyte Biology: Signaling, Co-Stimulation, Regulation
Session Name: Lymphocyte Biology: Signaling, Co-Stimulation, Regulation
Session Type: Poster Abstract
Session Date & Time: None. Available on demand.
*Purpose: The broadly expressed ATP-binding purinergic receptor, P2X7 (P2X7R) is involved in the Th17 mediated cellular immune response to allo- and select self-antigens (Collagen type V [ColV], vimentin, kα1-tubulin). Inhibition of the P2X7R abates these responses without loss of Th1 mediated reactivity to bacterial/viral challenge. Normal regulation of these Th17 mediated responses is controlled by Tregs positive for CD39, an enzyme required for hydrolysis of extracellular ATP. Together these results identify the P2X7R as a promising target for selective inhibition of allogenic responses while preserving Th1 function. Importantly, naturally occurring functional polymorphisms conferring high and low pore activity exist in humans, which must be considered in therapeutic implementation of P2X7R inhibition. Based on these findings in humans, we sought to evaluate the role of the P2X7R in allo- and self-antigen responses in rhesus macaques (RMs) and to characterize the baseline functional polymorphisms within this species.
*Methods: Flow cytometric analyses of YO-PRO-1 dye uptake and IL-17 production were utilized to determine pore activity and Th17 polarization, respectively. Trans-vivo delayed type hypersensitivity assays (tv-DTH) to evaluate immunologic response were performed using PBMC from RMs.
*Results: Treg suppression via TGF-β neutralization or CD39 ATPase inhibition uncovered marked inflammatory responses to Col V, kα1-tubulin, and vimentin. Treg depletion, in lieu of molecular neutralization, similarly unmasked reactivity to these antigens. Importantly, the uncovered inflammatory responses were fully abrogated when performed in the presence of the P2X7R inhibitor, AZD9056. Compared to the baseline P2X7R functional polymorphisms observed in humans, RMs demonstrated similar population-level frequencies of high and low P2X7R pore activity. Furthermore, we found that high pore activity was associated with increased Th17 polarization, via enhanced IL-17 production by CD4+ T-cells.
*Conclusions: As observed in humans, RM P2X7R activity is involved in uncovered, Th17 specific cellular immune responses. Importantly, by revealing functional polymorphisms consistent with human variations, we validated their rigor as a preclinical model for P2X7R-targeted therapies. Based on these findings, we hypothesize that low pore activity is associated with a tolerogenic state and that P2X7R inhibition could enhance tolerance induction protocols. Studies are ongoing within our renal transplant tolerance model evaluating P2X7R activity and T-cell polarization.
To cite this abstract in AMA style:Little C, Sullivan J, Burlingham W, Kaufman D. P2X7 Receptor Activity Mediates Th17-Specific Self- and Alloreactivity in Non-Human Primates [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/p2x7-receptor-activity-mediates-th17-specific-self-and-alloreactivity-in-non-human-primates/. Accessed March 25, 2023.
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