@article{0f410309d2bd472d8cf937feecf291f5,
title = "P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes",
abstract = "Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of-function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation. Transient NLRP3 silencing in nonmutant T cells or overexpression in mutant T cells normalized the Th profile. Interestingly, IL-17 blockade reduced Th17 skewing of human T cells in vitro and abrogated the severe allograft vasculopathy and abnormal Th17 generation observed in preclinical models in which P2X7R was genetically deleted. This P2X7R intracellular region mutation thus impaired the modulatory effects of P2X7R on NLRP3 expression and function in T cells and led to NLRP3 dysregulation and Th17 skewing, delineating a high-risk group of cardiac-transplanted patients who may benefit from personalized therapy.",
author = "Francesca D'Addio and Andrea Vergani and Luciano Potena and Anna Maestroni and Vera Usuelli and {Ben Nasr}, Moufida and Roberto Bassi and Sara Tezza and Sergio Dellepiane and {El Essawy}, Basset and Maria Iascone and Attilio Iacovoni and Laura Borgese and Kaifeng Liu and Gary Visner and Sirano Dhe-Paganon and Domenico Corradi and Reza Abdi and Starling, {Randall C.} and Franco Folli and Zuccotti, {Gian Vincenzo} and Sayegh, {Mohamed H.} and Heeger, {Peter S.} and Anil Chandraker and Francesco Grigioni and Paolo Fiorina",
note = "Funding Information: FD is the recipient of a Societ{\`a} Italiana di Diabetologia (SID) Lombardia Grant and of the European Foundation for the Study of Diabetes (EFSD) Rising Star Fellowship Grant. PF is supported by the EFSD/Sanofi European Research Programme and by an American Heart Association Grant-in-Aid. PF and FD are supported by Italian Ministry of Health grant RF-2016-02362512. VU is supported by an FO.DI.RI SID fellowship. We thank the Fondazione Romeo e Enrica Invernizzi for the extraordinary support. We also thank Maddalena Ripamonti for technical assistance in fluorimeter analysis. The work was supported in part by NIH U01 grants AI63594 (to PH) and AI063623 (to AC). ClinicalTrials.gov Identifier: NCT02255123. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2018 American Society for Clinical Investigation. All rights reserved.",
year = "2018",
month = aug,
day = "1",
doi = "10.1172/JCI94524",
language = "English (US)",
volume = "128",
pages = "3490--3503",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "8",
}