TY - JOUR AU - D’Addio, Francesca AU - Vergani, Andrea AU - Potena, Luciano AU - Maestroni, Anna AU - Usuelli, Vera AU - Ben Nasr, Moufida AU - Bassi, Roberto AU - Tezza, Sara AU - Dellepiane, Sergio AU - El Essawy, Basset AU - Iascone, Maria AU - Iacovoni, Attilio AU - Borgese, Laura AU - Liu, Kaifeng AU - Visner, Gary AU - Dhe-Paganon, Sirano AU - Corradi, Domenico AU - Abdi, Reza AU - Starling, Randall C. AU - Folli, Franco AU - Zuccotti, Gian Vincenzo AU - Sayegh, Mohamed H. AU - Heeger, Peter S. AU - Chandraker, Anil AU - Grigioni, Francesco AU - Fiorina, Paolo T1 - P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes PY - 2018/08/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI94524 VL - 128 IS - 8 UR - https://doi.org/10.1172/JCI94524 SP - 3490 EP - 3503 PB - The American Society for Clinical Investigation ER -