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J Clin Invest. 2018 Aug 1;128(8):3490-3503. doi: 10.1172/JCI94524. Epub 2018 Jul 16.

P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes.

Author information

1
International Center for Type 1 Diabetes, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, "L. Sacco" Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
2
Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3
Heart Failure and Heart Transplant Program, Department of Experimental Diagnostic and Specialty Medicine, Alma Mater-University of Bologna, Bologna, Italy.
4
Medicine, Al-Azhar University, Cairo, Egypt.
5
Transplantation Research Center, Nephrology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
6
Laboratorio Genetica Medica and.
7
Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Bergamo, Italy.
8
Division of Respiratory Diseases, Boston Children's Hospital, Boston, Massachusetts, USA.
9
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
10
Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma, Italy.
11
Heart Failure Center, Heart & Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA.
12
Endocrinology and Metabolism, Department of Health Science, University of Milan, ASST Santi Paolo e Carlo, Milan, Italy.
13
Department of Pediatrics, Children's Hospital Buzzi, Milan, Italy.
14
American University of Beirut, Beirut, Lebanon.
15
Department of Medicine and Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
16
Endocrinology Division, ASST Fatebenefratelli Sacco, Milan, Italy.

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.

KEYWORDS:

Genetic variation; Immunology; Organ transplantation; T cells; Transplantation

PMID:
30010623
PMCID:
PMC6063506
DOI:
10.1172/JCI94524
[Indexed for MEDLINE]
Free PMC Article

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