期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 8, 页码 3490-3503出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI94524
关键词
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资金
- Societa Italiana di Diabetologia (SID) Lombardia Grant
- European Foundation for the Study of Diabetes (EFSD) Rising Star Fellowship Grant
- EFSD/Sanofi European Research Programme
- American Heart Association
- Italian Ministry of Health grant [RF-2016-02362512]
- FO.DI.RI SID fellowship
- NIH U01 grants [AI63594, AI063623]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [K24AI116925, U01AI063623, U01AI063594] Funding Source: NIH RePORTER
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.
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