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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts
  • Female
  • Graft Rejection / genetics
  • Graft Rejection / immunology*
  • Graft Rejection / pathology
  • Graft Rejection / therapy
  • Heart Transplantation*
  • Humans
  • Mutation*
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
  • Precision Medicine
  • Receptors, Purinergic P2X7 / genetics
  • Receptors, Purinergic P2X7 / immunology*
  • Th17 Cells / immunology*
  • Th17 Cells / pathology
  • Th2 Cells / immunology*
  • Th2 Cells / pathology


  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Receptors, Purinergic P2X7