Zfyve21 Activates T Cell Intrinsic, Nlrp3 Inflammasomes to Promote Allograft Vasculopathy
1Dept of Cardiovascular Medicine, Yale University, New Haven, CT, 2Dept of Cardiothoracic Surgery, Yale University, New Haven, CT, 3Yale University, New Haven, CT
Meeting: 2022 American Transplant Congress
Abstract number: 918
Keywords: Arteriosclerosis, Endothelial activation, T cells
Topic: Basic Science » Basic Science » 07 - Vascular, Lymphatic, Stromal and Parenchymal Cell Biology
Session Information
Session Name: Vascular, Lymphatic, Stromal and Parenchymal Cell Biology
Session Type: Poster Abstract
Date: Sunday, June 5, 2022
Session Time: 7:00pm-8:00pm
Presentation Time: 7:00pm-8:00pm
Location: Hynes Halls C & D
*Purpose: Allograft vasculopathy (AV) is a complication of chronic allograft rejection whose underlying mechanism(s) of etiopathogenesis are poorly defined. We examined the role of ZFYVE21, a Rab5 effector we recently identified, in the development of AV.
*Methods: Using a humanized mouse model and patient biospecimens, we employed genetic and pharmacologic approaches to examine the role of ZFYVE21 expression in T cells with regards to the formation of AV.
*Results: ZFYVE21 dysregulates a canonical wound repair pathway, Hedgehog (Hh) signaling, to promote the development of AV in human coronary arteries. Hh ligands released by endothelial cells (ECs) during ischemia reperfusion injury (IRI) generate an “Hh-responsive” subset (CD4+CD45RO+Ptch1hiPD1hi) highly expressing ZFYVE21 and displaying heightened effector and migratory responses. In Hh-responsive T cells, ZFYVE21 modulates T cell intrinsic inflammasome activity in an Akt-dependent manner to mediate IL-18-dependent potentiation of type 1 responses. This process furthers EC injury, propagating release of Hh ligands. Hh-responsive T cells, noncanonical Hh signaling, Hh-induced NLRP3 inflammasomes, and ZFYVE21 expression promote AV-like changes in a humanized mouse model. Hh-responsive T cells expressing ZFYVE21 and showing inflammasome activity are expanded in patients with IRI.
*Conclusions: Hh-induced ZFYVE21 assembles T cell intrinsic, NLRP3 inflammasomes to promote the development of allograft vasculopathy.
To cite this abstract in AMA style:
Antoine D, Jiang B, Jiang Q, Li X, Guiyu S, Fan M, Tellides G, Geirsson A, Jane-wit D. Zfyve21 Activates T Cell Intrinsic, Nlrp3 Inflammasomes to Promote Allograft Vasculopathy [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/zfyve21-activates-t-cell-intrinsic-nlrp3-inflammasomes-to-promote-allograft-vasculopathy/. Accessed November 23, 2024.« Back to 2022 American Transplant Congress