LAUSR

The zinc finger protein ZFYVE21 is involved in immune signaling. Using humanized mouse models, primary human cells, and patient samples, we identified a T cell–autonomous role for ZFYVE21 in promoting chronic vascular inflammation associated with allograft vasculopathy. Ischemia-reperfusion injury (IRI) stimulated endothelial cells to produce Hedgehog (Hh) ligands, which in turn induced the production of ZFYVE21 in a population of T memory cells with high amounts of the Hh receptor PTCH1 (PTCHhi cells, CD3+CD4+CD45RO+PTCH1hiPD-1hi), vigorous recruitment to injured endothelia, and increased effector responses in vivo. After priming by interferon-γ (IFN-γ), Hh-induced ZFYVE21 activated NLRP3 inflammasome activity in T cells, which potentiated IFN-γ responses. Hh-induced NLRP3 inflammasomes and T cell–specific ZFYVE21 augmented the vascular sequelae of chronic inflammation in mice engrafted with human endothelial cells or coronary arteries that had been subjected to IRI before engraftment. Moreover, the population of PTCHhi T cells producing high amounts of ZFYVE21 was expanded in patients with renal transplant–associated IRI, and sera from these patients expanded this population in control T cells in a manner that depended on Hh signaling. We conclude that Hh-induced ZFYVE21 activates NLRP3 inflammasomes in T cells, thereby promoting chronic inflammation. Description Endothelial SHH promotes T cell–mediated inflammation in allograft vasculopathy. Hedgehog stokes vascular inflammation Many patients who receive organ transplants develop allograft vasculopathy, a form of chronic vascular inflammation that is associated with ischemia-reperfusion injury (IRI) and may lead to organ failure. Because Hedgehog (Hh) ligands promote endothelial homeostasis and repair and can influence the effector functions of T cells, Jiang et al. explored the potential connection between Hh signaling and T cell–driven vascular inflammation. Using patient samples, primary human cells, and mice engrafted with human endothelial cells or arteries, the authors found that IRI induced endothelial cells to produce Sonic hedgehog (SHH), which stimulated a subset of memory T cells to produce the inflammasome-activating zinc finger protein ZFYVE21. The activation of NLRP3 inflammasomes in T cells enhanced their production of proinflammatory cytokines in response to endothelial-derived antigens, leading to immune cell infiltration and pathological changes in the endothelium. These findings shed light on the mechanisms that contribute to allograft vasculopathy. —AMV