Dysregulated Treg repair responses lead to chronic rejection after heart transplantation

移植 医学 心脏移植 免疫学 移植物排斥 铅(地质) 生物 内科学 古生物学
作者
Jordan Warunek,Lu Fan,Xue Zhang,Sihua Wang,Steven M. Sanders,Tengfang Li,Lisa Mathews,Gaelen K. Dwyer,Michelle A. Wood,Stephanie Traczek,Andrew Lesniak,Kassandra Baron,H. Trent Spencer,Johnny Bou Saba,Emmanuel León Colón,Tracy Tabib,Robert Lafyatis,Mark A. Ross,Anthony J. Demetris,Simon C. Watkins
出处
期刊:Journal of Clinical Investigation [American Society for Clinical Investigation]
卷期号:134 (23) 被引量:2
标识
DOI:10.1172/jci173593
摘要

Chronic rejection (CR) after organ transplantation is alloimmune injury manifested by graft vascular remodeling and fibrosis that is resistant to immunosuppression. Single-cell RNA-Seq analysis of MHC class II-mismatched (MHCII-mismatched) heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating macrophages and Tregs. Using IL-33-deficient donor mice, we show that graft fibroblast-derived IL-33 potently induced amphiregulin (Areg) expression by recipient Tregs. The assessment of clinical samples also confirmed increased expression of Areg by intragraft Tregs also during rejection. Areg is an EGF secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessment of recipient mice with Treg-specific deletion of Areg surprisingly uncovered that Treg secretion of Areg contributed to CR. Specifically, heart transplants from recipients with Areg-deficient Tregs showed less fibrosis, vasculopathy, and vessel-associated fibrotic niches populated by recipient T cells. Mechanistically, we show that Treg-secreted Areg functioned to increase fibroblast proliferation. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Tregs contributed to the progression of CR.
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