BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease
BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease
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DOI：
10.1172/jci89242
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发表时间：
2018-01
影响因子：
15.9
通讯作者：
E. Ullrich;Benjamin Abendroth;Johanna Rothamer;Carina Huber;M. Büttner-Herold;Vera Buchele;Tina Vogler;T. Longerich;S. Zundler;S. Völkl;A. Beilhack;S. Rose-John;S. Wirtz;G. Weber;Sakhila Ghimire;M. Kreutz;E. Holler;A. Mackensen;M. Neurath;K. Hildner
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文献类型：
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作者：
E. Ullrich;Benjamin Abendroth;Johanna Rothamer;Carina Huber;M. Büttner-Herold;Vera Buchele;Tina Vogler;T. Longerich;S. Zundler;S. Völkl;A. Beilhack;S. Rose-John;S. Wirtz;G. Weber;Sakhila Ghimire;M. Kreutz;E. Holler;A. Mackensen;M. Neurath;K. Hildner
急性移植物抗宿主病（GVHD）是异基因造血细胞移植（allo-HCT）后严重的T细胞驱动的炎症并发症。GVHD通常影响肠道，并与预后不良有关。虽然经常检测，肠组织浸润Th细胞亚群发挥的促炎机制仍有待充分阐明。在这里，我们表明，Th 17定义的转录因子碱性亮氨酸拉链转录因子ATF样（BATF）在人类和小鼠肠道GVHD组织中受到强烈调控。在完全MHC错配和轻微组织相容性错配（miHA错配）GVHD模型中的研究显示，表达BATF的T细胞在肠道GVHD表现中是功能上不可或缺的。在机制上，BATF控制结肠浸润性、IL-7受体阳性（IL-7 R+）、粒细胞-巨噬细胞集落刺激因子阳性（GM-CSF+）、供体T效应记忆（Tem）细胞的形成。该T细胞亚群足以促进肠道GVHD，而其发生在很大程度上依赖于T细胞内在BATF表达，需要IL-7-IL-7 R相互作用，并被GM-CSF增强。因此，本研究确定BATF依赖性致病性GM-CSF+效应T细胞作为GVHD中肠道炎症的关键启动子，因此puplasty提供了对先前假定为选择性Th 17驱动的炎症过程的机制见解。
Acute graft-versus-host disease (GVHD) represents a severe, T cell–driven inflammatory complication following allogeneic hematopoietic cell transplantation (allo-HCT). GVHD often affects the intestine and is associated with a poor prognosis. Although frequently detectable, proinflammatory mechanisms exerted by intestinal tissue–infiltrating Th cell subsets remain to be fully elucidated. Here, we show that the Th17-defining transcription factor basic leucine zipper transcription factor ATF-like (BATF) was strongly regulated across human and mouse intestinal GVHD tissues. Studies in complete MHC-mismatched and minor histocompatibility–mismatched (miHA-mismatched) GVHD models revealed that BATF-expressing T cells were functionally indispensable for intestinal GVHD manifestation. Mechanistically, BATF controlled the formation of colon-infiltrating, IL-7 receptor–positive (IL-7R+), granulocyte-macrophage colony-stimulating factor–positive (GM-CSF+), donor T effector memory (Tem) cells. This T cell subset was sufficient to promote intestinal GVHD, while its occurrence was largely dependent on T cell–intrinsic BATF expression, required IL-7–IL-7R interaction, and was enhanced by GM-CSF. Thus, this study identifies BATF-dependent pathogenic GM-CSF+ effector T cells as critical promoters of intestinal inflammation in GVHD and hence putatively provides mechanistic insight into inflammatory processes previously assumed to be selectively Th17 driven.