期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 3, 页码 916-930出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI89242
关键词
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资金
- Wilhelm Sander-Stiftung [2010.105.1]
- Max-Eder Research Program of the German Cancer Aid
- ELAN program of the University Erlangen-Nuremberg [09.08.19.1]
- Adolf Messer Foundation
- Interdisciplinary Center for Clinical Research Erlangen [A53]
- CELLEUROPE (FP7-People-ITN [315963]
- LOEWE Center for Cell and Gene Therapy, Frankfurt, Germany
- Hessian Ministry of Higher Education, Research and the Arts [III L4-518/17.004]
- Collaborative Research Center 1181 (DFG-CRC 1181, project B05) at the University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg
- Collaborative Research Center 221 (CRC/TR221-DFG, project B03)
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 coloninfiltrating, 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.
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