BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease
Evelyn Ullrich, Benjamin Abendroth, Johanna Rothamer, Carina Huber, Maike Büttner-Herold, Vera Buchele, Tina Vogler, Thomas Longerich, Sebastian Zundler, Simon Völkl, Andreas Beilhack, Stefan Rose-John, Stefan Wirtz, Georg F. Weber, Sakhila Ghimire, Marina Kreutz, Ernst Holler, Andreas Mackensen, Markus F. Neurath, Kai Hildner
Evelyn Ullrich, Benjamin Abendroth, Johanna Rothamer, Carina Huber, Maike Büttner-Herold, Vera Buchele, Tina Vogler, Thomas Longerich, Sebastian Zundler, Simon Völkl, Andreas Beilhack, Stefan Rose-John, Stefan Wirtz, Georg F. Weber, Sakhila Ghimire, Marina Kreutz, Ernst Holler, Andreas Mackensen, Markus F. Neurath, Kai Hildner
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Research Article Gastroenterology Immunology

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease

Abstract

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.

Authors

Evelyn Ullrich, Benjamin Abendroth, Johanna Rothamer, Carina Huber, Maike Büttner-Herold, Vera Buchele, Tina Vogler, Thomas Longerich, Sebastian Zundler, Simon Völkl, Andreas Beilhack, Stefan Rose-John, Stefan Wirtz, Georg F. Weber, Sakhila Ghimire, Marina Kreutz, Ernst Holler, Andreas Mackensen, Markus F. Neurath, Kai Hildner

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Figure 4

BATF-expressing T cells control intestinal but not hepatic GVHD in a miHA-mismatched model.

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BATF-expressing T cells control intestinal but not hepatic GVHD in a miH...
(A) Clinical GVHD score and survival rates following transfer of allogeneic WT (red squares) and Batf –/– (black triangles) CD3+ C57Bl/6 donor T cells into irradiated H-2b+ BALB.b mice after transplantation of T cell–depleted CD45.1+ B6.SJL WT BM. Results from 1 representative experiment are shown (n = 6 WT and n = 5 Batf–/– mice). (B) Representative endoscopic (upper row) and histologic cross-sectional (lower row) images showing GVHD-associated colitis activity during established GVHD on day 27. Scatter plots summarize the pooled results of colonoscopy and histology scores for WT (n = 4) and Batf–/– (n = 5) T cell–recipient mice. Scale bars: 100 μm. (C) Histopathologic evaluation of GVHD-associated liver lesions (scatter plot) assesses portal inflammation of the liver, and representative images of histopathologic cross-sections are shown. Scale bars: 50 μm. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001, by 2-sided, unpaired Student’s t test.