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 2

Acute GVHD is critically dependent on BATF-expressing donor T cells.

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Acute GVHD is critically dependent on BATF-expressing donor T cells. (A ...
(A and B) Clinical GVHD score (A) and survival (B) following transfer of allogeneic WT (red squares) and Batf–/– (black triangles) CD3+ C57Bl/6 donor T cells or no T cells (gray circles) into irradiated BALB/c mice after transplantation of T cell–depleted CD45.1 B6.SJL WT BM. Results from 1 representative experiment (n = 5 mice/group) of at least 4 independent experiments are shown. (C and D) Endoscopic (C) and histologic (D) assessment of GVHD-associated colitis activity at the onset of GVHD on day 15 (C, upper row) and when GVHD was fully established on day 30 (C, lower row). Representative images are shown, and scatter plots summarize the pooled results of colonoscopy scores derived from 3 independent experiments for day 15 (n = 12 noT mice; n = 11 WT mice; n = 12 Batf–/– mice) and from 2 independent experiments for day 30 (n = 14 noT mice; n = 11 WT mice; n = 17 Batf–/– mice). (D) In analogy, representative histopathologic cross-sections of the colon of each individual group 30 days after GVHD induction (C57Bl/6 in BALB/c) are shown, while scatter plots show the pooled histology scores from 3 independent experiments with noT (n = 10), WT (n = 12), and Batf–/– (n = 10) mice. Scale bars: 100 μm. (E) Detection and quantification of MPO+ cells in colonic tissue sections from the GVHD-prone BALB/c mice described in A. Scale bars: 50 μm. Scatter plots show the mean ± SEM of MPO+ cells/HPF representing pooled data for 7 to 8 mice per group from 3 independent experiments. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-sided, unpaired Student’s t test (A) and 1-way ANOVA with Bonferroni’s multiple comparisons post test (B–E).