BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease
Evelyn Ullrich, … , Markus F. Neurath, Kai Hildner
Evelyn Ullrich, … , Markus F. Neurath, Kai Hildner
Published March 1, 2018; First published January 29, 2018
Citation Information: J Clin Invest. 2018;128(3):916-930. https://doi.org/10.1172/JCI89242.
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Categories: 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 1

Intestinal GVHD is linked to BATF/Batf expression in humans and mice.

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Intestinal GVHD is linked to BATF/Batf expression in humans and mice. (A...
(A and B) Quantitative gene expression analyses of human BATF transcripts in colonic tissue biopsies derived from allo-HCT patients. Samples were categorized by (A) the histopathologic absence (–GVHD, n = 30 samples) or presence (+GVHD, n = 22 samples) of GVHD-associated lesions and by (B) the absence (–Apoptosis, n = 32 samples) or presence (+Apoptosis, n = 20 samples) of GVHD severity–related epithelial cell apoptosis. Data represent the mean ± SEM of normalized relative BATF expression levels calculated from a standard curve. (C) Murine Batf gene expression kinetics in colonic tissue from GVHD-induced mice (days 15 and 30) after transplantation of 5 × 106 allogeneic T cell–depleted CD45.1 B6.SJL WT BM on day 1 into total body–irradiated (8 Gy) BALB/c mice the day before, followed by adoptive transfer of 0.7 × 106 C57Bl/6 alloreactive WT donor CD3+ T cells (WT) or no T cells (noT) on day 2. Gene expression levels in colonic tissue represent the normalized relative fold-change in expression compared with day-15 colonic tissue expression in mice without donor T cell transfer (noT), with the expression level arbitrarily set at 1. Data represent the mean ± SEM and were derived from day-15 noT (n = 13) and WT (n = 14) and from day-30 noT (n = 15) and WT (n = 12) individual mice per group and are derived from at least 3 independent experiments. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by unpaired, 2-sided Student’s t test (A and B) and 1-way ANOVA with Bonferroni’s multiple comparisons post test (C).