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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 January 29, 2018
Citation Information: J Clin Invest. 2018;128(3):916-930. https://doi.org/10.1172/JCI89242.
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Research Article Gastroenterology Immunology Article has an altmetric score of 78

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

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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 6

Donor T cells express IL-6 and GM-CSF in a BATF-dependent manner.

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Donor T cells express IL-6 and GM-CSF in a BATF-dependent manner.
(A) Il...
(A) Il6, Csf2, Ifng, Tnfa, and Il17a gene expression in FACS-purified, donor-derived LP WT (black) and Batf–/– (white) CD4+ T cells from GVHD-prone mice (C57Bl/6 into BALB/c) were quantified on day 15. Expression represents normalized, relative fold-change expression compared with WT T cells (set at 1). Error bars represent the mean ± SEM of 3 samples per group from 2 independent experiments, with 6 mice per genotype. (B–E) Assessment of the pool of (B) GM-CSF–, IFN-γ–, and TNF-α–expressing H2d–CD45.2+CD4+ donor MLN T cells (day 15); (C) IFN-γ– and TNF-α–expressing, donor-derived CD45.2+CD3+CD4+ cLP T cells (day 15); and (D) IL-6– and (E) GM-CSF–expressing CD45.2+CD3+CD4+ cLP T cells (days 15 and 30) from the GVHD-prone mice described in A. Bar graphs show the mean ± SEM of 6 mice per genotype (B); (C) IFN-γ (n = 10 WT and n = 11 Batf–/– mice) and TNF-α (n = 8 WT and n = 11 Batf–/– mice); (D) day 15 (n = 8 WT and n = 10 Batf–/– mice) and day 30 (n = 8 WT and n = 8 Batf–/– mice); (E) day 15 (n = 16 WT and n = 17 Batf–/– mice) and day 30 (n = 21 WT and n = 22 Batf–/– mice) from 3 independent experiments (C–E). (F) GM-CSF+ and IFN-γ+ H2d–CD45.2+CD4+ and CD8+ cLP donor T cells, respectively, from GVHD-prone mice were assessed by flow cytometry (day 15). Bar graphs show the mean ± SEM of 6 mice per genotype. (G) Rag1–/– BMT BALB/c mice received CD45.1+ WT and CD45.2+ Batf–/– donor C57Bl/6 T cells in a 1:1 mixture (day 2), and GM-CSF+ H2d–CD45.1+ WT and CD45.2+ Batf–/– CD4+ T cell frequencies were determined (day 15). Representative contour plots and bar graph show the mean ± SEM (n = 7 mice). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-sided, unpaired Student’s t test (A–E) and 1-way ANOVA with Bonferroni’s multiple comparisons post test (F).

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