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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 3

BATF deficiency–related GVHD attenuation leads to reduced systemic and intestinal IL-6 expression.

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BATF deficiency–related GVHD attenuation leads to reduced systemic and i...
(A) Il6, Tnfa, and Il17a transcript levels in colonic tissues were determined by qPCR upon GVHD onset (day 15) and during (day 30) established GVHD–associated colitis following transfer of allogeneic WT (black bars) and Batf–/– (white bars) CD3+ C57Bl/6 donor T cells or no T cells (light gray bars). Gene expression levels were normalized to the expression levels that were detected on day 15 in the noT mice, with an arbitrarily determined expression level of 1. Error bars represent the mean ± SEM of pooled data from at least 3 independent experiments. Results represent Il6 expression (n = 13 noT, n = 12 WT, and n = 11 Batf–/– mice/time point); Tnfa expression (n = 8 noT, n = 10 WT, and n = 11 Batf–/– mice/time point); and Il17a expression (n = 4 noT, n = 10 WT, and n = 11 Batf–/– mice/time point). (B) IL-6, TNF-α, and IL-17A serum cytokine levels in the mice described in A were assessed by flow cytometry on days 7, 10, 15, and 30. Error bars represent the mean ± SEM. Results represent pooled data from 3 independent experiments for IL-6 measurements (n = 7 noT, n = 8 WT, and n = 12 Batf–/– individual mice/time point); TNF-α measurements (n = 3 noT, n = 4 WT, and n = 4 Batf–/– individual mice/time point); and IL-17A measurements (n = 6 noT, n = 6 WT, and n = 6 Batf–/– individual mice/time point). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Bonferroni’s and Dunn’s multiple comparisons post tests.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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