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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 7

GM-CSF aggravates intestinal GVHD.

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GM-CSF aggravates intestinal GVHD.
(A and B) Assessment of systemic (cli...
(A and B) Assessment of systemic (clinical score, A) and intestinal (endoscopic score, B) GVHD of allo-BMT BALB/c mice that received Batf–/– donor CD3+ T cells (red line and triangles) on day 2 (C57Bl/6 in BALB/c). Batf–/– T cell–treated mice received either daily i.p. injections (150 ng/injection) of recombinant GM-CSF (rGM-CSF) or vehicle only (red triangles and blue squares, respectively). As controls, noT mice (BMT only) received GM-CSF (gray line). Data from 2 independent experiments (n = 6 noT + rGM-CSF, n = 16 Batf–/– + rGM-CSF, and n = 11 Batf–/– + vehicle-only mice) are shown. (C–E) Systemic GVHD (clinical score, C), survival rates (D), and intestinal GVHD (endoscopic score, E) were assessed on day 28 in allo-BMT BALB/c mice treated with C57Bl/6 WT (red line and squares), Csf2–/– (blue line and triangles), or no (noT, gray line) CD3+ donor T cells. Data from 2 independent experiments were pooled (n = 10 noT, n = 9 WT, and n = 13 Csf2–/– mice). (F) Il6 gene expression levels were determined by qPCR analysis of colonic tissues 28 days after GVHD induction (C57Bl/6 in BALB/c), as described in C. Gene expression levels represent the normalized, relative fold-change of expression detected in noT mice (the expression level was arbitrarily set at 1). Bar graphs represent pooled data from 2 independent experiments (n = 9 noT; n = 8 WT, and n = 12 Csf2–/– mice. (G) IL-6–expressing, donor-derived CD45.2+CD3+CD4+ LP T cell frequencies were determined by flow cytometry 28 days after GVHD induction, as described in F. Bar graphs indicate the mean ± SEM and represent pooled data from 2 independent experiments (n = 8 WT and n = 4 Csf2–/– mice). Representative contour plots show intracellular IL-6 levels in CD45.2+CD3+CD4+ cLP T cells. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-sided, unpaired Student’s t test (A–E and G) and 1-way ANOVA test with Dunn’s multiple comparisons post test (F).

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