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

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 8

BATF controls the formation of IL-7RhiGM-CSF+ T cells.

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BATF controls the formation of IL-7RhiGM-CSF+ T cells. (A) GM-CSF+CD4+ T...
(A) GM-CSF+CD4+ T cell frequencies by intracellular flow cytometry on day 5 of in vitro culture under IFN-γ–neutralizing conditions, with or without IL-7. Bar graph represents pooled data from 4 independent experiments and indicates the mean ± SEM. Without IL-7 (–), n = 10 WT and n = 7 Batf–/– mice; with IL-7 (+), n = 16 WT and n = 12 Batf–/– mice. (B) GM-CSF–expressing, donor-derived CD45.2+CD3+CD4+ cLP T cell frequencies ex vivo in GVHD-prone mice after WT and Batf–/– CD3+ donor T cell transfer (C57Bl/6 into BALB/c). Bar graph indicates the mean ± SEM of 4 individual mice per group from 1 experiment. (C and D) Flow cytometric contour plots display IL-7R and GM-CSF levels of (C) MLN (day 15), cLP (days 15 and 28), and (D) cLP (day 27) donor-derived CD4+ T cells after GVHD induction by C57Bl/6 WT (red) and Batf–/– (black) CD3+ T cell transfer into (C) BALB/c and (D) BALB.b mice, respectively. Histograms show the IL-7R expression status of GM-CSF+CD45.2+CD4+ T cells compared with IL-7R isotype control staining (gray-shaded area). Mean values ± SEM represent frequencies (top) and absolute numbers of IL-7RhiGM-CSF+ cells within CD45.2+CD4+ donor T cells found in the MLN (C) and cLP (C, days 15 and 28; D, day 27). Results for WT mice (C, MLN and cLP, day 15: n = 7; cLP, day 28: n = 7; D, n = 4) and Batf–/– mice (C, MLN and cLP, day 15: n = 7; cLP, day 28: n = 4; D, n = 5) from 1 of 2 experiments are shown. (E) Relative frequencies and absolute numbers of CD45.2+CD3+CD4+IL-7RhiCD44+CD62L– cLP T cells (Tem cells) of the indicated genotypes 28 days after GVHD induction (C57Bl/6 into BALB/c), as described in B, were assessed by flow cytometry. Bar graphs indicate the mean ± SEM (n = 7 WT mice and n = 4 Batf–/– mice). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Bonferroni’s multiple comparisons post test (A and B) and unpaired Student’s t test (C–E).