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 5

BATF is dispensable for early, but not late, donor T cell expansion.

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BATF is dispensable for early, but not late, donor T cell expansion. (A ...
(A and B) Donor T cell expansion was assessed by in vivo BLI in GVHD-prone mice (C57Bl/6 in BALB/c) after adoptive transfer of luciferase-expressing WT and Batf–/– CD3+ T cells. (A) Representative images show 3 mice of 6 independently analyzed mice/group. (B) Mean values ± SEM of emitted photons detected (n = 6 mice/group). (C) WT (red squares) and Batf–/– (black triangles) CD3+C57Bl/6 T cells were transferred into CD45.1+ allo-BMT BALB/c mice. On day 12, α4β7+ and CCR9+ expression of MLN-resident H-2d–CD45.1–CD3+CD4+ donor T cells was assessed by flow cytometry. Scatter plots represent the mean ± SEM of the indicated subsets derived from 2 experiments (n = 8 WT and n = 7 Batf–/– mice). (D and E) Absolute CD45.2+CD3+CD4+ donor T cell numbers (C57Bl/6 in BALB/c) within MLN (day 15) and cLP (day 15 and day 30) were calculated by flow cytometry. Error bars represent the mean ± SEM of pooled data. (D) n = 6 mice/genotype and (E) n = 19 WT mice and n = 20 Batf–/– mice (day 15); n = 28 WT mice and n = 21 Batf–/– mice (day 30). (F) Allo-HCT (Rag1–/– BM) BALB/c mice received a 1:1 mixture of CFSE+ WT and CTY+ Batf–/– CD4+ T cells. One hour later, donor T cell tissue homing and migration were assessed by in vivo confocal microscopy (2 representative images are shown; Hoechst-stained nuclei are shown in blue, dextran-AF647–stained vasculature in white, CFSE-stained WT T cells in green, and CTY-stained Batf–/– T cells in orange, with the latter 2 indicated by colored arrows). Bar graph indicates donor T cell frequencies (n = 5 ROI/mouse; n = 6 mice/genotype). *P < 0.05, **P < 0.01, and ****P < 0.0001, by 2-sided, unpaired Student’s t test (B–D and F) and 1-way ANOVA with Bonferroni’s multiple comparisons post test (E).