BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease
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
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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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 10

IL-7RhiGM-CSF+ colonic T cells are sufficient to reestablish intestinal GVHD.

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IL-7RhiGM-CSF+ colonic T cells are sufficient to reestablish intestinal ...
(A–E) Effects of antibody-mediated IL-7R blockade on GVHD manifestations were dependent on T cell–intrinsic GM-CSF. C57Bl/6 WT (red squares) or Csf2–/– (blue diamonds) donor CD3+ T cells were transplanted into allo-BMT BALB/c mice and treated with anti–IL-7R 3 times per week until day 15. GVHD scores (A), colonoscopy scores on day 28 (B), histology scores, and representative colon cross-sections (C) of GVHD colitis are shown. (D and E) Total donor CD45.2+CD3+CD4+ T cells (D) and absolute numbers of IFN-γ+CD45.2+CD3+CD4+ donor cLP T cells in the GVHD-prone mice described in A were assessed by intracellular flow cytometry. In A and B, pooled data are from 2 independent experiments (n = 13 WT + anti–IL-7R and n = 14 anti–IL-7R + Csf2–/– mice). In C, data are from 1 experiment (n = 5 WT + anti–IL-7R and n = 8 anti–IL-7R + Csf2–/– mice). In D and E, data are from 1 experiment (n = 8 WT + anti–IL-7R and n = 5 Csf2–/– + anti–IL-7R mice). (F–I) Allo-BMT (CD45.2+ Rag1–/– BM) BALB/c mice received allogeneic CD45.2+CD3+C57BL6 Batf–/– T cells. (F) Ten days later, as a second transfer, mice received i.v. either 2 × 105 alloreactive B6.SJL CD45.1+CD3+IL-7Rhi cLP T cells (red squares; n = 6) that were sort purified from mice with established intestinal GVHD 28 days after GVHD induction or that were treated with PBS (vehicle) only (blue diamonds, n = 5). Clinical GVHD scores (F), colonoscopy scores (G), histology scores, and representative colon cross-sections (H) of GVHD colitis on day 47, i.e., 35 days after the second transfer. (I) Absolute numbers of CD45.1+CD4+GM-CSF+ WT (red) and CD45.2+CD4+GM-CSF+Batf–/– (blue) cLP T cells. The left bar (blue only) depicts GM-CSF+CD4+ T cells from vehicle-only–treated mice, while the right bar (blue and red) displays the absolute pool of GM-CSF+ cLP donor CD4+ T cells present in mice that received both CD45.1+IL-7Rhi cLP WT (red) and Batf–/– donor T cells (blue). Scale bars: 100 μm. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-sided, unpaired Student’s t test. P values in G and H were also determined by 2-sided, unpaired Student’s t test.