Human β-defensin 2 ameliorates acute GVHD by limiting ileal neutrophil infiltration and restraining T cell receptor signaling

Research output: Contribution to journalJournal articleResearchpeer-review

  • Tamina Rückert
  • Geoffroy Andrieux
  • Melanie Boerries
  • Kathrin Hanke-Müller
  • Nadine M. Woessner
  • Stephanie Doetsch
  • Christoph Schell
  • Konrad Aumann
  • Julia Kolter
  • Annette Schmitt-Graeff
  • Marcel Schiff
  • Lukas M. Braun
  • Eileen Haring
  • Sandra Kissel
  • Benjamin A. Siranosian
  • Ami S. Bhatt
  • Peter Nordkild
  • Jan Wehkamp
  • Susana Minguet
  • Justus Duyster
  • Robert Zeiser
  • Natalie Köhler

Acute graft-versus-host disease (aGVHD), which is driven by allogeneic T cells, has a high mortality rate and limited treatment options. Human β-defensin 2 (hBD-2) is an endogenous epithelial cell-derived host-defense peptide. In addition to its antimicrobial effects, hBD-2 has immunomodulatory functions thought to be mediated by CCR2 and CCR6 in myeloid cells. In this study, we analyzed the effect of recombinant hBD-2 on aGVHD development. We found that intestinal β-defensin expression was inadequately induced in response to inflammation in two independent cohorts of patients with aGVHD and in a murine aGVHD model. Treatment of mice with hBD-2 reduced GVHD severity and mortality and modulated the intestinal microbiota composition, resulting in reduced neutrophil infiltration in the ileum. Furthermore, hBD-2 treatment decreased proliferation and proinflammatory cytokine production by allogeneic T cells in vivo while preserving the beneficial graft-versus-leukemia effect. Using transcriptome and kinome profiling, we found that hBD-2 directly dampened primary murine and human allogeneic T cell proliferation, activation, and metabolism in a CCR2- and CCR6-independent manner by reducing proximal T cell receptor signaling. Furthermore, hBD-2 treatment diminished alloreactive T cell infiltration and the expression of genes involved in T cell receptor signaling in the ilea of mice with aGVHD. Together, we found that both human and murine aGVHD were characterized by a lack of intestinal β-defensin induction and that recombinant hBD-2 represents a potential therapeutic strategy to counterbalance endogenous hBD-2 deficiency.

Original languageEnglish
Article numbereabp9675
JournalScience Translational Medicine
Issue number676
Number of pages16
Publication statusPublished - 2022

ID: 332603936