Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset

Jan Hülsdünker, Katja J. Ottmüller, Hannes P. Neeff, Motoko Koyama, Zhan Gao, Oliver S. Thomas, Marie Follo, Ali Al-Ahmad, Gabriele Prinz, Sandra Duquesne, Heide Dierbach, Susanne Kirschnek, Tim Lämmermann, Martin J. Blaser, Brian T. Fife, Bruce R. Blazar, Andreas Beilhack, Geoffrey R. Hill, Georg Häcker and Robert Zeiser

Key points

  • Neutrophils migrate to the ileum after conditioning and contribute to GVHD.

  • JAK1/2 inhibition reduces neutrophil influx and MHC-II expression in the mesenteric lymph node.


Conditioning-induced damage of the intestinal tract plays a critical role during the onset of acute graft-versus-host disease (GVHD). Therapeutic interference with these early events of GVHD is difficult, and currently used immunosuppressive drugs mainly target donor T-cells. However not donor T-cells but neutrophils reach the sites of tissue injury first and therefore could be a potential target for GVHD-prevention. A detailed analysis of neutrophil fate during acute GVHD and impact on T-cells is difficult due to the short life-span of this cell type. By using a novel photoconverter reporter system we show that neutrophils that had been photoconverted in the ileum post-conditioning later migrated to mesenteric lymph nodes (mLN). This neutrophil migration was dependent on the intestinal microflora. In the mLN neutrophils colocalized with T-cells and presented antigen on MHC-II, thereby impacting T-cell expansion. Pharmacological JAK1/2 inhibition reduced neutrophil influx into the mLN and MHC-II expression thereby interfering with an early event in acute GVHD pathogenesis. In agreement with this finding, neutrophil-depletion reduced aGVHD. We conclude that neutrophils are attracted to the ileum, where the intestinal barrier is disrupted, and then migrate to the mLN where they participate in alloantigen-presentation. JAK1/2-inhibition can interfere with this process, which provides a potential therapeutic strategy to prevent early events of tissue damage-related innate immune cell activation and ultimately GVHD.

  • Submitted October 24, 2017.
  • Accepted February 9, 2018.