Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset
Hülsdünker J, Ottmüller KJ, Neeff HP, Koyama M, Gao Z, Thomas OS, Follo M, Al-Ahmad A, Prinz G, Duquesne S, Dierbach H, Kirschnek S, Lämmermann T, Blaser MJ, Fife BT, Blazar BR, Beilhack A, Hill GR, Häcker G, Zeiser R.
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.
