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Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome

Antiopi Varelias, Kate L. Ormerod, Mark D. Bunting, Motoko Koyama, Kate H. Gartlan, Rachel D. Kuns, Nancy Lachner, Kelly R. Locke, Chun Y. Lim, Andrea S. Henden, Ping Zhang, Andrew D. Clouston, Sumaira Z. Hasnain, Michael A. McGuckin, Bruce R. Blazar, Kelli P.A. MacDonald, Philip Hugenholtz and Geoffrey R. Hill

Key points

  • Recipient-derived IL-17A is critical for the prevention of intestinal acute GVHD.

  • Increased susceptibility to acute GVHD can be transferred to WT mice via cohousing with IL-17RA or IL-17RC deficient mice.

Abstract

Donor T-cell-derived IL-17A can mediate late immunopathology in graft-versus-host disease (GVHD), however protective roles remain unclear. Using multiple cytokine and cytokine receptor subunit knockout mice we demonstrate that stem cell transplant (SCT) recipients lacking the ability to generate or signal IL-17 develop intestinal hyper-acute GVHD. This protective effect is restricted to the molecular interaction of IL-17A and/or IL-17F with the IL-17RA/C receptor. The protection from GVHD afforded by IL-17A required secretion from, and signaling in, both hematopoietic and non-hematopoietic host tissue. Given the intestinal-specificity of the disease in these animals, we cohoused WT with IL-17RA and IL-17RC deficient mice, which dramatically enhanced the susceptibility of WT mice to acute GVHD. Furthermore, the gut microbiome of WT mice shifted towards that of the IL-17RA/C mice during cohousing prior to transplant, confirming that an IL-17-sensitive gut microbiota controls susceptibility to acute GVHD. Finally, induced IL-17A deletion peri-transplant also enhanced acute GVHD, consistent with an additional protective role for this cytokine independent of effects on dysbiosis.

  • Submitted August 8, 2016.
  • Accepted January 20, 2017.