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T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD

Trisha A. Dant, Kaifeng L. Lin, Danny W. Bruce, Stephanie A. Montgomery, Oleg V. Kolupaev, Hemamalini Bommiasamy, Lisa M. Bixby, John T. Woosley, Karen P. McKinnon, Frank J. Gonzalez, Bruce R. Blazar, Benjamin G. Vincent, James M. Coghill and Jonathan S. Serody

Key Points

  • Donor T cells lacking AhR demonstrate decreased aGVHD because of reduced donor T-cell proliferation early after transplant.

  • Absence of AhR on donor cells increased pTreg cells in the colon; in vitro blockade increased the number of human iTreg from CD4+ T cells.

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that affects the function and development of immune cells. Here, we show that recipient mice receiving AhR−/− T cells have improved survival and decreased acute graft-versus-host disease (aGVHD) in 2 different murine allogeneic bone marrow transplant (BMT) models. We also show that CD4+ T cells lacking AhR demonstrate reduced accumulation in secondary lymphoid tissue because of low levels of proliferation 4 days after BMT. Additionally, we found a significant increase in the quantity of peripherally induced regulatory donor T (pTreg) cells in the colon of recipients transplanted with AhR−/− T cells 14 days after transplant. Blockade of AhR using a clinically available AhR antagonist greatly enhanced the in vitro generation of inducible Treg (iTreg) cells from naïve CD4+ human T cells. We have identified AhR as a novel target on donor T cells that is critical to the pathogenesis of aGVHD.

  • Submitted August 15, 2016.
  • Accepted May 16, 2017.
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