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T cell expression of AhR inhibits the maintenance of pTreg cells in the GI 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 due to reduced donor T cell proliferation early after transplant.

  • Loss of AhR lead to increased numbers of pTregs in the colon, and in vitro blockade increased iTreg generation from human 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 two different murine allogeneic bone marrow transplant models (BMT). We also show that CD4+ T cells lacking AhR demonstrate reduced accumulation in secondary lymphoid tissue due to low levels of proliferation 4 days after BMT. Additionally, we found a significant increase in the quantity of peripherally induced regulatory donor T cells (pTregs) 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 Tregs 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.