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, Jonathan S. Serody

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)348-359
Number of pages12
JournalBlood
Volume130
Issue number3
DOIs
StatePublished - Jul 20 2017

Bibliographical note

Funding Information:
The authors would also like to thank the University of North Carolina Flow Cytometry Core for performing fluorescence-activated cell sorting. Animal histopathology was performed in the Lineberger Comprehensive Cancer Center (LCCC) Animal Histopathology Core Facility at the University of North Carolina at Chapel Hill with special assistance from Dawud Hilliard. This work was supported by grants from the National Cancer Institute (R01 CA166794 [J.S.S.] and P30 CA016086 [Flow Cytometry Core]) and National Heart, Lung, and Blood Institute (R01 HL115761 [J.S.S.] and R01 HL11879 [B.R.B.]), National Institutes of Health. Research reported in this publication was supported in part by the North Carolina Biotech Center Institutional Support Grant 2012-IDG-1006. The LCCC Animal Histopathology Core is supported in part by a National Cancer Institute Center Core Support Grant (2P30CA016086-40) (University of North Carolina LCCC).

Publisher Copyright:
© 2017, American Society of Hematology. All rights reserved.

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