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.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/immunology , Bone Marrow Transplantation , Colon/immunology , Graft vs Host Disease/prevention & control , Receptors, Aryl Hydrocarbon/immunology , T-Lymphocytes, Regulatory/immunology , Acute Disease , Animals , Basic Helix-Loop-Helix Transcription Factors/deficiency , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Proliferation , Colon/pathology , Gene Expression Regulation , Graft vs Host Disease/immunology , Graft vs Host Disease/mortality , Graft vs Host Disease/pathology , Humans , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Purines/pharmacology , Receptors, Aryl Hydrocarbon/deficiency , Receptors, Aryl Hydrocarbon/genetics , Sirolimus/pharmacology , Survival Analysis , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/transplantation , Transplantation, HeterologousABSTRACT
A randomized clinical trial of BM vs. blood stem cell transplants from unrelated donors showed that more plasmacytoid dendritic cells (pDCs) in BM grafts was associated with better post-transplant survival. Here, we describe differences in homing-receptor expression on pDC to explain observed differences following BM vs. blood stem cell transplantation.
