T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD.
Trisha A DantKaifeng L LinDanny W BruceStephanie A MontgomeryOleg V KolupaevHemamalini BommiasamyLisa M BixbyJohn T WoosleyKaren P McKinnonFrank J GonzalezBruce R BlazarBenjamin G VincentJames M CoghillJonathan S SerodyPublished in: Blood (2017)
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.
Keyphrases
- bone marrow
- transcription factor
- induced apoptosis
- liver failure
- endothelial cells
- drug induced
- signaling pathway
- poor prognosis
- stem cell transplantation
- type diabetes
- respiratory failure
- intensive care unit
- high glucose
- adipose tissue
- metabolic syndrome
- skeletal muscle
- oxidative stress
- insulin resistance
- acute respiratory distress syndrome
- mechanical ventilation