Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor

Abstract

Regulatory T cells (T(reg)) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of T(reg) cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 (T(H)17). Although T(reg) cell dysfunction and/or T(H)17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of T(reg) and T(H)17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional T(reg) cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with T(reg) cell development, boosted T(H)17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both T(reg) and T(H)17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation.

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…The role of the vitamin A metabolite retinoic acid ATRA has been well characterised in the context of T‐cell differentiation, and it is evident that either alone or in combination with other factors ATRA can induce either induce Treg or Th17 phenotypes by upregulating FOXP3 expression or ROR gamma expression, respectively 78. This axis can also be influenced by sensing toxins and pollutants via the aryl hydrocarbon receptor (AHR) 79, 80. Induction of FOXP3 in response to food metabolites including short‐chain fatty acids is now well characterised at the molecular levels and is particularly relevant for induced Treg generation in the gut.…”

Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR

“…Nevertheless, AHR is postulated to play important roles not only in the regulation of xenobiotic metabolism but also in the regulation of differentiation in pro-inflammatory T cells [19], ketarinocytes [20], myeloblastic leukemia cells [21], and Neuro2a cells [22].…”

Aryl hydrocarbon receptor inhibition downregulates the TGF-β/Smad pathway in human glioblastoma cells

“…Thereby, oxidative metabolic processes are induced that mediate the toxicity of dioxin-like compounds (Shimizu et al, 2000). The wide range of toxic effects induced by these compounds, including birth defects, impaired reproductive capacity and altered immune responses, have encouraged research on the interaction of AhR with sex steroid receptors and the immune system (Ohtake et al, 2008;Quintana et al, 2008;Veldhoen et al, 2008). AhR regulates cellular differentiation during development (Huang et al, 2004;Lahvis et al, 2000) and may promote cell cycle progression in the absence of exogenous ligand (Chang et al, 2007;Marlowe and Puga, 2005).…”