TCDD, FICZ, and Other High Affinity AhR Ligands Dose-Dependently Determine the Fate of CD4+ T Cell Differentiation

Abstract

FICZ and TCDD, two high-affinity AhR ligands, are reported to have opposite effects on T cell differentiation with TCDD inducing regulatory T cells and FICZ inducing Th17 cells. This dichotomy has been attributed to ligand-intrinsic differences in AhR activation, although differences in sensitivity to metabolism complicate the issue. TCDD is resistant to AhR-induced metabolism and produces sustained AhR activation following a single dose in the μg/kg range, whereas FICZ is rapidly metabolized and AhR activation is transient. Nonetheless, prior studies comparing FICZ with TCDD have generally used the same 10-50 μg/kg dose range, and thus the two ligands would not equivalently activate AhR. We hypothesized that high-affinity AhR ligands can promote CD4+ T cell differentiation into both Th17 cells and Tregs, with fate depending on the extent and duration of AhR activation. We compared the immunosuppressive effects of TCDD and FICZ, along with two other rapidly metabolized ligands (ITE and 11-Cl-BBQ) in an acute alloresponse mouse model. The dose and timing of administration of each ligand was optimized for TCDD-equivalent Cyp1a1 induction. When optimized, all of the ligands suppressed the alloresponse in conjunction with the induction of Foxp3- Tr1 cells on day 2 and the expansion of natural Foxp3+ Tregs on day 10. In contrast, a low dose of FICZ induced transient expression of Cyp1a1 and did not induce Tregs or suppress the alloresponse but enhanced IL-17 production. Interestingly, low doses of the other ligands, including TCDD, also increased IL-17 production on day 10. These findings support the conclusion that the dose and the duration of AhR activation by high-affinity AhR ligands are the primary factors driving the fate of T cell differentiation.

T helper 17 cell/regulatory T-cell imbalance in hidradenitis suppurativa/acne inversa: the link to hair follicle dissection, obesity, smoking and autoimmune comorbidities

“…Recent evidence underlines that smoking adversely affects the Th17/Treg balance. Smoking has been associated with increased expression of Th17 cells, IL‐17 expression and impaired numbers or function of Tregs . As with obesity, smoking has been related to macrophage dysfunction in HS .…”

“…Smoking has been associated with increased expression of Th17 cells, IL-17 expression and impaired numbers or function of Tregs. [86][87][88][89] As with obesity, smoking has been related to macrophage dysfunction in HS. 90 Furthermore, downregulation of Notch pathway gene expression has been reported in association with smoking.…”

An endogenous aryl hydrocarbon receptor ligand enhances de novo generation of regulatory T cells in humans

“…In fact, some ligands such as TCDD seem to promote immune suppression, whereas other ligands such as FICZ are likely to support proinflammatory effects and Th17 cell responses . This dichotomy has been attributed to ligand‐intrinsic differences in AhR activation as well as to the dose and duration of AhR activation . Herein, we show that ITE acts similarly to TCDD by supporting the immune regulation through the promotion of induced Tregs.…”

The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation

“…Confirmation that the dose and duration of AHR activation by high-affinity ligands are the primary drivers of T cell differentiation was provided by a recent examination of allogenic responses in mice (Ehrlich et al 2018) (Table 1).…”