Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331.
Toxicol Sci. 2018 Feb 1;161(2):310-320. doi: 10.1093/toxsci/kfx215.
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.
FICZ 和 TCDD 是两种高亲和力的 AhR 配体，据报道，它们对 T 细胞分化有相反的作用，TCDD 诱导调节性 T 细胞，而 FICZ 诱导 Th17 细胞。这种二分法归因于 AhR 激活的配体内在差异，尽管对代谢的敏感性差异使问题复杂化。TCDD 抵抗 AhR 诱导的代谢，并且在μg/kg 范围内的单次剂量后产生持续的 AhR 激活，而 FICZ 则迅速代谢，并且 AhR 激活是短暂的。尽管如此，先前比较 FICZ 与 TCDD 的研究通常使用相同的 10-50μg/kg 剂量范围，因此两种配体不会等效地激活 AhR。我们假设高亲和力的 AhR 配体可以促进 CD4+T 细胞分化为 Th17 细胞和 Tregs，其命运取决于 AhR 激活的程度和持续时间。我们在急性同种异体反应小鼠模型中比较了 TCDD 和 FICZ 以及另外两种快速代谢的配体（ITE 和 11-Cl-BBQ）的免疫抑制作用。每种配体的剂量和给药时间均针对 TCDD 等效 Cyp1a1 诱导进行了优化。优化后，所有配体均与第 2 天诱导 Foxp3-Tr1 细胞和第 10 天扩增天然 Foxp3+Treg 一起抑制同种异体反应。相比之下，低剂量的 FICZ 诱导 Cyp1a1 的瞬时表达，并且不诱导 Treg 或抑制同种异体反应，但增强了 IL-17 的产生。有趣的是，低剂量的其他配体，包括 TCDD，也在第 10 天增加了 IL-17 的产生。这些发现支持这样的结论，即高亲和力 AhR 配体对 AhR 的激活的剂量和持续时间是驱动 T 细胞分化命运的主要因素。
