Environmental Health Sciences Division, National Institute for Environmental Studies, Tsukuba 305-8506, Japan.
J Immunotoxicol. 2009 Sep;6(3):194-203. doi: 10.1080/15476910903124454.
Activation of aryl hydrocarbon receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in T-cells is required for TCDD-induced suppression of the allogeneic CTL response and for induction of CD25(hi)CD62L(low) adaptive regulatory T-cells. Here, the ability of a constitutively-active AhR (CA-AhR) expressed in T-cells alone to replicate the effects of TCDD was examined. The response of CA-AhR-expressing B6 donor T-cells in B6xD2F1 mice was compared to the response of wild-type B6 donor T-cells in B6xD2F1 mice given a single dose of TCDD. Expression of CA-AhR in donor T-cells enhanced the down-regulation of CD62L on Day 2 after injection, similar to a single oral dose of TCDD, but did not induce up-regulation of CD25 on Day 2 or affect CTL activity on Day 10. This suggests that activation of AhR in T-cells alone may not be sufficient to alter T-cell responses in this acute graft-versus-host (GvH) model. Since host APC are responsible for activating the donor T-cells, we examined the influence of the F1 host's AhR on donor T-cell responses by creating an AhR(-/-) B6xD2F1 host that had a greatly diminished AhR response to TCDD compared to wild-type F1 mice. As in AhR(+/+) B6xD2F1 mice, the CTL response in AhR(-/-) B6xD2F1 mice was completely suppressed by TCDD. This suggests that either CA-AhR dose not fully replicate the function of TCDD-activated AhR in suppression of the CTL response, or that minimal activation of AhR in host cells is required to combine with activation of AhR in T-cells to elicit the immunosuppressive effects of TCDD.
2,3,7,8-四氯二苯并对二恶英（TCDD）激活 T 细胞中的芳香烃受体（AhR）是 TCDD 诱导的抑制同种异体 CTL 反应和诱导 CD25（hi）CD62L（low）适应性调节性 T 细胞所必需的。在这里，研究了单独在 T 细胞中表达的组成型激活 AhR（CA-AhR）复制 TCDD 作用的能力。将 CA-AhR 表达的 B6 供体 T 细胞在 B6xD2F1 小鼠中的反应与给予 TCDD 单一剂量的 B6xD2F1 小鼠中野生型 B6 供体 T 细胞的反应进行了比较。CA-AhR 在供体 T 细胞中的表达增强了注射后第 2 天 CD62L 的下调，类似于 TCDD 的单次口服剂量，但没有诱导第 2 天 CD25 的上调，也没有影响第 10 天的 CTL 活性。这表明，单独在 T 细胞中激活 AhR 可能不足以改变这种急性移植物抗宿主（GvH）模型中的 T 细胞反应。由于宿主 APC 负责激活供体 T 细胞，我们通过创建一个 AhR（-/-）B6xD2F1 宿主来检查宿主的 AhR 对供体 T 细胞反应的影响，与野生型 F1 小鼠相比，该宿主对 TCDD 的 AhR 反应大大降低。与 AhR（+/+）B6xD2F1 小鼠一样，TCDD 完全抑制了 AhR（-/-）B6xD2F1 小鼠中的 CTL 反应。这表明，要么 CA-AhR 不能完全复制 TCDD 激活的 AhR 在抑制 CTL 反应中的功能，要么宿主细胞中 AhR 的最小激活与 T 细胞中 AhR 的激活相结合，以引发 TCDD 的免疫抑制作用。
