Constitutively active aryl hydrocarbon receptor expressed specifically in T-lineage cells causes thymus involution and suppresses the immunization-induced increase in splenocytes
Constitutively active aryl hydrocarbon receptor expressed specifically in T-lineage cells causes thymus involution and suppresses the immunization-induced increase in splenocytes
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DOI：
10.4049/jimmunol.174.5.2770
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发表时间：
2005-03-01
影响因子：
4.4
通讯作者：
Tohyama, C
中科院分区：
文献类型：
--
作者：
Nohara, K;Pan, XQ;Tohyama, C
芳烃受体（aryl hydrocarbon receptor, AhR）是一种属于碱性helix-loop-helix-PER-ARNT-SIM超家族的转录因子。异种生物，如2,3,7,8-四氯二苯并-对二恶英，结合受体并引发多种生物反应。胸腺细胞发育和T细胞依赖性免疫反应是ahr依赖性2,3,7,8-四氯二苯并-对二恶英毒性的敏感靶点。然而，在暴露于外源性配体的动物中，AhR在T细胞中的确切作用尚不清楚，因为活化的AhR在其他细胞类型中的间接作用不能排除。在这项研究中，我们产生了转基因（Tg）小鼠，在T细胞特异性CD2启动子的调控下表达AhR的组成型活性突变体，以检测AhR在T细胞中的功能。在Tg小鼠的胸腺和脾脏中表达了AhR组成型活性突变体和AhR诱导基因CYP1A1的mrna。在胸腺细胞、CD4和CD8 T细胞中明显检测到转基因表达，而在B细胞和胸腺基质细胞中未发现转基因表达。这些Tg小鼠胸腺细胞数量减少，CD8单阳性胸腺细胞百分比增加，但其脾细胞受到的影响要小得多。相比之下，Tg小鼠免疫后脾脏中T细胞和B细胞数量的增加明显受到抑制。这些结果清楚地表明，AhR在t系细胞中的激活直接参与胸腺细胞的损失和倾斜分化。他们还表明，在T细胞而不是B细胞中激活AhR抑制免疫诱导的T细胞和B细胞的增加。
The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the basic helix-loop-helix-PER-ARNT-SIM superfamily. Xenobiotics, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, bind the receptor and trigger diverse biological reactions. Thymocyte development and T cell-dependent immune reactions are sensitive targets of AhR-dependent 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity. However, the exact role of the AhR in T cells in animals exposed to exogenous ligands has not been clarified because indirect effects of activated AhR in other cell types cannot be excluded. In this study, we generated transgenic (Tg) mice expressing a constitutively active mutant of AhR under the regulation of a T cell-specific CD2 promoter to examine AhR function in T cells. The mRNAs of the constitutively active mutant of AhR and an AhR-induced gene, CYP1A1, were expressed in the thymus and spleen of the Tg mice. The transgene expression was clearly detected in the thymocytes, CD4, and CD8 T cells, but not in the B cells or thymus stromal cells. These Tg mice had a decreased number of thymocytes and an increased percentage of CD8 single-positive thymocytes, but their splenocytes were much less affected. By contrast, the increase in number of T cells and B cells taking place in the spleen after immunization was significantly suppressed in the Tg mice. These results clearly show that AhR activation in the T-lineage cells is directly involved in thymocyte loss and skewed differentiation. They also indicate that AhR activation in T cells and not in B cells suppresses the immunization-induced increase in both T cells and B cells.