Greenlee W F, Dold K M, Irons R D, Osborne R
Toxicol Appl Pharmacol. 1985 Jun 15;79(1):112-20. doi: 10.1016/0041-008x(85)90373-4.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acts on selected targets within the immune system to produce a characteristic profile of pathologic responses typified by thymic atrophy, suppressed cellular immunity, and inhibition of antibody production to T-lymphocyte-dependent antigens. Studies in inbred mice differing in sensitivity to TCDD indicate that TCDD-induced thymic atrophy is mediated by a receptor protein (designated the Ah receptor). To study the cellular and molecular basis for TCDD-induced thymic atrophy, primary cultures of thymic epithelial (TE) cells were established from C57BL/6 mice, a strain sensitive to TCDD. Treatment of TE monolayers with TCDD (0.1 to 10 nM) resulted in the altered maturation of cocultured syngeneic thymocytes as judged by suppression (40% of control at 10 nM TCDD) of TE-dependent responsiveness of thymocytes to the mitogens concanavalin A and phytohemagglutinin. TE-conditioned medium enhanced the mitogen responsiveness of thymocytes three- to four-fold; however, the enhanced mitogen response mediated by the TE-conditioned medium was not suppressed in thymocytes incubated in medium collected from TCDD-treated cultures or in TE-conditioned medium to which TCDD (10 nM) had been added directly. The suppression of TE-dependent maturation of thymocytes was concentration dependent (EC50 approximately 1 nM) and stereospecific, suggesting involvement of the Ah receptor. The Ah receptor in cytosol fractions from cultured TE cells was measured directly and was found to be present at a concentration 3 and 3.5 times greater than that measured in whole thymus and thymocytes, respectively. The results of this study indicate that TCDD can act directly on epithelial target cells in the thymus: one consequence of this action appears to be the altered thymus-dependent maturation of T-lymphocyte precursors, mediated through direct cell-cell contact between thymocytes and TE cells.
2,3,7,8-四氯二苯并-对-二噁英（TCDD）作用于免疫系统内的特定靶点，产生以胸腺萎缩、细胞免疫受抑制以及对T淋巴细胞依赖性抗原的抗体产生受抑制为典型特征的病理反应谱。对TCDD敏感性不同的近交系小鼠研究表明，TCDD诱导的胸腺萎缩是由一种受体蛋白（称为Ah受体）介导的。为了研究TCDD诱导胸腺萎缩的细胞和分子基础，从对TCDD敏感的C57BL/6小鼠建立了胸腺上皮（TE）细胞原代培养物。用TCDD（0.1至10 nM）处理TE单层细胞，通过胸腺细胞对丝裂原刀豆球蛋白A和植物血凝素的TE依赖性反应性受到抑制（在10 nM TCDD时为对照的40%）判断，共培养的同基因胸腺细胞的成熟发生改变。TE条件培养基使胸腺细胞的丝裂原反应性提高了三到四倍；然而，由TE条件培养基介导的增强的丝裂原反应在从TCDD处理的培养物收集的培养基中孵育的胸腺细胞或直接添加了TCDD（10 nM）的TE条件培养基中孵育的胸腺细胞中并未受到抑制。胸腺细胞的TE依赖性成熟的抑制是浓度依赖性的（半数有效浓度约为1 nM）且具有立体特异性，提示Ah受体参与其中。直接测量了培养的TE细胞胞质部分中的Ah受体，发现其浓度分别比在整个胸腺和胸腺细胞中测量到的浓度高3倍和3.5倍。本研究结果表明，TCDD可直接作用于胸腺中的上皮靶细胞：这种作用的一个后果似乎是T淋巴细胞前体的胸腺依赖性成熟改变，这是通过胸腺细胞与TE细胞之间的直接细胞间接触介导的。
