House R V, Pallardy M J, Dean J H
Department of Cellular and Molecular Toxicology, Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Int J Immunopharmacol. 1989;11(2):207-15. doi: 10.1016/0192-0561(89)90073-8.
Exposure of murine lymphocytes to the carcinogenic polycyclic aromatic hydrocarbon 7,12-dimethylbenz[a]anthracene (DMBA) results in significant suppression of a variety of immunological parameters, including the induction of cytotoxic T-lymphocytes (CTL). This CTL suppression may be reversed in vitro by the addition of exogenous cellular activation products, including IL-2. The current study demonstrated that DMBA-induced CTL suppression occurs throughout the induction process, with the most pronounced effect occurring within 24-48 h of initiation. IL-2-mediated restoration of suppression is effective only within this critical window. These findings suggest an effect by DMBA on both the T-helper (Th) and CTL-precursor (CTLp) subsets. Alloantigen-specific CTL generated from murine thymocytes in the presence of DMBA and Th-derived factors (thus circumventing the Th) displayed an almost identical degree of CTL suppression to that of splenocytes, indicating a direct effect of DMBA on the CTLp. Antigen nonspecific, polyclonal CTL activation by the lectin leucoagglutinin or by IL-2 (LAK cells) was unaffected by chemical exposure, indicating that DMBA preferentially affects antigen-specific activation rather than the cytolytic process itself. Conversely, polyclonal CTL induced with monoclonal antibodies directed against the T-cell receptor-associated subunit CD3, in the presence of conditioned medium, was suppressed in a manner similar to antigen-mediated CTL. The CD3 receptor subunit acts as a transmembrane activation signal following binding of antigen to the specific receptor, further implicating dysfunction of antigen recognition or signal processing following DMBA exposure. This was confirmed by the observation that DMBA exposure prevents the anamnestic response of CTL memory cells following re-exposure to eliciting tumor antigen.(ABSTRACT TRUNCATED AT 250 WORDS)
将小鼠淋巴细胞暴露于致癌性多环芳烃7,12 - 二甲基苯并[a]蒽（DMBA）会导致多种免疫参数受到显著抑制，包括细胞毒性T淋巴细胞（CTL）的诱导。通过添加外源性细胞激活产物（包括IL - 2），这种CTL抑制在体外可能会被逆转。当前研究表明，DMBA诱导的CTL抑制在整个诱导过程中都会发生，最显著的影响发生在起始后的24 - 48小时内。IL - 2介导的抑制恢复仅在这个关键窗口期内有效。这些发现表明DMBA对辅助性T细胞（Th）和CTL前体细胞（CTLp）亚群均有影响。在存在DMBA和Th衍生因子的情况下（从而避开Th）从小鼠胸腺细胞产生的同种异体抗原特异性CTL显示出与脾细胞几乎相同程度的CTL抑制，表明DMBA对CTLp有直接影响。凝集素白细胞凝集素或IL - 2（LAK细胞）对抗原非特异性的多克隆CTL激活不受化学物质暴露的影响，表明DMBA优先影响抗原特异性激活而非细胞溶解过程本身。相反，在条件培养基存在下，用针对T细胞受体相关亚基CD3的单克隆抗体诱导的多克隆CTL以类似于抗原介导的CTL的方式受到抑制。抗原与特异性受体结合后，CD3受体亚基作为跨膜激活信号，这进一步表明DMBA暴露后抗原识别或信号处理存在功能障碍。再次暴露于引发肿瘤抗原后，DMBA暴露会阻止CTL记忆细胞的回忆反应，这一观察结果证实了上述观点。（摘要截断于250字）
