Warren T K, Mitchell K A, Lawrence B P
Department of Pharmaceutical Sciences, Pharmacology/Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman, Washington 99164-6534, USA.
Toxicol Sci. 2000 Jul;56(1):114-23. doi: 10.1093/toxsci/56.1.114.
The immune response to influenza virus is exquisitely sensitive to suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); however, the cellular mechanisms underlying the suppressive effects of TCDD are unknown. Mice exposed to TCDD exhibited a dose-responsive increase in mortality following an otherwise non-lethal influenza virus infection. Given that cytotoxic T lymphocytes (CTL) are generally thought to resolve primary infections in the lung, we tested the hypothesis that exposure to TCDD suppresses T-cell responsiveness, leading to decreased CTL in the lung. After infection with influenza virus, naive CD8+ lymphocytes are activated and differentiate in the mediastinal lymph node (MLN). In mice exposed to TCDD and infected with influenza virus, the number of CD8+ MLN cells was reduced 60% compared to vehicle-treated mice. Moreover, MLN cells from TCDD-treated mice failed to develop cytolytic activity, and the production of interleukin (IL)-2 and interferon (IFN)-gamma was suppressed. Exposure to TCDD also altered the production of virus-specific antibodies, decreased the recruitment of CD8+ cells to the lung, reduced the percentage and number of bronchoalveolar lavage cells bearing a CTL phenotype (CD8+CD44hiCD62L(l) degrees ), and suppressed IL-12 levels in the lung. Despite our findings that exposure to TCDD suppressed T cell-dependent functions, the cytolytic activity of lung lavage cells from TCDD and vehicle treated mice was equivalent, and IFN gamma levels in the lungs of mice treated with TCDD were enhanced 10-fold. Thus, while exposure to TCDD suppressed a number of responses associated with the development of adaptive immunity to influenza virus, a direct link between these effects and enhanced susceptibility to influenza remains unclear.
对流感病毒的免疫反应对2,3,7,8-四氯二苯并对二恶英（TCDD）的抑制作用极为敏感；然而，TCDD抑制作用背后的细胞机制尚不清楚。暴露于TCDD的小鼠在感染原本不会致死的流感病毒后，死亡率呈剂量依赖性增加。鉴于细胞毒性T淋巴细胞（CTL）通常被认为可清除肺部的原发性感染，我们检验了以下假设：暴露于TCDD会抑制T细胞反应性，导致肺部CTL减少。感染流感病毒后，幼稚CD8 +淋巴细胞在纵隔淋巴结（MLN）中被激活并分化。在暴露于TCDD并感染流感病毒的小鼠中，与用赋形剂处理的小鼠相比，CD8 + MLN细胞数量减少了60％。此外，来自TCDD处理小鼠的MLN细胞未能产生溶细胞活性，白细胞介素（IL）-2和干扰素（IFN）-γ的产生受到抑制。暴露于TCDD还改变了病毒特异性抗体的产生，减少了CD8 +细胞向肺部的募集，降低了具有CTL表型（CD8 + CD44hiCD62L(l)度）的支气管肺泡灌洗细胞的百分比和数量，并抑制了肺中IL-12的水平。尽管我们发现暴露于TCDD会抑制T细胞依赖性功能，但TCDD处理小鼠和赋形剂处理小鼠的肺灌洗细胞的溶细胞活性相当，并且TCDD处理小鼠肺中的IFNγ水平提高了10倍。因此，虽然暴露于TCDD会抑制许多与对流感病毒适应性免疫发展相关的反应，但这些影响与对流感易感性增加之间的直接联系仍不清楚。
