Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration.
Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration.
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DOI：
10.1084/jem.182.4.1045
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发表时间：
1995-10-01
期刊：
影响因子：
--
通讯作者：
Biron CA
中科院分区：
文献类型：
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作者：
Orange JS;Wang B;Terhorst C;Biron CA
自然杀伤 (NK) 细胞的存在有助于早期防御鼠巨细胞病毒 (MCMV) 感染。尽管 NK 细胞可以介导针对 MCMV 的体内保护，但其作用机制尚未明确。本文介绍的研究评估了 MCMV 感染期间激活的 NK 细胞产生的细胞因子，以及 NK 细胞产生的细胞因子在早期体内抗病毒防御中的作用。使用正常 C57BL/6、T 细胞缺陷 C57BL/6 裸鼠和缺乏 T 细胞和 B 细胞的严重联合免疫缺陷小鼠进行的实验表明，在感染 MCMV 后的早期，可诱导干扰素 γ (IFN-γ) 和肿瘤坏死因子 (TNF) 的产生。用这些小鼠的细胞制备的条件培养基样品，在感染后第 2 天，产生了 11-43 pg/百万细胞的 IFN-γ 和 12-19 pg/百万细胞的 TNF，通过特定的蛋白酶联免疫吸附测定进行评估。对 NK 和 T 细胞缺陷型小鼠系 E26 进行的研究表明，NK 细胞仅负责 IFN-γ，但这些小鼠体内已通过消除 NK 细胞的抗体、抗去唾液酸神经节-N-四糖神经酰胺或抗 NK1.1 处理而耗尽了 NK 细胞，并且细胞群已通过抗 NK 细胞抗体 SW3A4 的补体处理而耗尽了 NK 细胞。 TNF 生产所需。体内缺乏 NK 细胞会导致免疫功能正常和免疫缺陷小鼠的病毒性肝炎和病毒复制增加，以及免疫缺陷小鼠的生存时间缩短。使用中和 IFN-γ 的抗体进行的体内治疗表明，该因子有助于 NK 细胞介导的抗病毒防御，并将病毒防御的测量参数降低到与 NK 细胞缺陷小鼠中观察到的水平无法区分的水平。这些效应似乎与细胞溶解活性无关，因为从抗 IFN-γ 处理的小鼠中分离出的 NK 细胞介导的杀伤水平与在对照处理的小鼠中观察到的水平相当。在 MCMV 感染的小鼠中评估了白细胞介素 12 (IL-12) 的后果，白细胞介素 12 是 NK 细胞产生 IFN-γ 的已知有效诱导剂。低 IL-12 剂量，即 1 ng/d，可将 NK 细胞的细胞毒性和 IFN-γ 的产生增加至两倍，从而改善抗病毒状态；病毒引起的肝炎减少了五倍，病毒负荷降低到检测水平以下。（摘要截断为 400 字）
The presence of natural killer (NK) cells contributes to early defense against murine cytomegalovirus (MCMV) infection. Although NK cells can mediate in vivo protection against MCMV, the mechanism by which they do so has not been defined. The studies presented here evaluate cytokine production by NK cells activated during MCMV infection and the role of NK cell-produced cytokines in early in vivo antiviral defenses. Experiments with normal C57BL/6, T cell-deficient C57BL/6 nude, and severe combined immunodeficient mice lacking T and B cells demonstrated that both interferon gamma (IFN-gamma) and tumor necrosis factor (TNF) production were induced at early times after infection with MCMV. Conditioned media samples prepared with cells from these mice, on day 2 after infection, produced 11-43 pg/million cells of IFN-gamma and 12-19 pg/million cells of TNF as evaluated by specific protein enzyme-linked immunosorbent assays. Studies in the NK- and T cell-deficient mouse line, E26, in mice that had been depleted in vivo of NK cells by treatment with antibodies eliminating NK cells, anti-asialo ganglio-N- tetraosylceramide or anti-NK1.1, and with populations of cells that had been depleted of NK cells by complement treatment with the anti-NK cell antibody, SW3A4, demonstrated that NK cells were solely responsible for the IFN-gamma but were not required for TNF production. The in vivo absence of NK cells was accompanied by increased viral hepatitis and viral replication in both immunocompetent and immunodeficient mice, as well as decreased survival time of immunodeficient mice. In vivo treatments with antibodies neutralizing IFN-gamma demonstrated that this factor contributed to the NK cell-mediated antiviral defense and reduced the measured parameters of viral defense to levels indistinguishable from those observed in NK cell-deficient mice. These effects appeared to be independent of cytolytic activity, as NK cells isolated from anti-IFN-gamma-treated mice mediated killing at levels comparable to those observed in control-treated mice. The consequences of interleukin 12 (IL-12) administration, a known potent inducer of IFN- gamma production by NK cells, were evaluated in MCMV-infected mice. Low IL-12 doses, i.e., 1 ng/d, increased NK cell cytotoxicity and IFN-gamma production up to twofold and resulted in improved antiviral status; virus-induced hepatitis was decreased as much as fivefold, and viral burdens were decreased to levels below detection.(ABSTRACT TRUNCATED AT 400 WORDS)