VIRUS-INDUCED IMMUNOSUPPRESSION - IMMUNE SYSTEM-MEDIATED DESTRUCTION OF VIRUS-INFECTED DENDRITIC CELLS RESULTS IN GENERALIZED IMMUNE SUPPRESSION
VIRUS-INDUCED IMMUNOSUPPRESSION - IMMUNE SYSTEM-MEDIATED DESTRUCTION OF VIRUS-INFECTED DENDRITIC CELLS RESULTS IN GENERALIZED IMMUNE SUPPRESSION
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DOI：
10.1128/jvi.69.2.1059-1070.1995
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发表时间：
1995-02-01
影响因子：
5.4
通讯作者：
OLDSTONE, MBA
中科院分区：
文献类型：
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作者：
BORROW, P;EVANS, CF;OLDSTONE, MBA
尽管病毒诱导的免疫抑制具有临床重要性，但病毒感染如何导致宿主免疫应答的普遍抑制仍知之甚少。为了阐明所涉及的原则，我们分析了淋巴细胞性脉络丛脑膜炎病毒（LCMV）变异体在其天然宿主小鼠中产生全身免疫抑制的机制。而成年小鼠静脉接种LCMV Armstrong迅速清除感染，并保持免疫活性，接种Armstrong衍生的LCMV变体克隆13，它不同于其亲本病毒在只有两个氨基酸的位置，相比之下，结果在持续感染和一个普遍的缺陷，在随后的免疫挑战的反应。在这里，我们表明，LCMV克隆13诱导的免疫抑制与CD8依赖性损失的指状突树突状细胞从动脉周围淋巴鞘在脾脏，功能上，与缺陷的能力，从感染的小鼠脾细胞刺激幼稚T细胞在初级混合淋巴细胞反应的增殖。树突状细胞在免疫活性Armstrong感染的小鼠中没有耗尽。LCMV Armstrong和克隆13在脾脏内的嗜性方面表现出差异，其中克隆13比Armstrong引起更高水平的白色髓中抗原呈递细胞的感染，包括动脉周围交错树突状细胞，从而使这些细胞成为被抗病毒CD 8+细胞毒性T淋巴细胞应答破坏的靶标，所述应答在用任一病毒感染后的早期诱导。我们的研究结果说明了病毒嗜性可能在确定致病性中发挥的关键作用，并进一步证明了病毒诱导的免疫抑制机制，这可能有助于与许多病毒感染（包括人类免疫缺陷病毒1型）相关的临床重要免疫抑制。
Despite the clinical importance of virus-induced immunosuppression, how virus infection may lead to a generalized suppression of the host immune response is poorly understood. To elucidate the principles involved, we analyzed the mechanism by which a lymphocytic choriomeningitis virus (LCMV) variant produces a generalized immune suppression in its natural host, the mouse. Whereas adult mice inoculated intravenously with LCMV Armstrong rapidly clear the infection and remain immunocompetent, inoculation with the Armstrong-derived LCMV variant clone 13, which differs from its parent virus at only two amino acid positions, by contrast results in persistent infection and a generalized deficit in responsiveness to subsequent immune challenge. Here we show that the immune suppression induced by LCMV clone 13 is associated with a CD8-dependent loss of interdigitating dendritic cells from periarteriolar lymphoid sheaths in the spleen and, functionally, with a deficit in the ability of splenocytes from infected mice to stimulate the proliferation of naive T cells in a primary mixed lymphocyte reaction. Dendritic cells are not depleted in immunocompetent Armstrong-infected mice. LCMV Armstrong and clone 13 exhibit differences in their tropism, within the spleen, with clone 13 causing a higher level of infection of antigen-presenting cells in the, white pulp, including periarterial interdigitating dendritic cells, than Armstrong, thereby rendering these cells targets for destruction by the antiviral CD8+ cytotoxic T-lymphocyte response which is induced at early times following infection with either virus. Our findings illustrate the key role that virus tropism may play in determining pathogenicity and, further, document a mechanism for virus-induced immunosuppression which may contribute to the clinically important immune suppression associated with many virus infections, including human immunodeficiency virus type 1.