Matloubian M, Concepcion R J, Ahmed R
Department of Microbiology and Immunology, University of California at Los Angeles School of Medicine 90024.
J Virol. 1994 Dec;68(12):8056-63. doi: 10.1128/JVI.68.12.8056-8063.1994.
In this study, we have examined the relative contributions of CD4+ and CD8+ T cells in controlling an acute or chronic lymphocytic choriomeningitis virus (LCMV) infection. To study acute infection, we used the LCMV Armstrong strain, which is cleared by adult mice in 8 to 10 days, and to analyze chronic infection, we used a panel of lymphocyte-tropic and macrophage-tropic variants of LCMV that persist in adult mice for several months. We show that CD4+ T cells are not necessary for resolving an acute LCMV infection. CD4+ T-cell-depleted mice were capable of generating an LCMV-specific CD8+ cytotoxic T-lymphocyte (CTL) response and eliminated virus with kinetics similar to those for control mice. The CD8+ CTL response was critical for resolving this infection, since beta 2-microglobulin knockout (CD8-deficient) mice were unable to control the LCMV Armstrong infection and became persistently infected. In striking contrast to the acute infection, even a transient depletion of CD4+ T cells profoundly affected the outcome of infection with the macrophage- and lymphocyte-tropic LCMV variants. Adult mice given a single injection of anti-CD4 monoclonal antibody (GK1.5) at the time of virus challenge became lifelong carriers with high levels of virus in most tissues. Unmanipulated adult mice infected with the different LCMV variants contained virus for prolonged periods (> 3 months) but eventually eliminated infection from most tissues, and all of these mice had LCMV-specific CD8+ CTL responses. Although the level of CTL activity was quite low, it was consistently present in all of the chronically infected mice that eventually resolved the infection. These results clearly show that even in the presence of an overwhelming viral infection of the immune system, CD8+ CTL can remain active for long periods and eventually resolve and/or keep the virus infection in check. In contrast, LCMV-specific CTL responses were completely lost in chronically infected CD4-depleted mice. Taken together, these results show that CD4+ T cells are dispensable for short-term acute infection in which CD8+ CTL activity does not need to be sustained for more than 2 weeks. However, under conditions of chronic infection, in which CD8+ CTLs take several months or longer to clear the infection, CD4+ T-cell function is critical. Thus, CD4+ T cells play an important role in sustaining virus-specific CD8+ CTL during chronic LCMV infection. These findings have implications for chronic viral infections in general and may provide a possible explanation for the loss of human immunodeficiency virus-specific CD8+ CTL activity that is seen during the late stages of AIDS, when CD4+ T cells become limiting.
在本研究中，我们检测了CD4⁺和CD8⁺ T细胞在控制急性或慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染中的相对作用。为研究急性感染，我们使用了LCMV阿姆斯特朗株，成年小鼠可在8至10天内清除该毒株；为分析慢性感染，我们使用了一组嗜淋巴细胞性和嗜巨噬细胞性的LCMV变异株，这些变异株可在成年小鼠体内持续存在数月。我们发现，清除急性LCMV感染并不需要CD4⁺ T细胞。CD4⁺ T细胞耗竭的小鼠能够产生LCMV特异性CD8⁺ 细胞毒性T淋巴细胞（CTL）反应，并以与对照小鼠相似的动力学清除病毒。CD8⁺ CTL反应对于清除这种感染至关重要，因为β2微球蛋白敲除（CD8缺陷）小鼠无法控制LCMV阿姆斯特朗株感染，并会持续感染。与急性感染形成鲜明对比的是，即使CD4⁺ T细胞短暂耗竭也会严重影响嗜巨噬细胞性和嗜淋巴细胞性LCMV变异株的感染结果。在病毒攻击时单次注射抗CD4单克隆抗体（GK1.5）的成年小鼠会成为终身携带者，大多数组织中都有高水平的病毒。未处理的感染不同LCMV变异株的成年小鼠会在较长时间内（>3个月）携带病毒，但最终会从大多数组织中清除感染，并且所有这些小鼠都有LCMV特异性CD8⁺ CTL反应。尽管CTL活性水平相当低，但在所有最终清除感染的慢性感染小鼠中都持续存在。这些结果清楚地表明，即使在免疫系统受到压倒性病毒感染的情况下，CD8⁺ CTL仍可长时间保持活性，并最终清除和/或控制病毒感染。相比之下，在慢性感染的CD4⁺ T细胞耗竭小鼠中，LCMV特异性CTL反应完全丧失。综上所述，这些结果表明，对于短期急性感染，CD4⁺ T细胞是可有可无的，其中CD8⁺ CTL活性不需要持续超过2周。然而，在慢性感染的情况下，CD8⁺ CTL需要数月或更长时间才能清除感染，此时CD4⁺ T细胞功能至关重要。因此，在慢性LCMV感染期间，CD4⁺ T细胞在维持病毒特异性CD8⁺ CTL方面发挥着重要作用。这些发现对一般慢性病毒感染具有启示意义，并可能为艾滋病晚期出现的人类免疫缺陷病毒特异性CD8⁺ CTL活性丧失提供一种可能的解释，此时CD4⁺ T细胞数量受限。
