Planz O, Bilzer T, Sobbe M, Stitz L
Institut für Virologie, Justus-Liebig-Universität, Giessen, Germany.
J Exp Med. 1993 Jul 1;178(1):163-74. doi: 10.1084/jem.178.1.163.
CD8+ as well as CD4+ T cells and macrophages are of crucial importance for the pathogenesis of Borna disease in rats. This virus-induced immunopathological disease of the brain is characterized by neurological symptoms in the acute phase and chronic debility associated with severe loss of brain tissue in the late stage. We demonstrate here the cytotoxic activity of T lymphocytes in the brain of intracerebrally infected rats. T cells isolated from the brain of infected rats lyse major histocompatibility complex (MHC) class I-bearing target cells in the absence of MHC class II. Borna disease virus (BDV)-infected syngeneic skin cells and astrocytes, the latter one of the relevant target cells in vivo, were significantly lysed whereas infected allogeneic target cells were not. Most relevant to the in vivo situation, primary brain cell cultures propagated from the hippocampus of BDV-infected rats containing considerable numbers of neurons were lysed in vitro. Blocking experiments using antibodies directed against MHC class I antigen provided further evidence for the presence and activity of classical cytotoxic T lymphocytes. Antibodies against MHC class II antigen did not influence lysis of skin target cells but had an effect on lysis of astrocytes at late time points. Lymphocytes isolated from spleen, peripheral blood, or lymph nodes did not show cytotoxic activity. These results verify, on the cellular level, earlier findings that strongly suggest the involvement of CD8+ T cells in brain cell lesions, resulting in brain atrophy long after infection of rats with BDV. This is further evidenced by the presence of CD8+ T cells in direct proximity to neuronal cell lesions. Interestingly, the cytolytic capacity, demonstrated in vitro and strongly correlated to organ destruction, does not result in elimination of the virus but the virus persists in the central nervous system.
CD8⁺以及CD4⁺T细胞和巨噬细胞对于大鼠博尔纳病的发病机制至关重要。这种由病毒引起的脑部免疫病理疾病的特征是急性期出现神经症状，后期出现与严重脑组织损失相关的慢性虚弱。我们在此展示了脑内感染大鼠脑中T淋巴细胞的细胞毒性活性。从感染大鼠脑中分离出的T细胞在没有MHC II类分子的情况下可裂解携带主要组织相容性复合体（MHC）I类分子的靶细胞。博尔纳病病毒（BDV）感染的同基因皮肤细胞和星形胶质细胞（后者是体内相关靶细胞之一）被显著裂解，而感染的异基因靶细胞则未被裂解。与体内情况最相关的是，从含有大量神经元的BDV感染大鼠海马体中培养的原代脑细胞在体外被裂解。使用针对MHC I类抗原的抗体进行的阻断实验为经典细胞毒性T淋巴细胞的存在和活性提供了进一步证据。针对MHC II类抗原的抗体不影响皮肤靶细胞的裂解，但在后期对星形胶质细胞的裂解有影响。从脾脏、外周血或淋巴结分离出的淋巴细胞未显示出细胞毒性活性。这些结果在细胞水平上证实了早期的发现，这些发现强烈表明CD8⁺T细胞参与了脑细胞损伤，导致大鼠感染BDV后很长时间出现脑萎缩。这进一步由紧邻神经元细胞损伤处存在CD8⁺T细胞所证明。有趣的是，体外显示的与器官破坏密切相关的细胞溶解能力并未导致病毒清除，而是病毒持续存在于中枢神经系统中。
