Autoimmunity or tolerance induction: control of CD8 T cell-mediated immune reactions against CNS oligodencrocytes by local infection

在中枢神经系统中，T淋巴细胞在免疫监视和感染过程中或自身免疫反应过程中分别发挥保护或有害作用。针对病原体的免疫反应也可能导致脑组织的永久性损伤；因此，决定是否应该销毁受感染的细胞来拯救宿主生物是很重要的。本项目研究CD8 T细胞(CTL)介导的少突胶质细胞(自身)免疫破坏机制，反之亦然。我们建立了一种转基因小鼠系，其卵清蛋白(OVA)作为自身抗原仅在少突胶质细胞(ODC-OVA小鼠)的细胞质中表达。外周感染表达OVA的李斯特菌可诱导OVA特异性CD8T细胞应答，其特征是CTL最初增殖并通过中枢神经系统循环，随后在没有临床症状和神经病理改变的情况下，自身反应性OVA特异性CD8T细胞克隆性删除。与之形成鲜明对比的是，同一病原体的脑内感染导致表达OVA的少突胶质细胞抗原特异性破坏，临床表现为伴有持续神经症状的偏瘫障碍。这些观察结果为我们的假设提供了理论基础，即中枢神经系统内的局部炎症刺激决定了脑内免疫反应是导致抗原表达细胞的破坏，还是导致有害的CD8 T细胞的消除。在这一点上，少突胶质细胞的直接敏化或小胶质细胞的间接激活都可能起作用。因此，本项目旨在确定感染部位(中枢神经系统内或外)与引起CTL反应的脱髓鞘之间的关系。在对我们的模型进行详细描述之后，将定义先天免疫系统和获得性免疫系统的几个组成部分的作用。特别是，我们将测试假设，在这种情况下，中枢神经系统中的Toll样受体是否具有关键相关性。

In the central nervous system, T lymphocytes may exert either protective or harmful effects during immunosurveillance and infections or during autoimmune reactions, respectively. Immune reactions directed against pathogens may also result in permanent damage of brain tissue; thus, the decision is important whether infected cells should be destroyed to save the host organism or not. This project addresses the mechanisms which allow either CD8 T cell (CTL) mediated destruction of oligodendrocytes ((auto)immunity) or, vice versa, induce destruction of the offending CTL (induction of tolerance).We have established a transgenic mouse line, which expresses ovalbumin (OVA) as autoantigen exclusively in the cytoplasm of oligodendrocytes (ODC-OVA mice). Peripheral infection with OVA-expressing Listeria induces an OVA-specific CD8 T cell response characterized by an initial proliferation of CTL and their circulation through the CNS followed by clonal deletion of the autoreactive OVA-specific CD8 T cells in the absence of clinical symptoms and neuropathological alterations. In striking contrast, intracerebral infection with the same pathogen leads to the antigen-specific destruction of OVA-expressing oligodendrocytes, clinically presenting as paretic disorder with persistent neurological symptoms. These observations provide the rationale for our hypothesis that local inflammatory stimuli within the CNS decide whether an intracerebral immune response results in destruction of the antigen-expressing cell or in elimination of the offending CD8 T cell. In this regard, either the direct sensitization of the oligodendrocyte or the indirect activation of microglia may play a role. Thus, this project aims at the identification of the relation between the site of an infection (within or outside the CNS) and a demyelination inducing CTL reaction. Following the detailed characterization of our model the role of several components of the innate and adaptive immune system will be defined. In particularly, we will test the hypothesis whether in this scenario toll-like receptors in the CNS are of pivotal relevance.