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

自身免疫或耐受诱导：通过局部感染控制 CD8 T 细胞介导的针对 CNS 少突胶质细胞的免疫反应

• 批准号: 226122717
• 负责人: Professorin Dr. Martina Deckert
• 金额: --
• 依托单位: Institut für Virologie und Immunbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226122717?language=en
• 关键词: Autoimmunity; tolerance; induction; control; CD8

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.

在中枢神经系统中，T 淋巴细胞可能在免疫监视和感染期间或在自身免疫反应期间分别发挥保护作用或有害作用。针对病原体的免疫反应也可能导致脑组织永久性损伤；因此，是否应该破坏受感染的细胞以拯救宿主生物体的决定很重要。该项目解决了允许 CD8 T 细胞 (CTL) 介导的少突胶质细胞破坏（（自身）免疫）的机制，或者反之亦然，诱导破坏有问题的 CTL（诱导耐受）。我们已经建立了转基因小鼠品系，仅在少突胶质细胞（ODC-OVA 小鼠）的细胞质中表达卵清蛋白 (OVA) 作为自身抗原。表达 OVA 的李斯特菌的外周感染会诱导 OVA 特异性 CD8 T 细胞反应，其特征是 CTL 最初增殖并通过 CNS 循环，然后在没有临床症状和神经病理学情况下克隆删除自身反应性 OVA 特异性 CD8 T 细胞变更。与此形成鲜明对比的是，相同病原体的脑内感染会导致表达 OVA 的少突胶质细胞发生抗原特异性破坏，临床上表现为伴有持续性神经系统症状的麻痹性疾病。这些观察结果为我们的假设提供了理论依据，即中枢神经系统内的局部炎症刺激决定脑内免疫反应是否会导致抗原表达细胞的破坏或导致攻击性 CD8 T 细胞的消除。在这方面，少突胶质细胞的直接致敏或小胶质细胞的间接激活可能发挥作用。因此，该项目旨在确定感染部位（中枢神经系统内部或外部）与脱髓鞘诱导的 CTL 反应之间的关系。在详细描述我们的模型之后，将定义先天性和适应性免疫系统的几个组成部分的作用。特别是，我们将检验这一假设，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。