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自身免疫反应期间发挥保护性或有害作用。针对病原体的免疫反应也可能导致脑组织永久损害。因此，决定是否应破坏感染细胞以拯救宿主生物，这是重要的。该项目解决了允许CD8 T细胞（CTL）介导的少突胶质细胞（（（自动）免疫）破坏的机制，或者反之亦然，会诱导有问题的CTL的破坏（诱导耐受性）。少突胶质细胞（ODC-ova小鼠）。表达OVA李斯特菌的外围感染诱导了OVA特异性CD8 T细胞反应，其特征是CTL初始增殖，并通过CNS通过CNS进行循环，然后在缺乏临床症状和神经病理学改变的情况下自身反应性OVA特异性CD8 T细胞的克隆缺失。在引人注目的对比中，具有相同病原体的脑内感染会导致表达OVA的抗原特异性破坏，从而临床上表现为具有持久神经系统症状的偏心疾病。这些观察结果为我们的假设提供了理由，即中枢神经系统内的局部炎症刺激决定是脑内免疫反应是否导致表达抗原的细胞或消除有问题的CD8 T细胞的破坏。在这方面，少突胶质细胞的直接敏化或小胶质细胞的间接激活可能起作用。因此，该项目旨在鉴定感染部位（CNS内部或外部）与脱髓鞘诱导CTL反应之间的关系。遵循我们模型的详细表征，将定义先天和适应性免疫系统的几个组成部分的作用。尤其是，我们将检验中枢神经系统中的类似收费的受体是否具有关键相关性。