The role of polysialic acid in adaptive immunity and peripheral tolerance

聚唾液酸在适应性免疫和外周耐受中的作用

• 批准号: 512908699
• 负责人: Professor Michael Sixt
• 金额: --
• 依托单位: Institute of Science and Technology Austria
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/512908699?language=en
• 关键词: role; polysialic; acid; adaptive; immunity

Wider research contextEvidence from animal models as well as human data suggest that polysialylation, a rare post-translational sugar-modification of proteins, is crucially involved in the balance between the adaptive immunity to pathogens and immunological self-tolerance. Specifically, we and others showed that the chemokine receptor CCR7 depends on polysialylation in order to recognize its chemokine ligand CCL21. CCR7 guides the migration of dendritic cells from peripheral tissues to the draining lymph node, where they present antigens ingested in the periphery, to T cells. Dendritic cell trafficking occurs during infection, where it is crucial for T cell activation, but also in the steady state, where it is required for maintaining self-tolerance of T cells. Although it seems plausible that polysialylation regulates immunity via the CCR7 axis, this has not been tested in animals. Furthermore, role of polysialic acid in CCL21-sensing is tissue dependent. The molecular context of this phenomenon is not understood.ObjectivesWe will use conditionally gene-targeted mouse models to test the consequences of polysialylation in vivo. We will further address how regulation of CCL21-sensing is controlled on a molecular level, when the chemokine is presented in peripheral tissues vs. lymphatic organs.ApproachWe will characterize the role of polysialylation in T cell priming using an influenza infection model. Using gene targeted mice specifically lacking polysialylic acid on different dendritic cell subsets vs. T cells we will pinpoint, which cell types depend on polysialylic acid and which immunologically relevant functions are affected in the absence of polysialylic acid. We will further address the cell type specific role of polysialylic acid in self-tolerance by studying spontaneously developing autoimmunity, which we know from preliminary data to develop in mice with a global deficiency to polysialylate in the hematopoietic system.Based on our previous work we know that non-cell autonomous effects modulate the polysialylic acid dependent mechanism of chemokine sensing. We will identify molecules, which present CCL21 so that its sensing is either dependent or independent of polysialylic acid. Candidates will be tested in a bottom-up reconstitution approach.InnovationOur question is not only relevant for the molecular understanding of adaptive immune priming but could also be of significant relevance for its manipulation. The CCR7 axis would be an attractive drug-target to control immunity and cancer metastasis, where the system is hijacked by trafficking tumor cells. However, CCR7 is notoriously promiscuous and many immune cell types depend on it, leading to pleiotropic effects upon blockade. Polysialylation only affects a subset of cells, tissues and CCR7 ligands, giving potential specificity to a putative drug-targeting approach.Primary researchers involved: Michael Sixt at the Institute of Science and Technology Austria.

更广泛的研究背景来自动物模型和人类数据的证据表明，聚唾液酸化，一种罕见的蛋白质翻译后糖修饰，在对病原体的适应性免疫和免疫自身耐受之间的平衡中起着至关重要的作用。具体来说，我们和其他人表明趋化因子受体CCR 7依赖于聚唾液酸化，以识别其趋化因子配体CCL 21。CCR7引导树突状细胞从外周组织迁移到引流淋巴结，在那里它们将在外周摄取的抗原呈递给T细胞。树突状细胞的运输发生在感染期间，在感染期间，树突状细胞对T细胞活化至关重要，但也发生在稳定状态下，在稳定状态下，树突状细胞是维持T细胞自身耐受性所必需的。虽然聚唾液酸化通过CCR7轴调节免疫似乎是合理的，但这尚未在动物中进行过测试。此外，聚唾液酸在CCL 21传感中的作用是组织依赖性的。这种现象的分子背景是不understood.ObjectivesWe将使用条件基因靶向小鼠模型来测试体内聚唾液酸化的后果。我们将进一步解决如何调控的CCL21传感控制在分子水平上，当趋化因子是在外周组织与淋巴organs.ApproachWe的特点聚唾液酸化的作用，在T细胞启动使用流感感染模型。使用在不同树突细胞亚群上特异性缺乏聚唾液酸的基因靶向小鼠与T细胞，我们将查明哪些细胞类型依赖于聚唾液酸，哪些免疫相关功能在不存在聚唾液酸的情况下受到影响。我们将通过研究自发发展的自身免疫来进一步探讨聚唾液酸在自身耐受中的细胞类型特异性作用，我们从初步数据中了解到，在造血系统中聚唾液酸缺乏的小鼠中，非细胞自主效应调节趋化因子传感的聚唾液酸依赖性机制。我们将确定分子，目前CCL21，使其传感是依赖或独立的聚唾液酸。候选人将在一个自下而上的重建approach.InnovationOur问题是不仅相关的适应性免疫启动的分子理解，但也可能是其操作的显着相关性。CCR7轴将是控制免疫和癌症转移的有吸引力的药物靶点，其中该系统被运输肿瘤细胞劫持。然而，CCR7是众所周知的混杂的，许多免疫细胞类型依赖于它，导致阻断后的多效性效应。多聚唾液酸化作用只影响一部分细胞、组织和CCR7配体，为一种假定的药物靶向方法提供了潜在的特异性。主要研究人员：奥地利科学技术研究所的Michael Sixt。