The role of polysialic acid in adaptive immunity and peripheral tolerance

更广泛的研究背景来自动物模型和人类数据的证据表明，多唾液酸化是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我耐受性之间的平衡中起着至关重要的作用。具体地说，我们和其他人证明了趋化因子受体CCR7依赖于多唾液酸化来识别其趋化因子配体CCL21。CCR7引导树突状细胞从外周组织迁移到引流淋巴结，在那里它们将摄取在外周的抗原递送到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细胞的激活至关重要，但也在稳定状态下发生，在稳定状态下，树突状细胞是维持T细胞自我耐受所必需的。尽管多唾液酸化通过CCR7轴调节免疫似乎是合理的，但这还没有在动物身上进行测试。此外，聚唾液酸在CCL21传感中的作用是组织相关的。这种现象的分子背景还不清楚。目的我们将使用有条件的基因靶向小鼠模型来测试体内多唾液酸化的后果。我们将进一步讨论当趋化因子出现在外周组织和淋巴组织中时，如何在分子水平上控制CCL21感知的调节。方法我们将使用流感感染模型来表征多唾液酸化在T细胞启动中的作用。在不同的树突状细胞亚群和T细胞上，使用缺乏聚唾液酸的基因靶向小鼠，我们将确定哪些细胞类型依赖于聚唾液酸，以及哪些免疫相关功能在没有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我耐受中的细胞类型特异性作用，我们从初步数据得知，在造血系统中存在整体缺陷的小鼠发生自身免疫。根据我们之前的工作，我们知道非细胞自主效应调节了趋化因子感知的聚唾液酸依赖机制。我们将识别呈现CCL21的分子，以便其感知要么依赖于聚唾液酸，要么独立于聚唾液酸。候选人将接受自下而上的重组方法的测试。创新我们的问题不仅与适应性免疫启动的分子理解相关，而且可能对其操作具有重要意义。CCR7轴将是控制免疫和癌症转移的一个有吸引力的药物靶点，在这些系统中，该系统被贩运的肿瘤细胞劫持。然而，CCR7是出了名的混杂，许多免疫细胞类型依赖于它，导致在阻断时产生多效性效应。多唾液酸化只影响细胞、组织和CCR7配体的子集，为推测的药物靶向方法提供了潜在的特异性。

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.