The role of polysialic acid in adaptive immunity and peripheral tolerance

• Applicant: Professor Michael Sixt
• Subject Area: Immunology ; Biochemistry ; Rheumatology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409784463

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.

• DFG Programme: Research Units
• Subproject of: FOR 2953: Sialic Acid as Regulator in Development and Immunity
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)