Human Frontier Science Program Career Development Award

Prize: Fellowship awarded competitivelyAcademic

Description

My goal is to elucidate the molecular mechanism of major histocompatibility class II (MHCII) trafficking to the immunological synapse (IS) between T-cells and dendritic cells (DCs). There is substantial evidence that in DCs peptide-bound MHCII is selectively trafficked from intracellular MHCII containing compartments (MIIC) to the IS where it interacts with the T-cell receptor for activation of T-cells. Nevertheless, the IS has been almost exclusively studied from the T-cell side and not from the DC and the molecular pathways that govern delivery of MHCII at the plasma membrane of DCs are still completely unknown. Specifically, the SNARE proteins, which are key trafficking proteins that catalyze intracellular membrane fusion, need to be identified. Based on my extensive experience in membrane trafficking in neuroendocrine cells, I propose to develop a new and innovative approach to identify the SNAREs responsible for MHCII trafficking to the IS. I will first position an IS between an antigen-specific T-cell and a DC parallel to the optical plane of a microscope with a micromanipulator, thereby enabling a high spatial resolution. I will then employ a combination of Förster resonance energy transfer (FRET)-based microscopy and functional assays to unequivocally identify the SNAREs that catalyze release of MIIC at the plasma membrane of DCs. Understanding how MHCII is selectively presented to the T-cell is essential for understanding the high sensitivity of T-cell activation by DCs. My study will also result in the development of new tools and insights that enable unraveling the release mechanisms of other surface exposed molecules and secreted cytokines from immune cells.
Degree of recognitionInternational
Granting OrganisationsHuman Frontiers Science Program Organisation

Keywords

  • HSFP Career Development Award

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