Protein Nanoclustering as Funcional Unit of Immune Cells

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Organization by compartmentalization is a general property of natural systems that efficiently facilitates and orchestrates biological events in space and time. In the last decade, compartmentalization of the plasma membrane of living cells has emerged as a dominant feature present at different spatiotemporal scales and regulating key functions of immune cells. I will discuss two important glycoproteins expressed on the surface of various human antigen-presenting cells (APCs), those spatiotemporal organization regulate their function: DC-SIGN and CD1d. DC-SIGN is a pathogen recognition receptor expressed on dendritic cells playing a decisive role in stimulation of different immune responses. Using a combination of multi-color single particle tracking and super-resolution microscopy approaches we investigated the effect of DC-SIGN molecular structure on the formation DC-SIGN nanoclusters and their dynamic interaction with other molecular components of the cell membrane, including the glycocalyx matrix, lipid nanodomains and clathrin coated pits. We find that DC-SIGN compartmentalizes at different spatiotemporal scales and that this hierarchical organization is crucial to facilitate its pathogen binding capabilities and clathrin-dependent endocytosis. In the second example, I will focus on CD1d, a non-classical MHC protein, involved in the presentation of lipid antigens to T cells. Using a combination of advanced biophysical techniques we found that CD1d molecules organize in nanoclusters on the membrane of APCs. We further discover that the actin cytoskeleton prevents enhanced CD1d nanoclustering by hindering physical encountering between CD1d diffusing nanoclusters, reducing basal activation of invariant natural killer T (iNKT) cells. Our results indicate that regulation of CD1d nanoclustering through the actin cytoskeleton constitutes a novel mechanism to fine-tune peripheral iNKT cell autoreactivity.