The SYNECT team investigates synaptic ectosomes. Synaptic ectosomes are vesicles that bud from the plasma membrane of the T cell toward antigen presenting cells. We discovered these small extracellular vesicles in the immunological synapse in 2014. The key attributes of these structures that distinguish them from other signals generated by T cells is that their composition is determined by the specific molecular interactions with the antigen presenting cells and they are thus customized for this communication. They are uniquely suited to generate combinatorial signals that remain with the antigen-presenting cell after the T cell disengages to sustain these signals. We have developed a platform of methods for analysis, characterization and functional analysis of human synaptic ectosomes. The information that we gain from these studies will help design better vaccines and may also generate new targets for treatment of autoimmune diseases.
We collaborated with Carola Vinuesa from Australia and Claudio Doglioni from Italy on the ability of human T follicular helper cells produce dopamine in response to antigen receptor engagement. Dr. David Saliba determined that the dopamine containing granules are concentrated at the immunological synapse and that the resulting up-regulation of ICOSL triggered in B cells dopamine enhances the release of CD40L into punctate structures in the central region of the immunological synapse, the synaptic ectocomes.
Dr. Viveka Mayya published in Cell Reports that motility behaviour is different between effector CD8 T cells, which form stable synapse, and other major T cells subsets (CD4 Naive, CD4 memory and CD8 naive), that form motile "kinapses" while detecting antigen. Dr. Mayya used trails of synaptic ectosomes to follow movement of the kinapse forming T-cells. He has followed this up with a paper in Journal of Immunology that demonstrates superior competition by memory CD8 T cells for sources of antigen compared to naive CD8 T cells. This has implications for vaccines where memory T cell with inferior antigen receptors may sometimes beat out naive T cells with optimal antigen receptors.
Dr. Ewoud Compeer has a paper that was supported by SYNECT that was just accepted at Nature Immunology documenting the effects of enforced Foxo1 nuclear localisation on immunological synapse formation. Constitutively active Foxo1 keeps T cells in a metabolically quiescent state even when they are forced to enter cell cell cycle and attempt differentiation. This leads to T cells in which the plasma membrane composition is deficient in cholesterol. These quiescent effector cells have a defect in generation of a cSMAC- the structure containing the synaptic ectosomes.
Dr. Saliba, Cespedes, Balint and Compeer published in Elife on the composition, structure and function of synaptic ectosomes released from helper T cells. These structures combine T cell antigen receptors and the effect molecule CD40L in ~100 nm vesicles that are delivered to the antigen presenting cell.
Dr. Balint and colleagues published in Science on the discovery of supramolecular attack particles that contain cytotoxic proteins in a core/shell structure. This is a new mechanisms for T cell mediated killing and the entities may be useful in cancer immunotherapy.
Dr Compeer will complete and submit a paper focus on in vivo role of synaptic ectosomes and age dependent changes in TSG101 levels in T cells that may contribute to poor vaccine responses in the elderly.
Work on supramolecular attack particles will be continued with the ERC Synergy Grant ATTACK-https://supramolecular-attack-particles.eu
