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Mechanisms of MTOC guidance and Genetic Transfer at the Immune Synapse: novel modes of Immuno-modulation

Final Report Summary - GENTRIS (Mechanisms of MTOC guidance and Genetic Transfer at the Immune Synapse: novel modes of Immuno-modulation.)

The Immune System is composed by highly autonomous and motile cells that patrol the organism. Cell-cell communication is essential for the interconnection and regulation of cell functionality, especially for the Immune System. T lymphocytes are in charge of adaptive Immunity, and they are helped in this function by professional Antigen-Presenting Cells (APCs) through the establishment of the Immune synapse (IS). The IS is a transient intercellular structure determined by the recognition of specific antigens by the T Cell Receptor (TCR) on the context of the Major Histocompatibility Complex (MHC) at the APC. Other receptors at the T cell-APC interface also set the nature and quality of this cell-cell contact. Gentris has identified the tetraspanin CD81 as a biomarker to determine the degree of maturation of the IS through the control of TCR dynamics during its positioning at peripheral or central part of the IS. The TCR position determines its activity. CD9 and CD151 tetraspanins control the localization and activity of integrins -adhesion receptors- at the peripheral zone of the IS, therefore supporting the cohesion of the T cell contact with the APCs and its duration. The molecular architecture of the IS is maintained thanks to the dynamics of cytoskeleton components beneath the plasma membrane at the IS. An important network for intracellular transport and a scaffold for IS is organized from the centrosome or MTOC (microtubule-organizing centre), a cell-polarity keeping organelle. The MTOC allows the polymerization and correct structure of microtubules, organizing a profuse system of cross-roads to help the T Cell Receptor downstream signaling at the IS. Gentris has determined that the traffic of membranous organelles at the IS is an important pathway for the intracellular transmission of external cues. We have assessed the relevance of the multivesicular bodies-dependent exocytosis of exosomes-extracellular nanovesicles- to the gap between the T cell and the APC, a close space determined by the adhesive contacts between their plasma membrane receptors. Exosomes contain genetic material such as microRNA (miRNA), able to modify the gene expression at the level of protein synthesis. The loading of miRNA in exosomes is directed by specific sequence motifs within these miRNAs that allow their interaction with particular proteins, such as hnRNPA2/B1. These exosomes are taken up by APCs and have an important impact in their global proteome and thus on their effector functions, such as their ability to be immunogenic. Gentris has demonstrated that T cell determines the control of exosome content and their polarized secretion to fine-tune the quality of immune responses.