Cell-cell synapses are an exquisitely evolved means of communication between cells. During the formation of the immune synapse (IS), diverse transmembrane and membrane associated molecules are reorganized into a highly segregated structure at the T cell–Antigen-Presenting Cell (APC) contact site. As part of this process, the tubulin cytoskeleton is vectorially directed toward the center of the IS, where the microtubule-organizing center (MTOC) localizes. MTOC translocation is an early event in IS formation that brings the secretory apparatus into close apposition with the APC, thus providing the basis for polarized secretion.
The proposal aims to define how the MTOC controls cytoskeletal rearrangement and communication at the IS, as a mechanism for macromolecule transport and nucleation of signalling molecules during synaptic contact. We will study the mechanisms of MTOC-mediated polarization of multivesicular bodies (MVB) and exosome delivery during IS formation, and will assess the role in these processes of MTOC translocation regulators (HDAC6) and microtubule (MT) polymerization promoters (Plk1 and EB1). MTOC-dependent mitochondrial polarization to the IS will be assessed as a bioenergetic source for cytoskeletal rearrangements, IS maturation and polarized exosomal delivery. In particular, our proposed study of the possible horizontal transfer of miRNAs during cognate interactions between immune cells has the potential to reveal how miRNAs can control the early initiation of immunity. We will investigate the mechanism of directional transfer of RNA-harbouring exosomes at the IS from T cell to APC, and will examine the functional consequences of this transfer on APC biology and on the immune response. These studies will open avenues for the treatment of immune-related diseases.
Fields of science
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