Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/8390
Mitochondrial DNA transfer through Exomes during Immune Synapsis primes Antiviral Innate Immune Response in Dendritic Cells
Torralba, Daniel CNIC
Date of defense
The generation of a specific immune response against a pathogen requires the initial interaction of an antigen-specific T cell with antigen-presenting cells (APCs), specifically dendritic cells (DCs). T cell recognition of major histocompatibility complex (MHC) bound to antigens leads to the formation of a stable intercellular junction between the cells, the immune synapse (IS). In T cells the IS involves a redistribution of membrane-associated receptors, the cytoskeleton, and the polarization of intracellular trafficking and secretory organelles. The transfer of bioactive molecules from the T cell to the DC through the IS constitutes a main vehicle of intercellular communication. T cells and DCs exchange numerous molecules, including cytokines, membrane receptors, membrane patches, signaling molecules or genetic material (mainly functional microRNAs) during IS formation. Extracellular vesicles are one of the cellular mechanisms mediating information transfer between the T cell and the DCs. EVs comprise apoptotic bodies, ectosomes or microvesicles, and exosomes. Exosomes are distinguished by their unique endocytic origin. Exosomes form by invagination of the multivesicular body (MVB) membrane and are released to the extracellular medium upon the fusion of the MVB with the plasma membrane. Exosomes are particularly enriched in genetic material, mostly RNA species such as small RNAs and long non-coding RNAs, as well as DNA. This makes them attractive candidates to mediate cell-to-cell communication. However, the ability of the genetic material contained within exosomes to evoke immune signaling responses in recipient cells is largely unexplored. Our data show that T cells secrete extracellular vesicles containing mitochondrial DNA (mtDNA) and mitochondrial proteins that can be transfer to the APC through cognate interactions. We provide evidence that mtDNA and related proteins segregate into MVB pathway. Blockage of exosome secretion alters mitochondrial function and morphology which suggests that release of mitochondrial content loaded into exosomes contributes to mitochondrial homeostasis. In addition, we demonstrate that both mitochondrial proteins and mtDNA are transferred during IS in a unidirectional way from the T cell to the APC. Finally, our results show that T cells prime DCs through the transfer of exosomal DNA, supporting a specific role for antigen-dependent contacts in conferring protection to DCs against subsequent viral infections. In conclusion, our data illustrate a way by which T cells promote an alert state in DCs that protects them against posterior infection driven by the vesicular transfer of DNA. These findings shed new light on how the reciprocal communication between innate and adaptive immune cells allow efficacious responses to unknown threats.
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