Objective MicroRNAs (miRNAs) can be transferred between cells, representing an exciting new dimension to intercellular communication, referred to as non-cell-autonomous gene regulation. We recently identified that distinct miRNAs are packaged and exported from TREG cells and delivered directly to TH1 cells, suppressing T cell-mediated disease. Different T cell populations express different miRNAs and release a distinctive set of extracellular miRNAs. In this proposal we will identify whether the transfer of miRNAs between cells contributes to T cell development, T cell differentiation and TH2-mediated allergy and anti-helminth immunity. miRNA-mediated gene silencing requires one of four catalytically active Argonaut (Ago) proteins to regulate gene expression. To investigate miRNA transport between cells, we have generated novel mice with miRNA-deficient T cells that can (Dicer–/–) or cannot (Dicer–/–Ago-1,-3,-4–/– Ago-2fl/fl) respond to exogenous miRNAs. Using these novel mice we will identify which Ago protein(s) specific miRNAs associate with and which Ago proteins are required for miRNA-mediated gene regulation in T cells. TH2 cells express unique miRNAs, which can be found within TH2 cells and in extracellular vesicles released from TH2 cells. We have generated several new TH2-associated miRNA-deficient mice to investigate the cell intrinsic (cell-autonomous) and extrinsic (non-cell-autonomous) role of these miRNAs in TH2-mediated allergy and anti-helminth immunity. Studies in plants and worms have identified various mechanisms of RNA transfer between cells, involving cell-contact dependent and independent mechanisms. We will translate these observations into mammalian systems and identify the mechanisms of miRNA transfer. Results from this work will identify novel miRNA-mediated pathways and incentivise state-of-the-art approaches for novel therapeutic intervention to treat inflammatory diseases. Fields of science medical and health scienceshealth sciencesinflammatory diseasesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencescell biologymedical and health sciencesclinical medicineallergologynatural sciencesbiological sciencesgeneticsRNA Keywords micro RNA (miRNA) T lymphocyte Type-2 immunity Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-CoG-2014 - ERC Consolidator Grant Call for proposal ERC-2014-CoG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution THE FRANCIS CRICK INSTITUTE LIMITED Net EU contribution € 1 762 510,00 Address 1 MIDLAND ROAD NW1 1AT London United Kingdom See on map Region London Inner London — West Camden and City of London Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 762 510,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all THE FRANCIS CRICK INSTITUTE LIMITED United Kingdom Net EU contribution € 1 762 510,00 Address 1 MIDLAND ROAD NW1 1AT London See on map Region London Inner London — West Camden and City of London Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 762 510,00