Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses

ABSTRACT Natural killer (NK) cells recognise and kill target cells undergoing different types of stress. NK cells are also capable of modulating immune responses. In particular, they regulate T cell functions. Small RNA next-generation sequencing of resting and activated NK cells and their secreted EVs led to the identification of a specific repertoire of NK-EV-associated microRNAs and their post-transcriptional modifications signature. Several microRNAs of NK-EVs, namely miR-10b-5p, miR-92a-3p and miR-155-5p, specifically target molecules involved in Th1 responses. NK-EVs promote the downregulation of GATA-3 mRNA in CD4 + T cells and subsequent T-bet de-repression that leads to Th1 polarization and IFN-γ and IL-2 production. NK-EVs also have an effect on monocyte and moDCs function, driving their activation and increased presentation and co-stimulatory functions. Nanoparticle-delivered NK-EV microRNAs partially recapitulate NK-EV effects in vivo . Our results provide new insights on the immunomodulatory roles of NK-EVs that may help to improve their use as immunotherapeutic tools.