Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses
- Universidad Autónoma de Madrid, Spain
- INSERM U932, Institut Curie, PSL Research University, France
- National Center for Cardiovascular Research, Spain
- Unidad Asociada al Centro Nacional de Biotecnología, Spain
- Spanish National Research Council, Spain
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 human 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 GATA3 mRNA in CD4+ T cells and subsequent TBX21 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 mice. Our results provide new insights on the immunomodulatory roles of NK-EVs that may help to improve their use as immunotherapeutic tools.
Data availability
Sequencing data have been deposited in the Gene Expression Omnibus and are available to readers under record GSE185171. EV isolation procedures are available at EV‐TRACK knowledgebase (EV‐TRACK ID: EV210234.
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Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responsesNCBI Gene Expression Omnibus, GSE185171.
Article and author information
Author details
Ana Rodriguez-Galan
Francisco Sánchez Madrid
Lola Fernandez-Messina
Funding
Spanish National Plan for Scientific and Technical Research and Innovation (PD1-2020-120412RB-100)
- Francisco Sánchez Madrid
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental methods and protocols were approved by the CNIC and the Comunidad Autónoma de Madrid and conformed to European Commission guidelines and regulations (PROEX-206.1/20)
Copyright
© 2022, Dosil et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses
eLife 11:e76319.
https://doi.org/10.7554/eLife.76319
Further reading
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- Immunology and Inflammation
Natural killer (NK) cells recognize target cells through germline-encoded activation and inhibitory receptors enabling effective immunity against viruses and cancer. The Ly49 receptor family in the mouse and killer immunoglobin-like receptor family in humans play a central role in NK cell immunity through recognition of major histocompatibility complex class I (MHC-I) and related molecules. Functionally, these receptor families are involved in the licensing and rejection of MHC-I-deficient cells through missing-self. The Ly49 family is highly polymorphic, making it challenging to detail the contributions of individual Ly49 receptors to NK cell function. Herein, we showed mice lacking expression of all Ly49s were unable to reject missing-self target cells in vivo, were defective in NK cell licensing, and displayed lower KLRG1 on the surface of NK cells. Expression of Ly49A alone on an H-2Dd background restored missing-self target cell rejection, NK cell licensing, and NK cell KLRG1 expression. Thus, a single inhibitory Ly49 receptor is sufficient to license NK cells and mediate missing-self in vivo.
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