MicroRNA‐181a restricts human γδ T cell differentiation by targeting Map3k2 and Notch2

• Published in: EMBO reports Vol. 23; no. 1; pp. e52234 - n/a
• Main Authors: Gordino, Gisela, Costa‐Pereira, Sara, Corredeira, Patrícia, Alves, Patrícia, Costa, Luís, Gomes, Anita Q, Silva‐Santos, Bruno, Ribot, Julie C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-01-2022; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: cancer; Cell Differentiation; Cytotoxicity; Differentiation (biology); effector T lymphocytes; EMBO03; EMBO19; EMBO36; Health surveillance; Humans; Immunotherapy; Inflammation; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Male; MAP kinase; MAP Kinase Kinase Kinase 2 - metabolism; MicroRNAs; MicroRNAs - genetics; miRNA; miR‐181a; Prostate cancer; Prostatic Neoplasms; Receptor, Notch2 - metabolism; Ribonucleic acid; RNA; Signal Transduction; T-Lymphocytes - cytology; Tumor necrosis factor; Tumors; γδ T cells; microRNAs; γδ T cells; cancer; miR‐181a; effector T lymphocytes; miR-181a
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202052234

γδ T cells are a conserved population of lymphocytes that contributes to anti‐tumor responses through its overt type 1 inflammatory and cytotoxic properties. We have previously shown that human γδ T cells acquire this profile upon stimulation with IL‐2 or IL‐15, in a differentiation process dependent on MAPK/ERK signaling. Here, we identify microRNA‐181a as a key modulator of human γδ T cell differentiation. We observe that miR‐181a is highly expressed in patients with prostate cancer and that this pattern associates with lower expression of NKG2D, a critical mediator of cancer surveillance. Interestingly, miR‐181a expression negatively correlates with an activated type 1 effector profile obtained from
in vitro
differentiated γδ T cells and miR‐181a overexpression restricts their levels of NKG2D and TNF‐α. Upon
in silico
analysis, we identify two miR‐181a candidate targets, Map3k2 and Notch2, which we validate
via
overexpression coupled with luciferase assays. These results reveal a novel role for miR‐181a as critical regulator of human γδ T cell differentiation and highlight its potential for manipulation of γδ T cells in next‐generation immunotherapies.
Synopsis
The miR‐181a targets Map3k2 and Notch2 and thereby regulates human γδ T cell differentiation. This limits the expression of NKG2D and TNF‐α, both involved in γδ T cell‐mediated cancer surveillance.
High levels of miR‐181a associate with low expression of NKG2D in circulating γδ T cells from prostate cancer patients.
miR‐181a expression negatively correlates with activated type 1 effector profiles in human γδ T cell differentiated cultures.
miR‐181a overexpression limits the induction of NKG2D and TNF‐α expression in differentiating γδ T cells.
Map3k2 and Notch2 are direct miR‐181a targets.
Graphical Abstract
The miR‐181a targets Map3k2 and Notch2 and thereby regulates human γδ T cell differentiation. This limits the expression of NKG2D and TNF‐α, both involved in γδ T cell‐mediated cancer surveillance.