Journal
EMBO REPORTS
Volume 23, Issue 1, Pages -Publisher
WILEY
DOI: 10.15252/embr.202052234
Keywords
cancer; effector T lymphocytes; microRNAs; miR-181a; gamma delta T cells
Categories
Funding
- Fundacao para a Ciencia e Tecnologia (FCT) [IF/00013/2014, SFRH/BD/128866/2017]
- Fundo de Investigacao para a Saude/INFARMED [FIS-FIS-2015-01_ONC_20150630-162]
- la Caixa Foundation [100010434, LCF/PR/HR19/52160011]
- Fundacao para a Ciencia e a Tecnologia (FCT)/Ministerio da Ciencia, Tecnologia e Ensino Superior (MCTES) [UIDB/50005/2020]
- FEDER from POR Lisboa 2020-Programa Operacional Regional de Lisboa, Portugal 2020 [LISBOA-01-0145-FEDER-016394]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/128866/2017, UIDB/50005/2020] Funding Source: FCT
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The research identified miR-181a as a key regulator of human gamma delta T cell differentiation, with its overexpression leading to reduced levels of NKG2D and TNF-alpha. This highlights the potential of miR-181a in manipulating gamma delta T cells for next-generation immunotherapies.
gamma delta 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 gamma delta 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 gamma delta 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 uitro differentiated gamma delta T cells and miR-181a overexpression restricts their levels of NKG2D and TNF-alpha. Upon in silico analysis, we identify two miR-181a candidate targets, Map3k2 and Notch2, which we validate uia overexpression coupled with luciferase assays. These results reveal a novel role for miR-181a as critical regulator of human gamma delta T cell differentiation and highlight its potential for manipulation of gamma delta T cells in next-generation immunotherapies.
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