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Advisor(s)
Abstract(s)
The ability of murine γδ T cells to rapidly produce the pro-inflammatory cytokines interleukin 17 (IL-17) or interferon-γ (IFN-γ) underlies their crucial roles in several (patho)physiological contexts. This
capacity stems from a complex process of ‘developmental pre-programming in the thymus, after which
a large fraction of γδ T cells migrate to peripheral sites already committed to producing either the IL-17
or IFN-γ. We have previously found that one microRNA, miR-146a, maintains peripheral γδ T cell identity
by inhibiting IFN-g production by the IL-17-committed CD27− gδ T cell subset. To further and more globally
address the role of microRNAs in effector γδ T cell differentiation, we established a double reporter IL17-GFP:IFN-γ-YFP mouse strain and isolated pure IL-17+ and IFN-γ+ γδ T cell populations from the
peripheral lymphoid organs to perform small RNA-sequencing. This allowed us to identify clearly distinct
microRNA signatures associated with cytokine expression in γδ T cells, from which we selected ten
candidate microRNAs differentially expressed between IL-17+ and IFN-γ+ γδ T cells to study further. We
characterized the detailed expression pattern of each candidate microRNA in γδ T cell subsets throughout
mouse ontogeny and upon gain-of-function studies in in vitro cultures of γδ T cells. Our results indicate
that while some microRNAs, such as miR-128-3p and miR181a-5p, regulate γδ T cell development in the
thymus, other candidates, including miR-7a-5p, miR-139-5p, miR-322-5p, and miR-450b-3p, modulate
peripheral γδ T cell effector functions. More specifically, using a miR-181a deficient mouse model, we
have found that miR-181a, highly expressed in immature γδ T cell subsets in the thymus, shifts the in vivo
IL-17/IFN-γ balance towards the IL-17 pathway in neonatal life, which is further maintained in the
periphery during adult life. On the other hand, miR-7a-5p and miR-139-5p, overexpressed in peripheral
IFN-g+ γδ T cells, regulate peripheral γδ T cell effector functions, either acting as an IFN-γ auto-repressor
(miR-139-5p) or promoting functional plasticity (miR-7a-5p). Finally, miR-322-5p and miR-450b-3p,
overexpressed in IL-17+ γδ T cells, may have therapeutic potential by modulating the production of IFNγ, whose levels are critical in anti-tumoral and anti-viral responses. These data demonstrate the impact
of microRNAs on the differentiation and functional identity of effector γδ T cell subsets, which may open
new avenues for their manipulation in disease settings.
Description
Keywords
MicroRNA Cytokines
Citation
Inácio D, Amado T, Silva M, Sobral D, Cunha C, Gomes AQ, et al. A key role for microRNAs in the development and functional differentiation of γδ T cell subsets. In: 9th International gd T cell Conference [online], Zhuhai (China), November 5-8, 2021.