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Role of microRNAs on T cell differentiation during immune responses in vivo

2021-09Conference object Open access
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dc.contributor.authorCunha, Carolina
dc.contributor.authorRomero, Paula Vargas
dc.contributor.authorPelicano, Catarina
dc.contributor.authorPais, Ana Teresa
dc.contributor.authorInácio, Daniel
dc.contributor.authorPappoto, Pedro
dc.contributor.authorAmado, Tiago
dc.contributor.authorSilva-Santos, Bruno
dc.contributor.authorGomes, Anita Q.
dc.date.accessioned2022-03-04T12:03:01Z
dc.date.available2022-03-04T12:03:01Z
dc.date.issued2021-09
dc.description.abstractCD4+ T cells are key players in host defense against pathogens, but an incorrect balance between CD4+ T cell subsets, namely pro-inflammatory effector cells, including T helper 1 (Th)1 and Th17 cells (IFN-γ- and IL-17-producers, respectively), and anti-inflammatory regulatory cells (Treg; Foxp3+ subset), can lead to immune-mediated diseases. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. While individual miRNAs were shown to regulate the differentiation of specific CD4+ T cell populations, a holistic approach based on in vivo responses is missing and is critical to understanding how miRNA networks control this balance under physiological conditions. To address this, we have established a triple reporter mouse for Ifng, Il17, and Foxp3, and subject it to experimental autoimmune encephalomyelitis (EAE). We perform miRNA-seq analysis on Th1, Th17, and Treg cells isolated from the spleen (SPL) and lymph nodes (LNs) at the peak-plateau stage and found that 110 miRNAs are differentially expressed between effector and regulatory subsets. We further selected 8 candidate miRNAs that were specifically upregulated in one population versus the others. Both overexpression and inhibition studies showed that miR-126a limits IL-17+ expression in Th17 cells in vitro. Treatment with antagomiRs in vivo showed that silencing miR-122 increased the number of IL-17+ cells in the LNs and precipitated the onset of EAE, whereas inhibition of miR-1247 decreased the severity of the disease by reducing the number of IFN-γ+ cells, also in the LNs. Additionally, we identified IL-6 and TGF-β as the key cytokines upstream of miR-126a and miR-1247 expression, respectively. While both IL-6 and TGF-β also induce miR-122 expression, we found that IL-23 and IL-1β repress its expression. Interestingly, and given that IL-23 and IL-1β are critical to inducing Th17-mediated pathogenicity, we have consistently observed a pathogenic gene signature in CNS-derived Th17 cells when compared to peripheral Th17 cells with concomitantly decreased levels of miR-126a and miR-122. Overall, our results suggest that miR-126a and miR-122 regulate IL-17 expression and the pathogenic phenotype of Th17 cells to prevent excessive inflammation in the periphery while miR-1247 maintains the inflammatory phenotype of Th1 cells in an anti-inflammatory environment.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCunha C, Romero PV, Pelicano C, Pais AT, Inácio D, Gomes AQ, et al. Role of microRNAs on T cell differentiation during immune responses in vivo. In: III H&TRC BootCam, Hotel Aldeia dos Capuchos (Costa da Caparica), 15 de setembro de 2021.pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.21/14378
dc.language.isoengpt_PT
dc.peerreviewednopt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectMicroRNApt_PT
dc.subjectT-cell differentiationpt_PT
dc.titleRole of microRNAs on T cell differentiation during immune responses in vivopt_PT
dc.typeconference object
dspace.entity.typePublication
person.familyNameGomes
person.givenNameAnita
person.identifier.ciencia-id4B10-E015-52B7
person.identifier.orcid0000-0002-3348-0448
person.identifier.ridC-3580-2014
person.identifier.scopus-author-id7202386033
rcaap.rightsopenAccesspt_PT
rcaap.typeconferenceObjectpt_PT
relation.isAuthorOfPublication2b5a3f0a-29c2-4ecd-a83f-50d0b99a4875
relation.isAuthorOfPublication.latestForDiscovery2b5a3f0a-29c2-4ecd-a83f-50d0b99a4875

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