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microRNA-122 and microRNA-1247 regulate the pathogenic phenotype of effector CD4+ T cell subsets in (auto)immune responses in vivo

2022-11Conference 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.authorPapotto, Pedro
dc.contributor.authorSobral, Daniel
dc.contributor.authorAmado, Tiago
dc.contributor.authorGomes, Anita Q.
dc.contributor.authorSilva-Santos, Bruno
dc.date.accessioned2024-01-16T12:31:44Z
dc.date.available2024-01-16T12:31:44Z
dc.date.issued2022-11
dc.description.abstractAutoimmune diseases are often associated with an imbalance 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 Foxp3+ regulatory cells (Treg). The differentiation of these distinct CD4+ T cell subsets is known to be regulated by microRNAs (miRNAs), small non-coding RNAs that fine-tune gene expression at the post-transcriptional level. While various individual miRNAs have been implicated in this process, a holistic approach focused on in vivo immune responses is missing to better understand how miRNA networks shape the CD4+ T cell compartment in pathophysiology. To address this biological question, we established a triple reporter mouse for Ifng, Il17, and Foxp3, and subjected it to experimental autoimmune encephalomyelitis (EAE), a widely used rodent model of Multiple Sclerosis (MS). We performed miRNA-seq analysis on Th1, Th17, and Treg cells isolated from the spleen and lymph nodes (LNs) at the peak-plateau stage of EAE, and found 110 miRNAs to be differentially expressed between the effector and regulatory subsets. From there, we studied the functional role of 5 candidate miRNAs as they were specifically upregulated in one population versus the others. In vivo miRNA modulation showed that silencing miR-122 (upregulated in Th17 cells) increased the frequency of IL-17A+ cells in the LNs and precipitated the onset of EAE, whereas upregulation of miR-1247 (highly expressed in the Th1 subset) decreased the severity of the disease reducing the number of IFN-γ+ cells in the LNs. We further found that both IL-6 and TGF-β induce miR-122 expression, whereas IL-23 and IL-1β repress its expression. Given that IL-23 and IL-1β are critical to induce Th17-mediated pathogenicity, our data suggests that miR-122 is expressed in a non-pathogenic context. Interestingly, we have observed a pathogenic gene signature in CNS-derived Th17 cells (when compared to peripheral Th17 cells) with concomitantly decreased levels of miR-122, suggesting that miR-122 may regulate Th17 pathogenicity. Similarly, we observed that once Th1 cells infiltrate the CNS, their levels of miR-1247 decrease, and they produce higher levels of IFN-γ. Furthermore, as we found that this miRNA is induced by the anti-inflammatory cytokines IL-10 and TGF-β, we propose that miR-1247 constitutes an auto-regulatory mechanism of Th1 cells in the periphery, which is disrupted upon CNS infiltration. Overall, our results suggest that miR-122 and miR-1247 control the pathogenic phenotype of effector Th17 and Th1 cells, respectively, during CNS autoimmunity. These findings may have important implications for autoimmune diseases, which we are now assessing in samples from MS patients.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. microRNA-122 and microRNA-1247 regulate the pathogenic phenotype of effector CD4+ T cell subsets in (auto)immune responses in vivo. In: Gene Expression and Signaling in the Immune System, Cold Spring Harbor Laboratory (CSHL) [virtual meeting], November 1-5, 2022.pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.21/16896
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relation.publisherversionhttps://meetings.cshl.edu/meetings.aspx?meet=IMMUNE&year=22pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectmicroRNA-122pt_PT
dc.subjectmicroRNA-1247pt_PT
dc.subjectCD4+ T cellpt_PT
dc.titlemicroRNA-122 and microRNA-1247 regulate the pathogenic phenotype of effector CD4+ T cell subsets in (auto)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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