Browsing by Author "Papotto, Pedro H."
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- Dissection of the microRNA transcriptomes of CD4+ T cell subsets in autoimmune inflammation identifies novel regulators of disease pathogenesisPublication . Cunha, Carolina; Romero, Paula Vargas; Inácio, Daniel; Pais, Ana Teresa; Pelicano, Catarina; Costa, Marina; Mensurado, Sofia; Gonçalves-Sousa, Natacha; Papotto, Pedro H.; Neves, Daniel; Sobral, Daniel; Enguita, Francisco; Silva-Santos, Bruno; Gomes, AnitaMicroRNAs (miRNAs) are key regulators of CD4+ T cell differentiation, but how they contribute to the course of an autoimmune disease in vivo remains poorly studied. Given the known roles in autoimmunity of pro-inflammatory T helper 1 (Th)1 and Th17 cells, and anti-inflammatory Foxp3+ regulatory cells, we established a triple reporter mouse for Ifng, Il17 and Foxp3, and subjected it to experimental autoimmune encephalomyelitis (EAE) to characterize the miRNomes of the corresponding CD4+ T cell subsets. We identified 110 miRNAs differentially expressed between the pro-inflammatory (Th1 and Th17 cells) and the Treg cell subsets. Among these, we found novel functions for miR-122-5p and miR-1247 as regulators of Th17 cell proliferation and Th1 cell differentiation, thus impacting the course or severity of EAE, respectively. Importantly, their expression patterns suggest miR-122-5p and miR-1247 act as peripheral brakes to CD4+ T cell pathogenicity that are subverted in the inflamed central nervous system.
- MicroRNA-146a controls functional plasticity in γδ T cells by targeting NOD1Publication . Schmolka, Nina; Papotto, Pedro H.; Romero, Paula Vargas; Amado, Tiago; Enguita, Francisco J.; Amorim, Ana; Rodrigues, Ana F.; Gordon, Katrina E.; Coroadinha, Ana S.; Boldin, Mark; Serre, Karine; Buck, Amy H.; Gomes, Anita Quintal; Silva-Santos, Brunoγδ T cells are major providers of proinflammatory cytokines. They are preprogrammed in the mouse thymus into distinct subsets producing either interleukin-17 (IL-17) or interferon-γ (IFN-γ), which segregate with CD27 expression. In the periphery, CD27- γδ (γδ27-) T cells can be induced under inflammatory conditions to coexpress IL-17 and IFN-γ; the molecular basis of this functional plasticity remains to be determined. On the basis of differential microRNA (miRNA) expression analysis and modulation in γδ T cell subsets, we identified miR-146a as a thymically imprinted post-transcriptional brake to limit IFN-γ expression in γδ27- T cells in vitro and in vivo. On the basis of biochemical purification of Argonaute 2-bound miR-146a targets, we identified Nod1 to be a relevant mRNA target that regulates γδ T cell plasticity. In line with this, Nod1-deficient mice lacked multifunctional IL-17+ IFN-γ+ γδ27- cells and were more susceptible to Listeria monocytogenes infection. Our studies establish the miR-146a/NOD1 axis as a key determinant of γδ T cell effector functions and plasticity.
- MicroRNA-146a controls IFN-g production and functional plasticity of murine gd T cells by targeting Nod1Publication . Schmolka, Nina; Papotto, Pedro H.; Romero, Paula Vargas; Amado, Tiago; Enguita, Francisco J.; Amorim, Ana; Gordon, Katrina E.; Boldin, Mark; Serre, Karine; Buck, Amy H.; Gomes, Anita Quintal; Silva-Santos, Brunoγδ T cells have emerged as key providers of the proinflammatory cytokines interleukin 17 (IL-17) and interferon-γ (IFN-γ) in various models of infection, inflammation, and autoimmunity. Our previous epigenetic and transcriptional analyses have shown that whereas CD27+ γδ T cells are committed to IFN-γ expression, the IL-17 producing CD27- subset has limited plasticity to co-express both cytokines under inflammatory conditions (Schmolka et al. Nat Immunol 2013). To further understand the molecular control of this plasticity we now investigated the potential role of microRNA (miRNA)-mediated post-transcriptional regulation.