Browsing by Author "Schmolka, Nina"
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- Cross-regulation between cytokine and microRNA pathways in T cellsPublication . Amado, Tiago; Schmolka, Nina; Metwally, Hozaifa; Silva-Santos, Bruno; Gomes, Anita QuintalmicroRNA (miRNA) mediated regulation of protein expression has emerged as an important mechanism in T-cell physiology, from development and survival to activation, proliferation, and differentiation. One of the major classes of proteins involved in these processes are cytokines, which are both key input signals and major products of T-cell function. Here, we summarize the current data on the molecular cross-talk between cytokines and miRNAs: how cytokines regulate miRNA expression, and how specific miRNAs control cytokine production in T cells. We also describe the inflammatory consequences of deregulating the miRNA/cytokine axis in mice and humans. We believe this topical area will have key implications for immune modulation and treatment of autoimmune pathology.
- Epigenetic and transcriptional signatures of stable versus plastic differentiation of proinflammatory gd T cell subsetsPublication . Schmolka, Nina; Serre, Karine; Grosso, Ana R.; Rei, Margarida; Pennington, Daniel J.; Gomes, Anita Q.; Silva-Santos, BrunoTwo distinct subsets of γδ T cells that produce interleukin 17 (IL-17) (CD27(-) γδ T cells) or interferon-γ (IFN-γ) (CD27(+) γδ T cells) develop in the mouse thymus, but the molecular determinants of their functional potential in the periphery remain unknown. Here we conducted a genome-wide characterization of the methylation patterns of histone H3, along with analysis of mRNA encoding transcription factors, to identify the regulatory networks of peripheral IFN-γ-producing or IL-17-producing γδ T cell subsets in vivo. We found that CD27(+) γδ T cells were committed to the expression of Ifng but not Il17, whereas CD27(-) γδ T cells displayed permissive chromatin configurations at loci encoding both cytokines and their regulatory transcription factors and differentiated into cells that produced both IL-17 and IFN-γ in a tumor microenvironment.
- Epigenetic mechanisms in the regulation of lymphocyte differentiationPublication . Schmolka, Nina; Silva-Santos, Bruno; Gomes, Anita Q.Epigenetics refers to heritable phenotype changes that do not involve alterations in the DNA sequence. While DNA methylation and histone modifications represent the classical epigenetic mechanisms, RNA-based interference can also be integrated into the epigenetic machinery. In particular, microRNAs play important roles in regulating gene expression at the posttranscriptional level. Thus, from the nucleus to the cytoplasm, various “epigenetic” mechanisms can control cell fate decisions and differentiation. This has been extensively documented in lymphocyte biology, from a commitment to the B- and T-cell lineages to the differentiation of multiple effector lymphocyte subsets. Here we review the accumulated knowledge that fundaments our understanding of how classical epigenetics and RNA-based regulatory mechanisms impact B- and T-cell differentiation.
- microRNA 181a regulates IFN-γ expression in effector CD8+T cell differentiationPublication . Amado, Tiago; Amorim, Ana; Enguita, Francisco J.; Romero, Paula V.; Inácio, Daniel; Miranda, Marta P.; Winter, Samntha J.; Simas, Pedro J.; Krueger, Andreas; Schmolka, Nina; Silva-Santos, Bruno; Gomes, Anita Q.In the past years, the importance of microRNAs in the development and maintenance of cell identity and on the regulation of cytokine expression within cells of the immune system has gained increasing strength. CD8+ T cells are key players in immunity against intracellular infections, namely viral infections, and tumors. The main cytokine associated with these protective responses is interferon-IFN-γ, whose production is known to be regulated at the transcriptional level during CD8+ T cell differentiation. In this study, we show that microRNAs constitute a post-transcriptional brake to IFN-γ expression by CD8+ T cells as the genetic interference with the Dicer processing machinery resulted in the increased production of IFNγ by both thymic and peripheral CD8+ T cells. Using a YFP reporter mouse for IFN-γ locus activity we compared the microRNA repertoires associated with the presence or absence of IFN-γ expression. This allowed us to identify a set of candidates, including miR-181a and miR-451, which were functionally tested in overexpression experiments using synthetic mimics in peripheral CD8+ T cell cultures. We found that miR-181a limits IFN-γ production by suppressing the expression of the transcription factor Id2, which in turn promotes the Ifng expression program. Importantly, upon MuHV-4 challenge, miR-181a-deficient mice showed a more vigorous IFNγ+ CD8+ T cell response, and were able to control murid gammaherpesvirus-4 virus infection significantly more efficiently than control mice. Collectively, these data establish a novel role for miR-181a in regulating IFN-γ–mediated effector CD8+ T cell responses in vitro and in vivo.
- 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.
- MicroRNA-181a regulates IFN-γ expression in effector CD8+ T cell differentiationPublication . Amado, Tiago; Amorim, Ana; Enguita, Francisco J.; Romero, Paula V.; Inácio, Daniel; Miranda, Marta Pires; Winter, Samantha J.; Simas, J. Pedro; Krueger, Andreas; Schmolka, Nina; Silva-Santos, Bruno; Gomes, Anita Q.CD8+ T cells are key players in immunity against intracellular infections and tumors. The main cytokine associated with these protective responses is interferon-γ (IFN-γ), whose production is known to be regulated at the transcriptional level during CD8+ T cell differentiation. Here we found that microRNAs constitute a posttranscriptional brake to IFN-γ expression by CD8+ T cells since the genetic interference with the Dicer processing machinery resulted in the overproduction of IFN-γ by both thymic and peripheral CD8+ T cells. Using a gene reporter mouse for IFN-γ locus activity, we compared the microRNA repertoires associated with the presence or absence of IFN-γ expression. This allowed us to identify a set of candidates, including miR-181a and miR-451, which were functionally tested in overexpression experiments using synthetic mimics in peripheral CD8+ T cell cultures. We found that miR-181a limits IFN-γ production by suppressing the expression of the transcription factor Id2, which in turn promotes the Ifng expression program. Importantly, upon the MuHV-4 challenge, miR-181a-deficient mice showed a more vigorous IFN-γ+ CD8+ T cell response and were able to control viral infection significantly more efficiently than control mice. These data collectively establish a novel role for miR-181a in regulating IFN-γ-mediated effector CD8+ T cell responses in vitro and in vivo.