Examinando por Autor "Fernández, Dominique"

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    CD73 and CD39 ectonucleotidases in T cell differentiation: Beyond immunosuppression
    (Elsevier B.V., 2015-07) Bono, María Rosa; Fernández, Dominique; Flores-Santibáñez, Felipe; Rosemblatt, Mario; Sauma, Daniela
    Extracellular ATP is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. However, extracellular adenosine acts as an immunoregulatory signal that modulates the function of several cellular components of the adaptive and innate immune response. Consequently, the balance between ATP and adenosine concentration is crucial in immune homeostasis. CD39 and CD73 are two ectonucleotidases that cooperate in the generation of extracellular adenosine through ATP hydrolysis, thus tilting the balance towards immunosuppressive microenvironments. Extracellular adenosine can prevent activation, proliferation, cytokine production and cytotoxicity in T cells through the stimulation of the A2A receptor; however, recent evidence has shown that adenosine may also affect other processes in T-cell biology. In this review, we discuss evidence that supports a role of CD73 and CD39 ectonucleotidases in controlling naive T-cell homeostasis and memory cell survival through adenosine production. Finally, we propose a novel hypothesis of a possible role of these ectonucleotidases and autocrine adenosine signaling in controlling T-cell differentiation. © 2015 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.
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    CD73-mediated adenosine production promotes stem cell-like properties in mouse Tc17 cells
    (Blackwell Publishing Ltd, 2015-12) Flores-Santibáñez, Felipe; Fernández, Dominique; Meza, Daniel; Tejón, Gabriela; Vargas, Leonardo; Varela-Nallar, Lorena; Arredondo, Sebastián; Guixé, Victoria; Rosemblatt, Mario; Bono, María Rosa; Sauma, Daniela
    The CD73 ectonucleotidase catalyses the hydrolysis of AMP to adenosine, an immunosuppressive molecule. Recent evidence has demonstrated that this ectonucleotidase is up-regulated in T helper type 17 cells when generated in the presence of transforming growth factor-β (TGF-β), and hence CD73 expression is related to the acquisition of immunosuppressive potential by these cells. TGF-β is also able to induce CD73 expression in CD8+ T cells but the function of this ectonucleotidase in CD8+ T cells is still unknown. Here, we show that Tc17 cells present high levels of the CD73 ectonucleotidase and produce adenosine; however, they do not suppress the proliferation of CD4+ T cells. Interestingly, we report that adenosine signalling through A2A receptor favours interleukin-17 production and the expression of stem cell-associated transcription factors such as tcf-7 and lef-1 but restrains the acquisition of Tc1-related effector molecules such as interferon-γ and Granzyme B by Tc17 cells. Within the tumour microenvironment, CD73 is highly expressed in CD62L+ CD127+ CD8+ T cells (memory T cells) and is down-regulated in GZMB+ KLRG1+ CD8+ T cells (terminally differentiated T cells), demonstrating that CD73 is expressed in memory/naive cells and is down-regulated during differentiation. These data reveal a novel function of CD73 ectonucleotidase in arresting CD8+ T-cell differentiation and support the idea that CD73-driven adenosine production by Tc17 cells may promote stem cell-like properties in Tc17 cells.
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    Purinergic Signaling as a Regulator of Th17 Cell Plasticity
    (PUBLIC LIBRARY SCIENCE, 2016-06) Fernández, Dominique; Flores-Santibáñez, Felipe; Neira, Jocelyn; Osorio-Barrios, Francisco; Tejón, Gabriela; Nuñez, Sarah; Hidalgo, Yessia; Fuenzalida, Maria Jose; Meza, Daniel; Ureta, Gonzalo; Lladser, Alvaro; Pacheco, Rodrigo; Acuña-Castillo, Claudio; Guixé, Victoria; Quintana, Francisco J.; Bono, Maria Rosa; Rosemblatt, Mario; Sauma, Daniela
    T helper type 17 (Th17) lymphocytes, characterized by the production of interleukin-17 and other pro-inflammatory cytokines, are present in intestinal lamina propria and have been described as important players driving intestinal inflammation. Recent evidence, supporting the notion of a functional and phenotypic instability of Th17 cells, has shown that Th17 differentiate into type 1 regulatory (Tr1) T cells during the resolution of intestinal inflammation. Moreover, it has been suggested that the expression of CD39 ectonucleotidase endows Th17 cells with immunosuppressive properties. However, the exact role of CD39 ectonucleotidase in Th17 cells has not been studied in the context of intestinal inflammation. Here we show that Th17 cells expressing CD39 ectonucleotidase can hydrolyze ATP and survive to ATP-induced cell death. Moreover, in vitro-generated Th17 cells expressing the CD39 ectonucleotidase produce IL-10 and are less pathogenic than CD39 negative Th17 cells in a model of experimental colitis in Rag-/- mice. Remarkably, we show that CD39 activity regulates the conversion of Th17 cells to IL-10-producing cells in vitro, which is abrogated in the presence of ATP and the CD39-specific inhibitor ARL67156. All these data suggest that CD39 expression by Th17 cells allows the depletion of ATP and is crucial for IL-10 production and survival during the resolution of intestinal inflammation.
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    Vitamin A Impairs the Reprogramming of Tregs into IL-17-Producing Cells during Intestinal Inflammation
    (Hindawi Publishing Corporation, 2015) Tejón, Gabriela; Manríquez, Valeria; De Calisto, Jaime; Flores-Santibáñez, Felipe; Hidalgo, Yessia; Crisóstomo, Natalia; Fernández, Dominique; Sauma, Daniela; Mora, J. Rodrigo; Bono, Mariá R.; Rosemblatt, Mario
    Maintaining the identity of Foxp3+ regulatory T cells (Tregs) is critical for controlling immune responses in the gut, where an imbalance between Tregs and T effector cells has been linked to inflammatory bowel disease. Accumulating evidence suggests that Tregs can convert into Th17 cells and acquire an inflammatory phenotype. In this study, we used an adoptive transfer model of Ag-specific T cells to study the contribution of different factors to the reprogramming of in vitro-generated Treg cells (iTreg) into IL-17-producing cells in a mouse model of gut inflammation in vivo. Our results show that intestinal inflammation induces the reprogramming of iTreg cells into IL-17-producing cells and that vitamin A restrains reprogramming in the gut. We also demonstrate that the presence of IL-2 during the in vitro generation of iTreg cells confers resistance to Th17 conversion but that IL-2 and retinoic acid (RA) cooperate to maintain Foxp3 expression following stimulation under Th17-polarizing conditions. Additionally, although IL-2 and RA differentially regulate the expression of different Treg cell suppressive markers, Treg cells generated under different polarizing conditions present similar suppressive capacity. © 2015 Gabriela Tejón et al.