Examinando por Autor "Rosemblatt, M."
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Ítem In vitro-generated Tc17 cells present a memory phenotype and serve as a reservoir of Tc1 cells in vivo(Frontiers Media, 2018-02) Flores-Santibáñez, F.; Cuadra, B.; Fernández, D.; Rosemblatt, M.V.; Núñez, S.; Cruz, P.; Gálvez-Cancino, F.; César Cárdenas, J.; Lladser, A.; Rosemblatt, M.; Bono, M.R.; Sauma, D.Memory CD8+ T cells are ideal candidates for cancer immunotherapy because they can mediate long-term protection against tumors. However, the therapeutic potential of different in vitro-generated CD8+ T cell effector subsets to persist and become memory cells has not been fully characterized. Type 1 CD8+ T (Tc1) cells produce interferon-γ and are endowed with high cytotoxic capacity, whereas IL-17-producing CD8+ T (Tc17) cells are less cytotoxic but display enhanced self-renewal capacity. We sought to evaluate the functional properties of in vitro-generated Tc17 cells and elucidate their potential to become long lasting memory cells. Our results show that in vitro-generated Tc17 cells display a greater in vivo persistence and expansion in response to secondary antigen stimulation compared to Tc1 cells. When transferred into recipient mice, Tc17 cells persist in secondary lymphoid organs, present a recirculation behavior consistent with central memory T cells, and can shift to a Tc1 phenotype. Accordingly, Tc17 cells are endowed with a higher mitochondrial spare respiratory capacity than Tc1 cells and express higher levels of memory-related molecules than Tc1 cells. Together, these results demonstrate that in vitro-generated Tc17 cells acquire a central memory program and provide a lasting reservoir of Tc1 cells in vivo, thus supporting the use of Tc17 lymphocytes in the design of novel and more effective therapies.Ítem Interleukin-4 Selectively Inhibits Interleukin-2 Secretion by Lipopolysaccharide-Activated Dendritic Cells(Wiley, 2004-02) Sauma, D.; Michea, P.; Lennon-Dumenil, A.; Fierro, A.; Morales, J.; Rosemblatt, M.; Bono, M.Dendritic cells (DCs) generated in vitro from bone marrow precursors using granulocyte-macrophage colony-stimulating factor (GM-CSF) secrete interleukin-2 (IL-2) upon activation, an event probably associated to the initiation of adaptive immune responses. Additionally, they produce IL-12, a cytokine related to T-cell polarization. To analyse the effect of IL-4 on DC differentiation and function, we assessed the capacity of murine bone marrow dendritic cells (BMDCs) differentiated with GM-CSF in the presence or absence of IL-4 to produce IL-2 and IL-12 upon lipopolysaccharide (LPS) activation. We found that although IL-4 enhanced DC IL-12p70 production, it strongly impaired IL-2 secretion by BMDCs. This inhibition, which depends on the presence of IL-4 during LPS activation, is DC specific, as IL-4 did not affect IL-2 secretion by T cells. Interestingly, inhibition of DC IL-2 production did not prevent DC priming of T lymphocytes. These results illustrate a new putative role for IL-4 on the regulation of the immune response and should help clarify the controversial reports on the effect of IL-4 on DCs.Ítem Lymphoid B cells induce NF-κB activation in high endothelial cells from human tonsils(Oxford University Press [University Publisher] Japanese Society for Immunology [Associate Organisation], 2006-02) Naves, R.; Reyes, L.; Rosemblatt, M.; Jacobelli, S.; Gonzalez, A.; Bono, M.Immune surveillance depends on still poorly understood lymphocyte-endothelium interactions required for lymphocyte transendothelial migration into secondary lymphoid organs. The nuclear factor κB (NF-κB) regulatory system and its inhibitory IκB proteins control the inducible expression of adhesion molecules, cytokines and chemokines involved in endothelial activation and lymphocyte transmigration. Here we present results showing the activation of this system in response to the interaction of high endothelial cells from human tonsils (HUTEC) with human B and T lymphoid cell lines and primary tonsillar lymphocytes. Western blot and electrophoretic mobility shift assays show that adhesion of different lymphoid cells induce varying levels of NF-κB activation in HUTEC, with Daudi cells, tonsil-derived B cell line 10 (TBCL-10) and primary tonsillar B lymphocytes causing the strongest activation. The main NF-κB protein complexes translocated to the nucleus were p65/p50 and p50/p50. Results from reverse transcription-PCR and flow cytometry analysis of HUTEC indicate that the interaction with Daudi cells induce an increased expression of IL-6 and IL-8 mRNA and cell-surface expression of intercellular adhesion molecule-1, all of which were prevented by sodium salicylate, an inhibitor of NF-κB activation. Transwell experiments show that NF-κB activation and the response of HUTEC to the interaction of Daudi cells does not depend on direct cell-cell contact but rather on the production of soluble factors that require the presence of both cell types. These results suggest that lymphocytes and high endothelium establish a cross talk leading to NF-κB-mediated expression of cytokines and adhesion molecules, inducing endothelial cell activation.Ítem Retinoic acid as a modulator of T cell immunity(MDPI AG, 2016) Bono, M.R.; Tejon, G.; Flores-Santibañez, F; Fernandez, D.; Rosemblatt, M.; Sauma, D.Vitamin A, a generic designation for an array of organic molecules that includes retinal, retinol and retinoic acid, is an essential nutrient needed in a wide array of aspects including the proper functioning of the visual system, maintenance of cell function and differentiation, epithelial surface integrity, erythrocyte production, reproduction, and normal immune function. Vitamin A deficiency is one of the most common micronutrient deficiencies worldwide and is associated with defects in adaptive immunity. Reports from epidemiological studies, clinical trials and experimental studies have clearly demonstrated that vitamin A plays a central role in immunity and that its deficiency is the cause of broad immune alterations including decreased humoral and cellular responses, inadequate immune regulation, weak response to vaccines and poor lymphoid organ development. In this review, we will examine the role of vitamin A in immunity and focus on several aspects of T cell biology such as T helper cell differentiation, function and homing, as well as lymphoid organ development. Further, we will provide an overview of the effects of vitamin A deficiency in the adaptive immune responses and how retinoic acid, through its effect on T cells can fine-tune the balance between tolerance and immunity.Ítem Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells(Public Library of Science, 2017-07) Candia, E.; Reyes, P.; Covian, C.; Rodriguez, F.; Wainstein, N.; Morales, J.; Mosso, C.; Rosemblatt, M.; Fierro, J.A.Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been successfully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-β1, atRA and RAPA. The resulting cells were characterized by the expression of FOXP3, activation, surface and homing markers. Methylation of the Conserved Non-coding Sequence 2 was also evaluated. Functional comparison of the different culture conditions was performed by suppression assays in vitro. Culturing naive human T cells with IL-2/TGFβ1 resulted in the generation of 54.2% of Treg cells (CD4+CD25+FOXP3+) whereas the addition of 100 nM atRA increased the yield of Treg cells to 66% (p = 0.0088). The addition of RAPA did not increase the number of Treg cells in any of these settings. Treg cells generated in the presence of atRA had an increased expression of the β7 integrin to nearly 100% of the generated Treg cells, while RAPA treated cells showed enhanced expression of CXCR4. The differential expression of homing molecules highlights the possibility of inducing Treg cells with differential organ-specific homing properties. Neither atRA nor RAPA had an effect on the highly methylated CNS2 sites, supporting reports that their contribution to the lineage stability of Treg cells is not mediated by methylation changes in this locus. Treg cells generated in the presence of RAPA show the most potent suppression effect on the proliferation of effector cells.Ítem The demethylase inhibitor GSK-J4 limits inflammatory colitis by promoting de novo synthesis of retinoic acid in dendritic cells(Nature Research, 2021-12) Doñas, C.; Neira, J.; Osorio-Barrios, F.; Carrasco, M.; Fernández, D.; Prado, C.; Loyola, A.; Pacheco, R.; Rosemblatt, M.Dendritic cells (DCs) promote T-cell mediated tolerance to self-antigens and induce inflammation to innocuous-antigens. This dual potential makes DCs fundamental players in inflammatory disorders. Evidence from inflammatory colitis mouse models and inflammatory bowel diseases (IBD) patients indicated that gut inflammation in IBD is driven mainly by T-helper-1 (Th1) and Th17 cells, suggesting an essential role for DCs in the development of IBD. Here we show that GSK-J4, a selective inhibitor of the histone demethylase JMJD3/UTX, attenuated inflammatory colitis by reducing the inflammatory potential and increasing the tolerogenic features of DCs. Mechanistic analyses revealed that GSK-J4 increased activating epigenetic signals while reducing repressive marks in the promoter of retinaldehyde dehydrogenase isoforms 1 and 3 in DCs, enhancing the production of retinoic acid. This, in turn, has an impact on regulatory T cells (Treg) increasing their lineage stability and gut tropism as well as potentiating their suppressive activity. Our results open new avenues for the treatment of IBD patients. © 2021, The Author(s).Ítem Transplant Tolerance: New Insights and Strategies for Long-Term Allograft Acceptance(Hindawi Limited, 2013) Ruiz, P.; Maldonado, P.; Hidalgo, Y.; Gleisner, A.; Sauma, D.; Silva, C.; Saez, J.; Nuñez, S.; Rosemblatt, M.; Bono, M.One of the greatest advances in medicine during the past century is the introduction of organ transplantation. This therapeutic strategy designed to treat organ failure and organ dysfunction allows to prolong the survival of many patients that are faced with no other treatment option. Today, organ transplantation between genetically dissimilar individuals (allogeneic grafting) is a procedure widely used as a therapeutic alternative in cases of organ failure, hematological disease treatment, and some malignancies. Despite the potential of organ transplantation, the administration of immunosuppressive drugs required for allograft acceptance induces severe immunosuppression in transplanted patients, which leads to serious side effects such as infection with opportunistic pathogens and the occurrence of neoplasias, in addition to the known intrinsic toxicity of these drugs. To solve this setback in allotransplantation, researchers have focused on manipulating the immune response in order to create a state of tolerance rather than unspecific immunosuppression. Here, we describe the different treatments and some of the novel immunotherapeutic strategies undertaken to induce transplantation tolerance.Ítem Trichostatin a promotes the generation and suppressive functions of regulatory T cells(Hindawi Limited, 2013-05) Doñas, C.; Fritz, M.; Manríquez, V.; Tejón, G.; Bono, M.; Loyola, A.; Rosemblatt, M.Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+ T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that the foxp3 gene promoter becomes hyperacetylated in in vitro differentiated Tregs compared to naïve CD4 + T cells. We also show that the histone deacetylase inhibitor TSA stimulated the in vitro differentiation of naïve CD4+ T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+ Treg cells.