RESUMEN
Adipose tissue homeostasis relies on the interplay between several regulatory lineages, such as type 2 innate lymphoid cells (ILC2s), T helper 2 (Th2) cells, regulatory T cells, eosinophils, and type 2 macrophages. Among them, ILC2s are numerically the dominant source of type 2 cytokines and are considered as major regulators of adiposity. Despite the overlap in immune effector molecules and sensitivity to alarmins (thymic stromal lymphopoietin and interleukin-33) between ILC2s and resident memory Th2 lymphocytes, the role of the adaptive axis of type 2 immunity remains unclear. We show that mice deficient in CD27, a member of the tumor necrosis factor receptor superfamily, are more resistant to obesity and associated disorders. A comparative analysis of the CD4 compartment of both strains revealed higher numbers of fat-resident memory Th2 cells in the adipose tissue of CD27 knockout mice, which correlated with decreased programmed cell death protein 1-induced apoptosis. Our data point to a non-redundant role for Th2 lymphocytes in obesogenic conditions.
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Inmunidad Innata , Linfocitos , Animales , Ratones , Citocinas/metabolismo , Homeostasis , Interleucina-33 , Grasa Intraabdominal/metabolismo , Linfocitos/metabolismo , Células Th2 , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis TumoralRESUMEN
In this study melt electro written (MEW) scaffolds of poly(ε-caprolactone) PCL are decorated with anti-inflammatory yeast-derived peptide for skin wound healing. Initially, 13 different yeast-derived peptides were screened and analyzed using both in vitro and in vivo assays. The MEW scaffolds are functionalized with the selected peptide VLSTSFPPW (VW-9) with the highest activity in reducing pro-inflammatory cytokines and stimulating fibroblast proliferation, migration, and collagen production. The peptide was conjugated to the MEW scaffolds using carbodiimide (CDI) and thiol chemistry, with and without plasma treatment, as well as by directly mixing the peptide with the polymer before printing. The MEW scaffolds modified using CDI and thiol chemistry with plasma treatment showed improved fibroblast and macrophage penetration and adhesion, as well as increased cell proliferation and superior anti-inflammatory properties, compared to the other groups. When applied to full-thickness excisional wounds in rats, the peptide-modified MEW scaffold significantly enhanced the healing process compared to controls (p < 0.05). This study provides proof of concept for using yeast-derived peptides to functionalize biomaterials for skin wound healing.
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Saccharomyces cerevisiae , Andamios del Tejido , Ratas , Animales , Andamios del Tejido/química , Cicatrización de Heridas , Péptidos/farmacologíaRESUMEN
Introduction: Most T lymphocytes, including regulatory T cells, express the CD27 costimulatory receptor in steady state conditions. There is evidence that CD27 engagement on conventional T lymphocytes favors the development of Th1 and cytotoxic responses in mice and humans, but the impact on the regulatory lineage is unknown. Methods: In this report, we examined the effect of constitutive CD27 engagement on both regulatory and conventional CD4+ T cells in vivo, in the absence of intentional antigenic stimulation. Results: Our data show that both T cell subsets polarize into type 1 Tconvs or Tregs, characterized by cell activation, cytokine production, response to IFN-γ and CXCR3-dependent migration to inflammatory sites. Transfer experiments suggest that CD27 engagement triggers Treg activation in a cell autonomous fashion. Conclusion: We conclude that CD27 may regulate the development of Th1 immunity in peripheral tissues as well as the subsequent switch of the effector response into long-term memory.
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Subgrupos de Linfocitos T , Linfocitos T Reguladores , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Animales , Humanos , Ratones , Antígenos/metabolismo , Ligando CD27/metabolismo , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
The prolyl hydroxylase domain/hypoxia-inducible factor (PHD/HIF) pathway has been implicated in a wide range of immune and inflammatory processes, including in the oxygen-deprived tumor microenvironment. To examine the effect of HIF stabilization in antitumor immunity, we deleted Phd2 selectively in T lymphocytes using the cre/lox system. We show that the deletion of PHD2 in lymphocytes resulted in enhanced regression of EG7-OVA tumors, in a HIF-1α-dependent manner. The enhanced control of neoplastic growth correlated with increased polyfunctionality of CD8+ tumor-infiltrating lymphocytes, as indicated by enhanced expression of IFNγ, TNFα, and granzyme B. Phenotypic and transcriptomic analyses pointed to a key role of glycolysis in sustaining CTL activity in the tumor bed and identified the PHD2/HIF-1 pathway as a potential target for cancer immunotherapy.
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Prolina Dioxigenasas del Factor Inducible por Hipoxia , Neoplasias , Humanos , Procolágeno-Prolina Dioxigenasa/metabolismo , Oxígeno , Linfocitos T CD8-positivos/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Microambiente TumoralRESUMEN
Despite advances in targeted therapies and immunotherapy in lung cancer, chemotherapy remains the backbone of treatment in most patients at different stages of the disease. Inhaled chemotherapy is a promising strategy to target lung tumours and to limit the induced severe systemic toxicities. Cisplatin dry powder for inhalation (CIS-DPI) was tested as an innovative way to deliver cisplatin locally via the pulmonary route with minimal systemic toxicities. In vivo, CIS-DPI demonstrated a dose-dependent antiproliferative activity in the M109 orthotopic murine lung tumour model and upregulated the immune checkpoint PD-L1 on lung tumour cells. Combination of CIS-DPI with the immune checkpoint inhibitor anti-PD1 showed significantly reduced tumour size, increased the number of responders and prolonged median survival over time in comparison to the anti-PD1 monotherapy. Furthermore, the CIS-DPI and anti-PD1 combination induced an intra-tumour recruitment of conventional dendritic cells and tumour infiltrating lymphocytes, highlighting an anti-tumour immune response. This study demonstrates that combining CIS-DPI with anti-PD1 is a promising strategy to improve lung cancer therapy.
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Cisplatino , Neoplasias Pulmonares , Humanos , Animales , Ratones , Cisplatino/uso terapéutico , Polvos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Pulmón/patología , InmunidadRESUMEN
CD27/CD70 costimulation enhances T-cell survival, memory formation and Th1-cell differentiation and effector function. In addition to promoting Th1 responses, CD27 signaling has been shown to exert a negative regulatory role on IL-17 production, resulting in increased sensitivity of CD27 KO mice to EAE. By inducing EAE in full CD27 KO mice, and in a novel, T-cell specific CD27 KO mouse strain (CD4-Cre x CD27flox/flox ), we demonstrate herein that CD27 engagement by its natural ligand (CD70) suppresses IL-17 production in a cell autonomous fashion. We further show that CD27 engagement by an agonistic antibody given after EAE induction or at symptom onset similarly suppresses IL-17 production by activated CD4+ T cells infiltrating the inflamed CNS while IFN-γ production was unaffected, leading to an amelioration of inflammatory-related symptoms. These findings propose CD27 costimulation as a potential candidate for therapeutic manipulation to treat autoimmune and autoinflammatory diseases characterized by excessive IL-17 production.
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Ligando CD27 , Encefalomielitis Autoinmune Experimental , Animales , Interleucina-17 , Ligandos , Ratones , Ratones Endogámicos C57BL , Células TH1 , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis TumoralRESUMEN
The oxygen sensor prolyl hydroxylase domain 2 (PHD2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types, including T lymphocytes. The role of oxygen sensor on immune cells, particularly on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTreg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon, and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine, and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing a Th1-like effector phenotype. Concomitantly, the expression of innate-type cytokines such as Il1b, Il12a, Il12b, and Tnfa was found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTreg mice also displayed an enhanced sensitivity to dextran sodium sulfate-induced colitis and toxoplasmosis, suggesting that PHD2-deficient Tregs did not efficiently control inflammatory response in vivo, particularly those characterized by IFN-γ production. Further analysis revealed that Treg dysregulation was largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTreg mice), but not in PHD2-HIF1α (PHD2-HIF1αΔTreg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs identified the STAT1 pathway as a target of the PHD2-HIF2α axis in regulatory T cell phenotype and in vivo function.
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Colitis , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Linfocitos T Reguladores , Animales , Colitis/inducido químicamente , Subunidad alfa del Factor 1 Inducible por Hipoxia , Ratones , Oxígeno , Procolágeno-Prolina Dioxigenasa , Prolil HidroxilasasRESUMEN
Recent observations clearly highlight the critical role of type 2 innate lymphoid cells in maintaining the homeostasis of adipose tissues in humans and mice. This cell population promotes beiging and limits adiposity directly and indirectly by sustaining a Th2-prone environment enriched in eosinophils and alternatively activated macrophages. Accordingly, the number and function of type 2 innate lymphoid cells (ILC2s) are strongly impaired in obese individuals. In this work, we identify the PD-1-PD-L1 pathway as a factor leading to ILC2 destabilization upon high-fat feeding resulting in impaired tissue metabolism. Tumor necrosis factor (TNF) appears to play a central role, triggering interleukin-33 (IL-33)-dependent PD-1 expression on ILC2s and recruiting and activating PD-L1hi M1 macrophages. PD-1 blockade partially restores the type 2 innate axis, raising the possibility of restoring tissue homeostasis.
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Inmunidad Innata , Linfocitos/metabolismo , Obesidad/inmunología , Obesidad/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Eosinófilos/metabolismo , Homeostasis , Inflamación/patología , Interleucina-33/metabolismo , Activación de Macrófagos , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones Obesos , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
To analyze the potential role of Tregs in controlling the TCR repertoire breadth to a non-self-antigen, a TCRß transgenic mouse model (EF4.1) expressing a limited, yet polyclonal naïve T-cell repertoire was used. The response of EF4.1 mice to an I-Ab-associated epitope of the F-MuLV envelope protein is dominated by clones expressing a Vα2 gene segment, thus allowing a comprehensive analysis of the TCRα repertoire in a relatively large cohort of mice. Control and Treg-depleted EF4.1 mice were immunized, and the extent of the Vα2-bearing, antigen-specific TCR repertoire was characterized by high-throughput sequencing and spectratyping analysis. In addition to increased clonal expansion and acquisition of effector functions, Treg depletion led to the expression of a more diverse TCR repertoire comprising several private clonotypes rarely observed in control mice or in the pre-immune repertoire. Injection of anti-CD86 antibodies in vivo led to a strong reduction in TCR diversity, suggesting that Tregs may influence TCR repertoire diversity by modulating costimulatory molecule availability. Collectively, these studies illustrate an additional mechanism whereby Tregs control the immune response to non-self-antigens.
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Anticuerpos Antivirales/inmunología , Antígeno B7-2/inmunología , Virus de la Leucemia Murina de Friend/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T Reguladores/inmunología , Animales , Células Cultivadas , Depleción Linfocítica , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Proteínas del Envoltorio Viral/inmunologíaRESUMEN
An important question is how chemotherapy may (re-)activate tumor-specific immunity. In this study, we provide a phenotypic, functional and genomic analysis of tumor-specific CD8+ T cells in tumor (P815)-bearing mice, treated or not with cyclophosphamide. Our data show that chemotherapy favors the development of effector-type lymphocytes in tumor bed, characterized by higher KLRG-1 expression, lower PD-1 expression and increased cytotoxicity. This suggests re-engagement of T lymphocytes into the effector program. IFN-I appears involved in this remodeling. Our findings provide some insight into how cyclophosphamide regulates the amplitude and quality of tumor-specific immune responses.
RESUMEN
In theory, the immunotherapy of cancer should induce the selective destruction of cancer cells and a long-term specific protection, based on the specificity and memory of immunity. This contrasts with the collateral damages of conventional therapies and their toxic effects on host tissues. However, recent data suggest that chemotherapy may potentiate ongoing immune responses, through homeostatic mechanisms. Massive tumor death, empty "immune" niches and selected cytokines may act as a danger signal, alerting the immune system and amplifying pre-existing antitumor reactivity.
RESUMEN
In the last decade, a growing body of evidence has highlighted the major role of cancer immunosurveillance. The immune system can recognize tumor cells and keep them under check for long period of time, but is impeded by escape mechanisms induced by the tumor itself. Interestingly, the efficacy of chemotherapy has been shown to depend on the immune response, which in turn is potentiated by chemical agents, creating a positive feedback loop leading to long term tumor resistance. In this review, we summarize some mechanisms underlying the synergy between chemo- and immuno-therapy.
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Antineoplásicos/uso terapéutico , Inmunoterapia , Neoplasias/terapia , Animales , Terapia Combinada/métodos , Sinergismo Farmacológico , Humanos , Vigilancia Inmunológica/efectos de los fármacos , Vigilancia Inmunológica/fisiología , Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/patología , Resultado del Tratamiento , Escape del Tumor/efectos de los fármacos , Escape del Tumor/inmunologíaRESUMEN
Apolipoproteins L (ApoLs) are Bcl-2-like proteins expressed under inflammatory conditions in myeloid and endothelial cells. We found that Toll-like receptor (TLR) stimuli, particularly the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)), specifically induce ApoLs7/11 subfamilies in murine CD8α(+) dendritic cells (DCs). This induction requires the TLR3/TRIF (where TRIF is TIR domain containing adapter-inducing interferon ß) signaling pathway and is dependent on IFN-ß in all ApoLs subfamilies except for ApoL7c. Poly(I:C) treatment of DCs is also associated with induction of both cell death and autophagy. ApoLs expression is related to promotion of DC death by poly(I:C), as ApoLs7/11 knockdown increases DC survival and ApoLs7 are associated with the anti-apoptotic protein Bcl-xL (where Bcl-xL is B-cell lymphoma extra large). Similarly, in human monocyte-derived DCs poly(I:C) induces both cell death and the expression of ApoLs, principally ApoL3. Finally, the BH3-like peptide of ApoLs appears to be involved in the DC death-promoting activity. We would like to propose that ApoLs are involved in cell death linked to activation of DCs by viral stimuli.
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Apolipoproteínas/inmunología , Apoptosis , Células Dendríticas/citología , Transducción de Señal , Receptor Toll-Like 3/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Antígenos CD8/metabolismo , Línea Celular , Células Cultivadas , Células Dendríticas/metabolismo , Humanos , Interferón beta/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Poli I-C/farmacología , Isoformas de Proteínas/inmunología , Proteína bcl-X/metabolismoRESUMEN
Transplantation of mesenchymal stem cells (MSCs) into injured or diseased tissue-for the in situ delivery of a wide variety of MSC-secreted therapeutic proteins-is an emerging approach for the modulation of the clinical course of several diseases and traumata. From an emergency point-of-view, allogeneic MSCs have numerous advantages over patient-specific autologous MSCs since "off-the-shelf" cell preparations could be readily available for instant therapeutic intervention following acute injury. Although we confirmed the in vitro immunomodulatory capacity of allogeneic MSCs on antigen-presenting cells with standard coculture experiments, allogeneic MSC grafts were irrevocably rejected by the host's immune system upon either intramuscular or intracerebral transplantation. In an attempt to modulate MSC allograft rejection in vivo, we transduced MSCs with an interleukin-13 (IL13)-expressing lentiviral vector. Our data clearly indicate that prolonged survival of IL13-expressing allogeneic MSC grafts in muscle tissue coincided with the induction of an alternatively activated macrophage phenotype in vivo and a reduced number of alloantigen-reactive IFNγ- and/or IL2-producing CD8(+) T cells compared to nonmodified allografts. Similarly, intracerebral IL13-expressing MSC allografts also exhibited prolonged survival and induction of an alternatively activated macrophage phenotype, although a peripheral T cell component was absent. In summary, this study demonstrates that both innate and adaptive immune responses are effectively modulated in vivo by locally secreted IL13, ultimately resulting in prolonged MSC allograft survival in both muscle and brain tissue. Stem Cells 2016;34:1971-1984.
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Supervivencia de Injerto/inmunología , Interleucina-13/farmacología , Isoantígenos/inmunología , Activación de Linfocitos/efectos de los fármacos , Macrófagos/metabolismo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Linfocitos T/inmunología , Aloinjertos/efectos de los fármacos , Aloinjertos/inmunología , Animales , Formación de Anticuerpos/efectos de los fármacos , Células Presentadoras de Antígenos/efectos de los fármacos , Células Dendríticas/citología , Células Dendríticas/efectos de los fármacos , Ingeniería Genética , Inmunomodulación/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Ratones , Microglía/efectos de los fármacos , Microglía/patología , Linfocitos T/efectos de los fármacosRESUMEN
Regulatory T cells (Tregs) are critical to maintain the homeostasis of the organism, i.e., to prevent (excessive) inflammatory reactions against self and nonself. Data in the literature suggest that a variety of suppressive mechanisms exist that may act selectively depending on the tissue environment. An interesting question is whether dendritic cells (DCs), which are involved in immunity and tolerance, are targets of Tregs. We review herein some experimental evidence indicating that some suppressive mechanisms involve DCs, altering their function and inducing an immune control at the very first step of the immune response.
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Células Dendríticas/inmunología , Vigilancia Inmunológica , Linfocitos T Reguladores/inmunología , Animales , Humanos , Terapia de Inmunosupresión , Modelos InmunológicosRESUMEN
Tissue hypoxia can occur in physiological and pathological conditions. When O2 availability decreases, the transcription factor hypoxia-inducible factor (HIF)-1α is stabilized and regulates cellular adaptation to hypoxia. The objective of this study was to test whether HIF-1α regulates T cell fate and to define the molecular mechanisms of this control. Our data demonstrate that Th1 cells lose their capacity to produce IFN-γ when cultured under hypoxia. HIF-1α(-/-) Th1 cells were insensitive to hypoxia, underlining a critical role for HIF-1α. Our results point to a role for IL-10, as suggested by the increased IL-10 expression at low O2 levels and the unchanged IFN-γ production by IL-10-deficient Th1 cells stimulated in hypoxic conditions. Accordingly, STAT3 phosphorylation is increased in Th1 cells under hypoxia, leading to enhanced HIF-1α transcription, which, in turn, may inhibit suppressor of cytokine signaling 3 transcription. This positive-feedback loop reinforces STAT3 activation and downregulates Th1 responses that may cause collateral damage to the host.
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Factor 1 Inducible por Hipoxia/metabolismo , Inmunomodulación , Células TH1/inmunología , Células TH1/metabolismo , Animales , Diferenciación Celular , Hipoxia de la Célula , Células Cultivadas , Citocinas/metabolismo , Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Interferón gamma/biosíntesis , Interleucina-10/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células TH1/citologíaRESUMEN
The severity and intensity of autoimmune disease in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) patients and in scurfy mice emphasize the critical role played by thymus-derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here, we demonstrate that tTregs selectively inhibit CD27/CD70-dependent Th1 priming, while leaving the IL-12-dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN-γ-secreting CD4(+) T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27-dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responses.
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Ligando CD27/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Timo/inmunología , Timo/metabolismo , Animales , Ligando CD27/genética , Células Dendríticas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
Leishmania major is an obligate intracellular parasite hosted by phagocytes, including dendritic cells (DCs). Lysophosphatidylcholine (LPC) a pro-oxidant by-product of phospholipase A2 activity can modulate the maturation and function of DCs. However, little is known about its role in L. major infection. This study examined the effects of LPC and lipopolysaccharide (LPS) in BALB/c mouse-derived DC infection by L. major promastigotes, in vitro. Our results showed early divergent effects of LPS and LPC, which lasted up to 24h. In contrast to LPS, LPC worsened DC infection by reversing the immune balance IL-10 vs. TNF-α and IL-6, and inducing a sharp down regulation of CD40 and iNOsynthase activity. In addition, LPC potentiated xanthine oxidase stress, the production of kynurenine by indoleamine 2,3 dioxygenase (IDO), and arginase1 activity in the expense of iNOsynthase. Taken together, our results highlight some biochemical events bypassing the protective Th1 response. They suggest that LPC could facilitate the proliferation of this obligate intracellular parasite by neutralizing oxidative and nitrosative stresses and sustaining both IDO and arginase1 activities.
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Arginasa/metabolismo , Células Dendríticas/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interleucina-10/metabolismo , Leishmania major/inmunología , Leishmaniasis Cutánea/inmunología , Lisofosfatidilcolinas/metabolismo , Animales , Diferenciación Celular , Células Cultivadas , Células Dendríticas/microbiología , Progresión de la Enfermedad , Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo , Balance Th1 - Th2RESUMEN
The classical view of the Th1/Th2 paradigm posits that the pathogen nature, infectious cycle, and persistence represent key parameters controlling the choice of effector mechanisms operating during an immune response. Thus, efficient Th1 responses are triggered by replicating intracellular pathogens, while Th2 responses would control helminth infection and promote tissue repair during the resolution phase of an infectious event. However, this vision does not account for a growing body of data describing how pathogens exploit the polarization of the host immune response to their own benefit. Recently, the study of macrophages has illustrated a novel aspect of this arm race between pathogens and the immune system, and the central role of macrophages in homeostasis, repair and defense of all tissues is now fully appreciated. Like T lymphocytes, macrophages differentiate into distinct effectors including classically (M1) and alternatively (M2) activated macrophages. Interestingly, in addition to represent immune effectors, M1/M2 cells have been shown to represent potential reservoir cells to a wide range of intracellular pathogens. Subversion of macrophage cell metabolism by microbes appears as a recently uncovered immune escape strategy. Upon infection, several microbial agents have been shown to activate host metabolic pathways leading to the production of nutrients necessary to their long-term persistence in host. The purpose of this review is to summarize and discuss the strategies employed by pathogens to manipulate macrophage differentiation, and in particular their basic cell metabolism, to favor their own growth while avoiding immune control.
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The identification of DC-derived signals orchestrating activation of Th1 and Th17 immune responses has advanced our understanding on how these inflammatory responses develop. However, whether specific signals delivered by DCs also participate in the regulation of Th2 immune responses remains largely unknown. In this study, we show that administration of antigen-loaded, IL-6-deficient DCs to naïve mice induced an exacerbated Th2 response, characterized by the differentiation of GATA-3-expressing T lymphocytes secreting high levels of IL-4, IL-5, and IL-13. Coinjection of wild type and IL-6-deficient bone marrow-derived dendritic cells (BMDCs) confirmed that IL-6 exerted a dominant, negative influence on Th2-cell development. This finding was confirmed in vitro, where exogenously added IL-6 was found to limit IL-4-induced Th2-cell differentiation. iNKT cells were required for optimal Th2-cell differentiation in vivo although their activation occurred independently of IL-6 secretion by the BMDCs. Collectively, these observations identify IL-6 secretion as a major, unsuspected, mechanism whereby DCs control the magnitude of Th2 immunity.