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1.
EMBO J ; 36(16): 2404-2418, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28716804

RESUMEN

Type 2 inflammation is a defining feature of infection with parasitic worms (helminths), as well as being responsible for widespread suffering in allergies. However, the precise mechanisms involved in T helper (Th) 2 polarization by dendritic cells (DCs) are currently unclear. We have identified a previously unrecognized role for type I IFN (IFN-I) in enabling this process. An IFN-I signature was evident in DCs responding to the helminth Schistosoma mansoni or the allergen house dust mite (HDM). Further, IFN-I signaling was required for optimal DC phenotypic activation in response to helminth antigen (Ag), and efficient migration to, and localization with, T cells in the draining lymph node (dLN). Importantly, DCs generated from Ifnar1-/- mice were incapable of initiating Th2 responses in vivo These data demonstrate for the first time that the influence of IFN-I is not limited to antiviral or bacterial settings but also has a central role to play in DC initiation of Th2 responses.


Asunto(s)
Células Dendríticas/inmunología , Interferón Tipo I/metabolismo , Células Th2/inmunología , Alérgenos/inmunología , Animales , Ratones , Ratones Noqueados , Pyroglyphidae/inmunología , Receptor de Interferón alfa y beta/deficiencia , Schistosoma mansoni/inmunología
2.
Parasitology ; 145(7): 848-854, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29179788

RESUMEN

X-ray micro-computed tomography (µCT) is a technique which can obtain three-dimensional images of a sample, including its internal structure, without the need for destructive sectioning. Here, we review the capability of the technique and examine its potential to provide novel insights into the lifestyles of parasites embedded within host tissue. The current capabilities and limitations of the technology in producing contrast in soft tissues are discussed, as well as the potential solutions for parasitologists looking to apply this technique. We present example images of the mouse whipworm Trichuris muris and discuss the application of µCT to provide unique insights into parasite behaviour and pathology, which are inaccessible to other imaging modalities.


Asunto(s)
Imagenología Tridimensional , Parásitos/anatomía & histología , Microtomografía por Rayos X , Animales , Ratones , Tricuriasis/diagnóstico por imagen , Trichuris/anatomía & histología
3.
Immunol Cell Biol ; 94(4): 400-10, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26657145

RESUMEN

Dendritic cells (DCs) are the key initiators of T-helper (Th) 2 immune responses against the parasitic helminth Schistosoma mansoni. Although the liver is one of the main sites of antigen deposition during infection with this parasite, it is not yet clear how distinct DC subtypes in this tissue respond to S. mansoni antigens in vivo, or how the liver microenvironment might influence DC function during establishment of the Th2 response. In this study, we show that hepatic DC subsets undergo distinct activation processes in vivo following murine infection with S. mansoni. Conventional DCs (cDCs) from schistosome-infected mice upregulated expression of the costimulatory molecule CD40 and were capable of priming naive CD4(+) T cells, whereas plasmacytoid DCs (pDCs) upregulated expression of MHC class II, CD86 and CD40 but were unable to support the expansion of either naive or effector/memory CD4(+) T cells. Importantly, in vivo depletion of pDCs revealed that this subset was dispensable for either maintenance or regulation of the hepatic Th2 effector response during acute S. mansoni infection. Our data provides strong evidence that S. mansoni infection favors the establishment of an immunogenic, rather than tolerogenic, liver microenvironment that conditions cDCs to initiate and maintain Th2 immunity in the context of ongoing antigen exposure.


Asunto(s)
Células Dendríticas/inmunología , Hígado/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Células Th2/inmunología , Animales , Antígenos Helmínticos/inmunología , Diferenciación Celular , Células Cultivadas , Células Dendríticas/parasitología , Hígado/parasitología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL
4.
Int Immunol ; 27(11): 589-96, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25899567

RESUMEN

The archetypal Th2 cytokine IL-4 has previously been shown to alternatively activate murine macrophages and, more recently, dendritic cells (DCs) both in vitro and in vivo. IL-4 has also been shown to induce Aldh1a2 (aldehyde dehydrogenase 1a2) expression in murine macrophages recruited to the peritoneal cavity. However, the influence of IL-4 on DC Aldh1a2 induction in vivo has not yet been addressed. In this work, we found that DCs show enhanced aldehyde dehydrogenase enzyme activity in vivo, which led us to investigate the impact of the vitamin A metabolite all-trans retinoic acid (RA) on DC alternative activation and function. Antagonism of RA receptors reduced production of resistin-like molecule alpha by DCs responding to IL-4, while addition of exogenous RA enhanced production of this marker of alternative activation. Functionally, RA increased DC induction of CD4(+) T-cell IL-10, while reducing CD4(+) T-cell IL-4 and IL-13, revealing a previously unidentified role for RA in regulating the ability of alternatively activated DCs to influence Th2 polarization.


Asunto(s)
Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Inmunomodulación/efectos de los fármacos , Tretinoina/farmacología , Aldehído Deshidrogenasa/metabolismo , Animales , Antígenos de Superficie/metabolismo , Células Dendríticas/metabolismo , Activación Enzimática/efectos de los fármacos , Femenino , Inmunofenotipificación , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Interleucina-4/farmacología , Ratones , Fenotipo , Receptores de Ácido Retinoico/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo
5.
Eur J Immunol ; 44(6): 1835-41, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24578067

RESUMEN

Th1 and Th2 cell fates are traditionally viewed as mutually exclusive, but recent work suggests that these lineages may be more plastic than previously thought. When isolating splenic CD4(+) T cells from mice infected with the parasitic helminth Schistosoma mansoni, we observed a defined population of IFN-γ/IL-4 double-positive cells. These IFN-γ(+) IL-4(+) cells showed differences in DNA methylation at the Ifng and Il4 loci when compared with IFN-γ(+) IL-4(-) (Th1) and IFN-γ(-) IL-4(+) (Th2) cells, demonstrating that they represent a distinct effector cell population. IFN-γ(+) IL-4(+) cells also displayed a discrete DNA methylation pattern at a CpG island within the body of the Gata3 gene, which encodes the master regulator of Th2 identity. DNA methylation at this region correlated with decreased Gata3 levels, suggesting a possible role in controlling Gata3 expression. These data provide important insight into the molecular mechanisms behind the co-existence of Th1 and Th2 characteristics.


Asunto(s)
Metilación de ADN/inmunología , Interferón gamma/inmunología , Interleucina-4/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Células TH1/inmunología , Células Th2/inmunología , Animales , Islas de CpG/inmunología , Femenino , Factor de Transcripción GATA3/inmunología , Regulación de la Expresión Génica/inmunología , Ratones , Esquistosomiasis mansoni/patología , Células TH1/patología , Células Th2/patología
6.
J Immunol ; 187(3): 1411-20, 2011 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-21705620

RESUMEN

The immune suppression that characterizes human helminth infections can hinder the development of protective immunity or help to reduce pathogenic inflammation. Signaling through the T cell costimulator glucocorticoid-induced TNFR-related protein (GITR) counteracts immune downregulation by augmenting effector T cell responses and abrogating suppression by Foxp3(+) regulatory T cells. Thus, superphysiological Ab-mediated GITR costimulation represents a novel therapy for promoting protective immunity toward parasitic helminths, whereas blocking physiological GITR-GITR ligand (GITRL) interactions may provide a mechanism for dampening pathogenic Th2 inflammation. We investigated the superphysiological and physiological roles of the GITR-GITRL pathway in the development of protective and pathogenic Th2 responses in murine infection models of filariasis (Litomosoides sigmodontis) and schistosomiasis (Schistosoma mansoni). Providing superphysiological GITR costimulation using an agonistic anti-GITR mAb over the first 12 d of L. sigmodontis infection initially increased the quantity of Th2 cells, as well as their ability to produce Th2 cytokines. However, as infection progressed, the Th2 responses reverted to normal infection levels, and parasite killing remained unaffected. Despite the Th2-promoting role of superphysiological GITR costimulation, Ab-mediated blockade of the GITR-GITRL pathway did not affect Th2 cell priming or maintenance during L. sigmodontis infection. Blockade of GITR-GITRL interactions during the acute egg phase of S. mansoni infection resulted in reduced Th2 responses, but this effect was confined to the spleen and did not lead to changes in liver pathology. Thus, although superphysiological GITR costimulation can therapeutically enhance Th2 responses, physiological GITR-GITRL interactions are not required for the development of Th2-mediated resistance or pathology in murine models of filariasis and schistosomiasis.


Asunto(s)
Filarioidea/inmunología , Proteína Relacionada con TNFR Inducida por Glucocorticoide/metabolismo , Activación de Linfocitos/inmunología , Schistosoma mansoni/inmunología , Células Th2/inmunología , Células Th2/parasitología , Factores de Necrosis Tumoral/metabolismo , Animales , Femenino , Filariasis/inmunología , Filariasis/patología , Filariasis/terapia , Proteína Relacionada con TNFR Inducida por Glucocorticoide/genética , Proteína Relacionada con TNFR Inducida por Glucocorticoide/fisiología , Humanos , Inmunidad Innata/genética , Ligandos , Activación de Linfocitos/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/patología , Esquistosomiasis mansoni/terapia , Células Th2/patología , Factores de Necrosis Tumoral/genética
8.
Am J Respir Crit Care Med ; 184(5): 569-81, 2011 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-21680953

RESUMEN

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial. OBJECTIVES: To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved. METHODS: We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P = 0.0083) and a-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase 1. The alternative macrophage marker CD163 was expressed on lung macrophages from patients with IPF. Depletion of Ly6Chi circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number of Ym1- positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer during fibrogenesis exacerbated fibrosis (P = 0.0304); however, adoptively transferred CD45.1 Ly6Chi cells were not found in the lungs of recipient CD45.2 mice. CONCLUSIONS: We demonstrate the importance of circulating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importance of the alternatively activated macrophage phenotype. We show that Ly6Chi monocytes facilitate the progression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, we provide empirical data to suggest that macrophages may have a resolution-promoting role during the reversible phase of bleomycin-induced pulmonary fibrosis.


Asunto(s)
Inmunidad Celular , Activación de Macrófagos/inmunología , Macrófagos Alveolares/inmunología , Monocitos/fisiología , Fibrosis Pulmonar/etiología , Animales , Bleomicina/toxicidad , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Activación de Macrófagos/genética , Macrófagos Alveolares/patología , Ratones , Fenotipo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología
9.
Front Immunol ; 13: 906338, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35958580

RESUMEN

Schistosomiasis is a disease of global significance, with severity and pathology directly related to how the host responds to infection. The immunological narrative of schistosomiasis has been constructed through decades of study, with researchers often focussing on isolated time points, cell types and tissue sites of interest. However, the field currently lacks a comprehensive and up-to-date understanding of the immune trajectory of schistosomiasis over infection and across multiple tissue sites. We have defined schistosome-elicited immune responses at several distinct stages of the parasite lifecycle, in three tissue sites affected by infection: the liver, spleen, and mesenteric lymph nodes. Additionally, by performing RNA-seq on the livers of schistosome infected mice, we have generated novel transcriptomic insight into the development of schistosome-associated liver pathology and fibrosis across the breadth of infection. Through depletion of CD11c+ cells during peak stages of schistosome-driven inflammation, we have revealed a critical role for CD11c+ cells in the co-ordination and regulation of Th2 inflammation during infection. Our data provide an updated and high-resolution account of how host immune responses evolve over the course of murine schistosomiasis, underscoring the significance of CD11c+ cells in dictating host immunopathology against this important helminth infection.


Asunto(s)
Esquistosomiasis mansoni , Esquistosomiasis , Animales , Antígeno CD11c , Inmunidad , Inflamación , Ratones , Schistosoma mansoni
10.
Immunohorizons ; 5(8): 721-732, 2021 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-34462311

RESUMEN

Plasmacytoid dendritic cells (pDCs) are potent producers of type I IFN (IFN-I) during viral infection and respond to IFN-I in a positive feedback loop that promotes their function. IFN-I shapes dendritic cell responses during helminth infection, impacting their ability to support Th2 responses. However, the role of pDCs in type 2 inflammation is unclear. Previous studies have shown that pDCs are dispensable for hepatic or splenic Th2 responses during the early stages of murine infection with the trematode Schistosoma mansoni at the onset of parasite egg laying. However, during S. mansoni infection, an ongoing Th2 response against mature parasite eggs is required to protect the liver and intestine from acute damage and how pDCs participate in immune responses to eggs and adult worms in various tissues beyond acute infection remains unclear. We now show that pDCs are required for optimal Th2 cytokine production in response to S. mansoni eggs in the intestinal-draining mesenteric lymph nodes throughout infection and for egg-specific IFN-γ at later time points of infection. Further, pDC depletion at chronic stages of infection led to increased hepatic and splenic pathology as well as abrogated Th2 cell cytokine production and activation in the liver. In vitro, mesenteric lymph node pDCs supported Th2 cell responses from infection-experienced CD4+ T cells, a process dependent on pDC IFN-I responsiveness, yet independent of Ag. Together, these data highlight a previously unappreciated role for pDCs and IFN-I in maintaining and reinforcing type 2 immunity in the lymph nodes and inflamed tissue during helminth infection.


Asunto(s)
Citocinas/inmunología , Células Dendríticas/inmunología , Activación de Linfocitos/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/parasitología , Citocinas/metabolismo , Células Dendríticas/parasitología , Femenino , Citometría de Flujo/métodos , Interacciones Huésped-Parásitos/inmunología , Recuento de Linfocitos , Ratones Endogámicos C57BL , Ratones Noqueados , Schistosoma mansoni/fisiología , Esquistosomiasis mansoni/metabolismo , Esquistosomiasis mansoni/parasitología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/parasitología , Células Th2/inmunología , Células Th2/metabolismo , Células Th2/parasitología
11.
Front Immunol ; 11: 183, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32117307

RESUMEN

Methyl-CpG-binding domain-2 (Mbd2) acts as an epigenetic regulator of gene expression, by linking DNA methylation to repressive chromatin structure. Although Mbd2 is widely expressed in gastrointestinal immune cells and is implicated in regulating intestinal cancer, anti-helminth responses and colonic inflammation, the Mbd2-expressing cell types that control these responses are incompletely defined. Indeed, epigenetic control of gene expression in cells that regulate intestinal immunity is generally poorly understood, even though such mechanisms may explain the inability of standard genetic approaches to pinpoint the causes of conditions like inflammatory bowel disease. In this study we demonstrate a vital role for Mbd2 in regulating murine colonic inflammation. Mbd2-/- mice displayed dramatically worse pathology than wild type controls during dextran sulfate sodium (DSS) induced colitis, with increased inflammatory (IL-1ß+) monocytes. Profiling of mRNA from innate immune and epithelial cell (EC) populations suggested that Mbd2 suppresses inflammation and pathology via control of innate-epithelial cell crosstalk and T cell recruitment. Consequently, restriction of Mbd2 deficiency to CD11c+ dendritic cells and macrophages, or to ECs, resulted in increased DSS colitis severity. Our identification of this dual role for Mbd2 in regulating the inflammatory capacity of both CD11c+ cells and ECs highlights how epigenetic control mechanisms may limit intestinal inflammatory responses.


Asunto(s)
Colitis/etiología , Colon/inmunología , Proteínas de Unión al ADN/fisiología , Células Dendríticas/inmunología , Mucosa Intestinal/inmunología , Animales , Antígenos CD11/análisis , Colitis/inmunología , Susceptibilidad a Enfermedades , Femenino , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Transcriptoma
12.
EMBO Mol Med ; 9(12): 1696-1710, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29109128

RESUMEN

Fibrosis and organ failure is a common endpoint for many chronic liver diseases. Much is known about the upstream inflammatory mechanisms provoking fibrosis and downstream potential for tissue remodeling. However, less is known about the transcriptional regulation in vivo governing fibrotic matrix deposition by liver myofibroblasts. This gap in understanding has hampered molecular predictions of disease severity and clinical progression and restricted targets for antifibrotic drug development. In this study, we show the prevalence of SOX9 in biopsies from patients with chronic liver disease correlated with fibrosis severity and accurately predicted disease progression toward cirrhosis. Inactivation of Sox9 in mice protected against both parenchymal and biliary fibrosis, and improved liver function and ameliorated chronic inflammation. SOX9 was downstream of mechanosignaling factor, YAP1. These data demonstrate a role for SOX9 in liver fibrosis and open the way for the transcription factor and its dependent pathways as new diagnostic, prognostic, and therapeutic targets in patients with liver fibrosis.


Asunto(s)
Cirrosis Hepática/patología , Factor de Transcripción SOX9/genética , Animales , Conductos Biliares/cirugía , Tetracloruro de Carbono/toxicidad , Células Cultivadas , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Células Estrelladas Hepáticas/citología , Células Estrelladas Hepáticas/metabolismo , Humanos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Hepatopatías/metabolismo , Hepatopatías/patología , Macrófagos/citología , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Ratas , Factor de Transcripción SOX9/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal
13.
Immunobiology ; 220(7): 924-33, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25700973

RESUMEN

Tissue resident macrophages have vital homeostatic roles in many tissues but their roles are less well defined in the heart. The present study aimed to identify the density, polarisation status and distribution of macrophages in the healthy murine heart and to investigate their ability to respond to immune challenge. Histological analysis of hearts from CSF-1 receptor (csf1-GFP; MacGreen) and CX3CR1 (Cx3cr1(GFP/+)) reporter mice revealed a sparse population of GFP positive macrophages that were evenly distributed throughout the left and right ventricular free walls and septum. F4/80+CD11b+ cardiac macrophages, sorted from myocardial homogenates, were able to phagocytose fluorescent beads in vitro and expressed markers typical of both 'M1' (IL-1ß, TNF and CCR2) and 'M2' activation (Ym1, Arg 1, RELMα and IL-10), suggesting no specific polarisation in healthy myocardium. Exposure to Th2 challenge by infection of mice with helminth parasites Schistosoma mansoni, or Heligmosomoides polygyrus, resulted in an increase in cardiac macrophage density, adoption of a stellate morphology and increased expression of Ym1, RELMα and CD206 (mannose receptor), indicative of 'M2' polarisation. This was dependent on recruitment of Ly6ChighCCR2+ monocytes and was accompanied by an increase in collagen content. In conclusion, in the healthy heart resident macrophages are relatively sparse and have a phagocytic role. Following Th2 challenge this population expands due to monocyte recruitment and adopts an 'M2' phenotype associated with increased tissue fibrosis.


Asunto(s)
Corazón/parasitología , Macrófagos/inmunología , Miocardio/inmunología , Esquistosomiasis mansoni/inmunología , Infecciones por Strongylida/inmunología , Animales , Antígenos de Diferenciación/metabolismo , Antígeno CD11b/metabolismo , Receptor 1 de Quimiocinas CX3C , Proteínas Fluorescentes Verdes/genética , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Lectinas/biosíntesis , Lectinas Tipo C/biosíntesis , Receptor de Manosa , Lectinas de Unión a Manosa/biosíntesis , Ratones , Ratones Noqueados , Nematospiroides dubius/inmunología , Fagocitosis/inmunología , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Receptores de Superficie Celular/biosíntesis , Receptores de Quimiocina/genética , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/parasitología , Infecciones por Strongylida/parasitología , Células Th2/inmunología , beta-N-Acetilhexosaminidasas/biosíntesis
14.
Nat Commun ; 6: 6920, 2015 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-25908537

RESUMEN

Dendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function. In the absence of Mbd2, DCs display reduced phenotypic activation and a markedly impaired capacity to initiate Th2 immunity against helminths or allergens. These data identify an epigenetic mechanism that is central to the activation of CD4(+) T-cell responses by DCs, particularly in Th2 settings, and reveal methyl-CpG-binding proteins and the genes under their control as possible therapeutic targets for type-2 inflammation.


Asunto(s)
Proteínas de Unión al ADN/inmunología , Células Dendríticas/inmunología , Regulación de la Expresión Génica/genética , ARN Mensajero/metabolismo , Células Th2/inmunología , Alérgenos , Animales , Linfocitos T CD4-Positivos/inmunología , Polaridad Celular , Inmunoprecipitación de Cromatina , Metilación de ADN , Proteínas de Unión al ADN/genética , Ensayo de Inmunoadsorción Enzimática , Epigénesis Genética , Citometría de Flujo , Hipersensibilidad/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Pyroglyphidae/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología
15.
Cancer Res ; 74(18): 5019-5031, 2014 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-25038228

RESUMEN

Natural killer (NK) cells are critical for innate tumor immunity due to their specialized ability to recognize and kill neoplastically transformed cells. However, NK cells require a specific set of cytokine-mediated signals to achieve optimal effector function. Th1-associated cytokines promote effector functions that are inhibited by the prototypic Th2 cytokine IL4 and the TGFß superfamily members TGFß1 and activin-A. Interestingly, the largest subgroup of the TGFß superfamily are the bone morphogenetic proteins (BMP), but the effects of BMP signaling on NK cell effector functions have not been evaluated. Here, we demonstrate that blood-circulating NK cells express type I and II BMP receptors, BMP-2 and BMP-6 ligands, and phosphorylated isoforms of Smad-1/-5/-8, which mediate BMP family member signaling. In opposition to the inhibitory effects of TGFß1 or activin-A, autocrine BMP signaling was supportive to NK cell function. Mechanistic investigations in cytokine and TLR-L-activated NK cells revealed that BMP signaling optimized IFNγ and global cytokine and chemokine production, phenotypic activation and proliferation, and autologous dendritic cell activation and target cytotoxicity. Collectively, our findings identify a novel auto-activatory pathway that is essential for optimal NK cell effector function, one that might be therapeutically manipulated to help eradicate tumors. Cancer Res; 74(18); 5019-31. ©2014 AACR.


Asunto(s)
Proteínas Morfogenéticas Óseas/inmunología , Células Asesinas Naturales/inmunología , Comunicación Autocrina , Receptores de Proteínas Morfogenéticas Óseas/inmunología , Receptores de Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Morfogenéticas Óseas/biosíntesis , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular/inmunología , Humanos , Células Asesinas Naturales/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transducción de Señal
16.
J Exp Med ; 207(10): 2089-96, 2010 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-20819926

RESUMEN

Although dendritic cells (DCs) are adept initiators of CD4(+) T cell responses, their fundamental importance in this regard in Th2 settings remains to be demonstrated. We have used CD11c-diphtheria toxin (DTx) receptor mice to deplete CD11c(+) cells during the priming stage of the CD4(+) Th2 response against the parasitic helminth Schistosoma mansoni. DTx treatment significantly depleted CD11c(+) DCs from all tissues tested, with 70-80% efficacy. Even this incomplete depletion resulted in dramatically impaired CD4(+) T cell production of Th2 cytokines, altering the balance of the immune response and causing a shift toward IFN-γ production. In contrast, basophil depletion using Mar-1 antibody had no measurable effect on Th2 induction in this system. These data underline the vital role that CD11c(+) antigen-presenting cells can play in orchestrating Th2 development against helminth infection in vivo, a response that is ordinarily balanced so as to prevent the potentially damaging production of inflammatory cytokines.


Asunto(s)
Presentación de Antígeno , Antígeno CD11c/inmunología , Células Dendríticas/inmunología , Esquistosomiasis mansoni/inmunología , Células Th2/inmunología , Animales , Basófilos/inmunología , Antígeno CD11c/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Factor de Crecimiento Similar a EGF de Unión a Heparina , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/inmunología , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Procedimientos de Reducción del Leucocitos , Activación de Linfocitos , Ratones , Schistosoma mansoni/inmunología
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