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2.
Life Sci Alliance ; 6(12)2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37833072

RESUMEN

The tumor microenvironment is a dynamic network of stromal, cancer, and immune cells that interact and compete for resources. We have previously identified the Vanin1 pathway as a tumor suppressor of sarcoma development via vitamin B5 and coenzyme A regeneration. Using an aggressive sarcoma cell line that lacks Vnn1 expression, we showed that the administration of pantethine, a vitamin B5 precursor, attenuates tumor growth in immunocompetent but not nude mice. Pantethine boosts antitumor immunity, including the polarization of myeloid and dendritic cells towards enhanced IFNγ-driven antigen presentation pathways and improved the development of hypermetabolic effector CD8+ T cells endowed with potential antitumor activity. At later stages of treatment, the effect of pantethine was limited by the development of immune cell exhaustion. Nevertheless, its activity was comparable with that of anti-PD1 treatment in sensitive tumors. In humans, VNN1 expression correlates with improved survival and immune cell infiltration in soft-tissue sarcomas, but not in osteosarcomas. Pantethine could be a potential therapeutic immunoadjuvant for the development of antitumor immunity.


Asunto(s)
Linfocitos T CD8-positivos , Sarcoma , Humanos , Ratones , Animales , Coenzima A/farmacología , Ácido Pantoténico/farmacología , Sarcoma/tratamiento farmacológico , Microambiente Tumoral
3.
Life Sci Alliance ; 6(6)2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37024121

RESUMEN

Aggressive tumors often display mitochondrial dysfunction. Upon oxidative stress, mitochondria undergo fission through OMA1-mediated cleavage of the fusion effector OPA1. In yeast, a redox-sensing switch participates in OMA1 activation. 3D modeling of OMA1 comforted the notion that cysteine 403 might participate in a similar sensor in mammalian cells. Using prime editing, we developed a mouse sarcoma cell line in which OMA1 cysteine 403 was mutated in alanine. Mutant cells showed impaired mitochondrial responses to stress including ATP production, reduced fission, resistance to apoptosis, and enhanced mitochondrial DNA release. This mutation prevented tumor development in immunocompetent, but not nude or cDC1 dendritic cell-deficient, mice. These cells prime CD8+ lymphocytes that accumulate in mutant tumors, whereas their depletion delays tumor control. Thus, OMA1 inactivation increased the development of anti-tumor immunity. Patients with complex genomic soft tissue sarcoma showed variations in the level of OMA1 and OPA1 transcripts. High expression of OPA1 in primary tumors was associated with shorter metastasis-free survival after surgery, and low expression of OPA1, with anti-tumor immune signatures. Targeting OMA1 activity may enhance sarcoma immunogenicity.


Asunto(s)
GTP Fosfohidrolasas , Sarcoma , Ratones , Animales , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Cisteína/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Mitocondrias/metabolismo , Sarcoma/genética , Sarcoma/metabolismo , Mamíferos/metabolismo , Metaloproteasas/genética , Metaloproteasas/metabolismo
4.
J Allergy Clin Immunol ; 150(5): 1194-1208, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35779666

RESUMEN

BACKGROUND: Epicutaneous immunotherapy (EPIT) protocols have recently been developed to restore tolerance in patients with food allergy. The mechanisms by which EPIT protocols promote desensitization rely on a profound immune deviation of pathogenic T- and B-cell responses. OBJECTIVE: To date, little is known about the contribution of skin dendritic cells (skDCs) to T-cell remodeling and EPIT efficacy. METHODS: We capitalized on a preclinical model of food allergy to ovalbumin (OVA) to characterize the phenotype and functions of OVA+ skDCs throughout the course of EPIT. RESULTS: Our results showed that both Langerhans cells and dermal conventional cDC1 and cDC2 subsets retained their ability to capture OVA in the skin and to migrate toward the skin-draining lymph nodes during EPIT. However, their activation/maturation status was significantly impaired, as evidenced by the gradual and selective reduction of CD86, CD40, and OVA protein expression in respective subsets. Phenotypic changes during EPIT were also characterized by a progressive diversification of single-cell gene signatures within each DC subset. Interestingly, we observed that OVA+ Langerhans cells progressively lost their capacity to prime CD4+ TEFF cells, but gained regulatory T-cell stimulatory properties. In contrast, cDC1 were inefficient in priming CD4+ TEFF cells or in reactivating TMEM cells in vitro, whereas cDC2 retained moderate stimulatory properties, and progressively biased type 2 immunity toward type 1 and type 17 responses. CONCLUSIONS: Our results therefore emphasize that the acquisition of distinct phenotypic and functional specializations by skDCs during EPIT is at the cornerstone of the desensitization process.


Asunto(s)
Hipersensibilidad a los Alimentos , Células de Langerhans , Humanos , Desensibilización Inmunológica/métodos , Ovalbúmina , Linfocitos T Reguladores , Alérgenos
5.
Commun Biol ; 5(1): 370, 2022 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-35440795

RESUMEN

The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD). Concurrent with glucose intolerance, pro-inflammatory/monocyte-derived colonic macrophages increased in mice fed a HFD. A link between macrophage numbers and glycemia was established by pharmacological dose-dependent ablation of macrophages. In particular, colon-specific macrophage depletion by intrarectal clodronate liposomes improved glucose tolerance, insulin sensitivity, and insulin secretion capacity. Colonic macrophage activation upon HFD was characterized by an interferon response and a change in mitochondrial metabolism, which converged in mTOR as a common regulator. Colon-specific mTOR inhibition reduced pro-inflammatory macrophages and ameliorated insulin secretion capacity, similar to colon-specific macrophage depletion, but did not affect insulin sensitivity. Thus, pharmacological targeting of colonic macrophages could become a potential therapy in obesity to improve glycemic control.


Asunto(s)
Dieta Alta en Grasa , Resistencia a la Insulina , Animales , Glucemia/metabolismo , Colon/metabolismo , Dieta Alta en Grasa/efectos adversos , Control Glucémico , Macrófagos/metabolismo , Ratones , Obesidad/etiología , Obesidad/metabolismo , Serina-Treonina Quinasas TOR/metabolismo
7.
Sci Immunol ; 6(65): eabj2132, 2021 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-34797692

RESUMEN

Alveolar macrophages are the most abundant macrophages in the healthy lung where they play key roles in homeostasis and immune surveillance against airborne pathogens. Tissue-specific differentiation and survival of alveolar macrophages rely on niche-derived factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor­ß (TGF-ß). However, the nature of the downstream molecular pathways that regulate the identity and function of alveolar macrophages and their response to injury remain poorly understood. Here, we identify that the transcription factor EGR2 is an evolutionarily conserved feature of lung alveolar macrophages and show that cell-intrinsic EGR2 is indispensable for the tissue-specific identity of alveolar macrophages. Mechanistically, we show that EGR2 is driven by TGF-ß and GM-CSF in a PPAR-γ­dependent manner to control alveolar macrophage differentiation. Functionally, EGR2 was dispensable for the regulation of lipids in the airways but crucial for the effective handling of the respiratory pathogen Streptococcus pneumoniae. Last, we show that EGR2 is required for repopulation of the alveolar niche after sterile, bleomycin-induced lung injury and demonstrate that EGR2-dependent, monocyte-derived alveolar macrophages are vital for effective tissue repair after injury. Collectively, we demonstrate that EGR2 is an indispensable component of the transcriptional network controlling the identity and function of alveolar macrophages in health and disease.


Asunto(s)
Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Macrófagos Alveolares/inmunología , Animales , Femenino , Humanos , Macrófagos Alveolares/patología , Masculino , Ratones , Infecciones Neumocócicas/inmunología , Infecciones Neumocócicas/patología , Streptococcus pneumoniae/inmunología
8.
PLoS Pathog ; 17(7): e1009749, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34324611

RESUMEN

The main avenue for the development of an HIV-1 vaccine remains the induction of protective antibodies. A rationale approach is to target antigen to specific receptors on dendritic cells (DC) via fused monoclonal antibodies (mAb). In mouse and non-human primate models, targeting of skin Langerhans cells (LC) with anti-Langerin mAbs fused with HIV-1 Gag antigen drives antigen-specific humoral responses. The development of these immunization strategies in humans requires a better understanding of early immune events driven by human LC. We therefore produced anti-Langerin mAbs fused with the HIV-1 gp140z Envelope (αLC.Env). First, we show that primary skin human LC and in vitro differentiated LC induce differentiation and expansion of naïve CD4+ T cells into T follicular helper (Tfh) cells. Second, when human LC are pre-treated with αLC.Env, differentiated Tfh cells significantly promote the production of specific IgG by B cells. Strikingly, HIV-Env-specific Ig are secreted by HIV-specific memory B cells. Consistently, we found that receptors and cytokines involved in Tfh differentiation and B cell functions are upregulated by LC during their maturation and after targeting Langerin. Finally, we show that subcutaneous immunization of mice by αLC.Env induces germinal center (GC) reaction in draining lymph nodes with higher numbers of Tfh cells, Env-specific B cells, as well as specific IgG serum levels compared to mice immunized with the non-targeting Env antigen. Altogether, we provide evidence that human LC properly targeted may be licensed to efficiently induce Tfh cell and B cell responses in GC.


Asunto(s)
Vacunas contra el SIDA/inmunología , Antígenos CD/inmunología , VIH-1/inmunología , Inmunidad Humoral/inmunología , Células de Langerhans/inmunología , Lectinas Tipo C/inmunología , Lectinas de Unión a Manosa/inmunología , Animales , Humanos , Activación de Linfocitos/inmunología , Ratones , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología
9.
Nat Med ; 27(6): 1043-1054, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34017133

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology.


Asunto(s)
Células Dendríticas/inmunología , Hígado Graso/inmunología , Enfermedad del Hígado Graso no Alcohólico/inmunología , Receptores de Quimiocina/genética , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/patología , Reprogramación Celular/genética , Reprogramación Celular/inmunología , Células Dendríticas/patología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Hígado Graso/genética , Hígado Graso/patología , Femenino , Humanos , Hígado/inmunología , Hígado/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Masculino , Ratones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Receptores de Quimiocina/inmunología , Linfocitos T/inmunología , Linfocitos T/patología
10.
Nat Commun ; 12(1): 2936, 2021 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-34006861

RESUMEN

Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav1.8+ sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav1.8-expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav1.8+ sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Dolor Nociceptivo/inmunología , Células Receptoras Sensoriales/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Herpes Simple/genética , Herpes Simple/virología , Herpesvirus Humano 1/fisiología , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Canal de Sodio Activado por Voltaje NAV1.8/genética , Canal de Sodio Activado por Voltaje NAV1.8/inmunología , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Infiltración Neutrófila/inmunología , Dolor Nociceptivo/genética , Dolor Nociceptivo/metabolismo , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/virología , Piel/inmunología , Piel/metabolismo , Piel/virología
11.
EMBO Rep ; 22(4): e52196, 2021 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-33719206

RESUMEN

T and B cells continually recirculate between blood and secondary lymphoid organs. To promote their trans-endothelial migration (TEM), chemokine receptors control the activity of RHO family small GTPases in part via GTPase-activating proteins (GAPs). T and B cells express several RHO-GAPs, the function of most of which remains unknown. The ARHGAP45 GAP is predominantly expressed in hematopoietic cells. To define its in vivo function, we describe two mouse models where ARHGAP45 is ablated systemically or selectively in T cells. We combine their analysis with affinity purification coupled to mass spectrometry to determine the ARHGAP45 interactome in T cells and with time-lapse and reflection interference contrast microscopy to assess the role of ARGHAP45 in T-cell polarization and motility. We demonstrate that ARHGAP45 regulates naïve T-cell deformability and motility. Under physiological conditions, ARHGAP45 controls the entry of naïve T and B cells into lymph nodes whereas under competitive repopulation it further regulates hematopoietic progenitor cell engraftment in the bone marrow, and T-cell progenitor thymus seeding. Therefore, the ARGHAP45 GAP controls multiple key steps in the life of T and B cells.


Asunto(s)
Linfocitos T , Internalización del Virus , Animales , Linfocitos B , Movimiento Celular , Proteínas Activadoras de GTPasa/genética , Ganglios Linfáticos , Ratones , Timo
12.
Dermatology ; 237(2): 296-302, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32344413

RESUMEN

BACKGROUND: Little information is available about the complexity and function of skin cells contributing to the high stability of tattoos. It has been shown that dermal macrophages play an important role in the storage and maintenance of pigment particles. By contrast, the impact of dermal fibroblasts, forming the connective tissue of the skin, on the stability of the tattoo is not known. METHOD: In this study, we compared the cell number and the particle load in dermal macrophages versus dermal fibroblasts, isolated from tail skin of tattooed mice. RESULTS: Microscopic analysis revealed that both cell populations contained the tattoo particles, although in largely different amounts. A small number of macrophages with high side scatter intensity contained a large quantity of pigment particles, whereas a high number of dermal fibroblasts harbored only a few pigment particles. Using the CD64dtr mouse model that allows for selective, diphtheria toxin-mediated depletion of macrophages, we have previously shown that macrophages hold the tattoo in place by capture-release and recapture cycles. In the tattooed skin of macrophage-depleted mice, the content of pigment particles in fibroblasts did not change; however, the total number of fibroblasts carrying particles increased. CONCLUSION: The present study demonstrates that dermal macrophages and fibroblasts contribute in different ways to the tattoo stability and further improves our knowledge on tattoo persistence.


Asunto(s)
Colorantes , Dermis/citología , Fibroblastos/fisiología , Macrófagos/fisiología , Tatuaje , Animales , Recuento de Células , Tinta , Ratones , Microscopía
13.
Nanomedicine ; 32: 102321, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33184020

RESUMEN

Ultra-small 1-2 nm gold nanoparticles (NP) were conjugated with a poorly-soluble peptide auto-antigen, associated with type 1 diabetes, to modify the peptide pharmacokinetics, following its intradermal delivery. Peptide distribution was characterized, in vivo, after delivery using either conventional intradermal injection or a hollow microneedle device. The poorly-soluble peptide was effectively presented in distant lymph nodes (LN), spleen and draining LN when conjugated to the nanoparticles, whereas peptide alone was only presented in the draining LN. By contrast, nanoparticle conjugation to a highly-soluble peptide did not enhance in vivo distribution. Transfer of both free peptide and peptide-NPs from the skin to LN was reduced in mice lacking lymphoid homing receptor CCR7, suggesting that both are actively transported by migrating dendritic cells to LN. Collectively, these data demonstrate that intradermally administered ultra-small gold nanoparticles can widen the distribution of poorly-soluble auto-antigenic peptides to multiple lymphoid organs, thus enhancing their use as potential therapeutics.


Asunto(s)
Antígenos/metabolismo , Oro/química , Nanopartículas del Metal/química , Péptidos/farmacología , Secuencia de Aminoácidos , Animales , Proliferación Celular , Células Dendríticas/efectos de los fármacos , Inyecciones Intradérmicas , Ratones Endogámicos C57BL , Ratones Transgénicos , Agujas , Péptidos/química , Péptidos/farmacocinética , Fenotipo , Piel/efectos de los fármacos , Solubilidad , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología
14.
Cell ; 183(2): 411-428.e16, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-32970988

RESUMEN

The colon is primarily responsible for absorbing fluids. It contains a large number of microorganisms including fungi, which are enriched in its distal segment. The colonic mucosa must therefore tightly regulate fluid influx to control absorption of fungal metabolites, which can be toxic to epithelial cells and lead to barrier dysfunction. How this is achieved remains unknown. Here, we describe a mechanism by which the innate immune system allows rapid quality check of absorbed fluids to avoid intoxication of colonocytes. This mechanism relies on a population of distal colon macrophages that are equipped with "balloon-like" protrusions (BLPs) inserted in the epithelium, which sample absorbed fluids. In the absence of macrophages or BLPs, epithelial cells keep absorbing fluids containing fungal products, leading to their death and subsequent loss of epithelial barrier integrity. These results reveal an unexpected and essential role of macrophages in the maintenance of colon-microbiota interactions in homeostasis. VIDEO ABSTRACT.


Asunto(s)
Microbioma Gastrointestinal/fisiología , Mucosa Intestinal/metabolismo , Macrófagos/metabolismo , Animales , Colon/metabolismo , Células Epiteliales/metabolismo , Epitelio , Femenino , Homeostasis , Inmunidad Innata/inmunología , Mucosa Intestinal/microbiología , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota , Transducción de Señal
15.
Artículo en Inglés | MEDLINE | ID: mdl-32638670

RESUMEN

OBJECTIVES: Unlike randomized controlled trials, lack of methodological rigor is a concern about real-world evidence (RWE) studies. The objective of this study was to characterize methodological practices of studies collecting pharmacoeconomic data in a real-world setting for the management of type 2 diabetes mellitus (T2DM). METHODS: A systematic literature review was performed using the PICO framework: population consisted of T2DM patients, interventions and comparators were any intervention for T2DM care or absence of intervention, and outcomes were resource utilization, productivity loss or utility. Only RWE studies were included, defined as studies that were not clinical trials and that collected de novo data (no retrospective analysis). RESULTS: The literature search identified 1,158 potentially relevant studies, among which sixty were included in the literature review. Many studies showed a lack of transparency by not mentioning the source for outcome and exposure measurement, source for patient selection, number of study sites, recruitment duration, sample size calculation, sampling method, missing data, approbation by an ethics committee, obtaining patient's consent, conflicts of interest, and funding. A significant proportion of studies had poor quality scores and was at high risk of bias. CONCLUSIONS: RWE from T2DM studies lacks transparency and credibility. There is a need for good procedural practices that can increase confidence in RWE studies. Standardized methodologies specifically adapted for RWE studies collecting pharmacoeconomic data for the management of T2DM could help future reimbursement decision making in this major public health problem.

16.
Cell Rep ; 30(12): 4110-4123.e4, 2020 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-32209472

RESUMEN

Within lymph nodes (LNs), T follicular helper (TFH) cells help B cells to produce antibodies, which can either be protective or autoreactive. Here, we demonstrate that murine LN stromal cells (LNSCs) suppress the formation of autoreactive TFH cells in an antigen-specific manner, thereby significantly reducing germinal center B cell responses directed against the same self-antigen. Mechanistically, LNSCs express and present self-antigens in major histocompatibility complex (MHC) class II, leading to the conversion of naive CD4+ T cells into T regulatory (TREG) cells in an interleukin-2 (IL-2)-dependent manner. Upon blockade of TREG cells, using neutralizing IL-2 antibodies, autoreactive TFH cells are allowed to develop. We conclude that the continuous presentation of self-antigens by LNSCs is critical to generate antigen-specific TREG cells, thereby repressing the formation of TFH cells and germinal center B cell responses. Our findings uncover the ability of LNSCs to suppress the early activation of autoreactive immune cells and maintain peripheral tolerance.


Asunto(s)
Linfocitos B/inmunología , Epítopos/inmunología , Ganglios Linfáticos/citología , Linfocitos T Reguladores/inmunología , Animales , Presentación de Antígeno/inmunología , Antígenos CD/metabolismo , Autoantígenos/inmunología , Centro Germinal/inmunología , Humanos , Interleucina-2/metabolismo , Ratones Endogámicos C57BL , Células del Estroma/citología
17.
Sci Immunol ; 5(45)2020 03 13.
Artículo en Inglés | MEDLINE | ID: mdl-32169954

RESUMEN

Conventional dendritic cells expressing the XCR1 chemokine receptor (cDC1s) excel at cross-presentation. Here, we developed and used a mouse model in which a Cre recombinase is expressed under the control of the Xcr1 gene while preserving XCR1 expression. We used it to generate mice with conditional deletion of MHC class II (MHCII) molecules on cDC1s. By preventing cDC1s to receive suppressive regulatory T cell inputs via MHCII-restricted interactions, the objective of the present study was to gauge whether MHCII-deficient cDC1s lose their capacity of tolerizing autoreactive CD8+ T cells. Whereas MHCII+ cDC1 readily cross-tolerized strongly autoreactive CD8+ T cells specific for a keratinocyte-derived self-antigen, MHCII-deficient cDC1s converted them into potent effectors capable of triggering a fast-onset lethal autoimmunity associated with severe skin histopathological manifestations. Preventing egress of such pathogenic self-reactive CD8+ T cell effectors from the cutaneous draining lymph nodes abrogated the autoimmune condition. Therefore, our results revealed that the cross-tolerizing capacity of cDC1s is not a property fully acquired at the time they undergo homeostatic maturation but needs to be enforced via MHCII-restricted, suppressive interactions with regulatory T cells.


Asunto(s)
Autoantígenos/inmunología , Autoinmunidad/inmunología , Reactividad Cruzada/inmunología , Células Dendríticas/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Animales , Ratones , Ratones Endogámicos C57BL
18.
Immunity ; 50(6): 1453-1466.e4, 2019 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-31053503

RESUMEN

In lymph nodes, subcapsular sinus macrophages (SSMs) form an immunological barrier that monitors lymph drained from peripheral tissues. Upon infection, SSMs activate B and natural killer T (NKT) cells while secreting inflammatory mediators. Here, we investigated the mechanisms regulating development and homeostasis of SSMs. Embryonic SSMs originated from yolk sac hematopoiesis and were replaced by a postnatal wave of bone marrow (BM)-derived monocytes that proliferated to establish the adult SSM network. The SSM network self-maintained by proliferation with minimal BM contribution. Upon pathogen-induced transient deletion, BM-derived cells contributed to restoring the SSM network. Lymphatic endothelial cells (LECs) were the main source of CSF-1 within the lymph node and conditional deletion of Csf1 in adult LECs decreased the network of SSMs and medullary sinus macrophages (MSMs). Thus, SSMs have a dual hematopoietic origin, and LECs are essential to the niche supporting these macrophages.


Asunto(s)
Células Endoteliales/metabolismo , Macrófagos/metabolismo , Animales , Biomarcadores , Comunicación Celular , Diferenciación Celular , Expresión Génica , Genes Reporteros , Hematopoyesis/genética , Hematopoyesis/inmunología , Homeostasis , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Vasos Linfáticos , Factor Estimulante de Colonias de Macrófagos/metabolismo , Macrófagos/citología , Macrófagos/inmunología , Ratones , Monocitos/citología , Monocitos/metabolismo , Saco Vitelino
19.
Immunity ; 49(2): 312-325.e5, 2018 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-30076102

RESUMEN

Heterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated. We show here that Zeb2 expression is a conserved feature of macrophages. Using Clec4f-cre, Itgax-cre, and Fcgr1-cre mice to target five different macrophage populations, we found that loss of ZEB2 resulted in macrophage disappearance from the tissues, coupled with their subsequent replenishment from bone-marrow precursors in open niches. Mechanistically, we found that ZEB2 functioned to maintain the tissue-specific identities of macrophages. In Kupffer cells, ZEB2 achieved this by regulating expression of the transcription factor LXRα, removal of which recapitulated the loss of Kupffer cell identity and disappearance. Thus, ZEB2 expression is required in macrophages to preserve their tissue-specific identities.


Asunto(s)
Macrófagos del Hígado/citología , Receptores X del Hígado/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Animales , Linaje de la Célula/inmunología , Transición Epitelial-Mesenquimal , Femenino , Regulación Neoplásica de la Expresión Génica , Macrófagos del Hígado/inmunología , Hígado/citología , Receptores X del Hígado/metabolismo , Pulmón/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
20.
J Exp Med ; 215(4): 1115-1133, 2018 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-29511065

RESUMEN

Here we describe a new mouse model that exploits the pattern of expression of the high-affinity IgG receptor (CD64) and allows diphtheria toxin (DT)-mediated ablation of tissue-resident macrophages and monocyte-derived cells. We found that the myeloid cells of the ear skin dermis are dominated by DT-sensitive, melanin-laden cells that have been missed in previous studies and correspond to macrophages that have ingested melanosomes from neighboring melanocytes. Those cells have been referred to as melanophages in humans. We also identified melanophages in melanocytic melanoma. Benefiting of our knowledge on melanophage dynamics, we determined the identity, origin, and dynamics of the skin myeloid cells that capture and retain tattoo pigment particles. We showed that they are exclusively made of dermal macrophages. Using the possibility to delete them, we further demonstrated that tattoo pigment particles can undergo successive cycles of capture-release-recapture without any tattoo vanishing. Therefore, congruent with dermal macrophage dynamics, long-term tattoo persistence likely relies on macrophage renewal rather than on macrophage longevity.


Asunto(s)
Macrófagos/patología , Piel/patología , Tatuaje , Animales , Dermis/patología , Toxina Diftérica/farmacología , Oído/patología , Perfilación de la Expresión Génica , Cinética , Macrófagos/efectos de los fármacos , Melanocitos/efectos de los fármacos , Melanocitos/patología , Melanocitos/ultraestructura , Melanoma/patología , Ratones , Modelos Biológicos , Monocitos/efectos de los fármacos , Monocitos/patología , Células Mieloides/efectos de los fármacos , Células Mieloides/patología , Pigmentación/efectos de los fármacos , Receptores de IgG/metabolismo
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