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1.
Cell ; 187(4): 962-980.e19, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38309258

RESUMEN

Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development.


Asunto(s)
Encéfalo , Microglía , Axones , Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Macrófagos/fisiología , Microglía/patología , Morfogénesis
2.
Cell ; 185(7): 1189-1207.e25, 2022 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-35325594

RESUMEN

Macrophage infiltration is a hallmark of solid cancers, and overall macrophage infiltration correlates with lower patient survival and resistance to therapy. Tumor-associated macrophages, however, are phenotypically and functionally heterogeneous. Specific subsets of tumor-associated macrophage might be endowed with distinct roles on cancer progression and antitumor immunity. Here, we identify a discrete population of FOLR2+ tissue-resident macrophages in healthy mammary gland and breast cancer primary tumors. FOLR2+ macrophages localize in perivascular areas in the tumor stroma, where they interact with CD8+ T cells. FOLR2+ macrophages efficiently prime effector CD8+ T cells ex vivo. The density of FOLR2+ macrophages in tumors positively correlates with better patient survival. This study highlights specific roles for tumor-associated macrophage subsets and paves the way for subset-targeted therapeutic interventions in macrophages-based cancer therapies.


Asunto(s)
Neoplasias de la Mama , Macrófagos , Mama/inmunología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/inmunología , Linfocitos T CD8-positivos , Femenino , Receptor 2 de Folato , Humanos , Linfocitos Infiltrantes de Tumor , Pronóstico
3.
Annu Rev Immunol ; 31: 563-604, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23516985

RESUMEN

Dendritic cells (DCs) form a remarkable cellular network that shapes adaptive immune responses according to peripheral cues. After four decades of research, we now know that DCs arise from a hematopoietic lineage distinct from other leukocytes, establishing the DC system as a unique hematopoietic branch. Recent work has also established that tissue DCs consist of developmentally and functionally distinct subsets that differentially regulate T lymphocyte function. This review discusses major advances in our understanding of the regulation of DC lineage commitment, differentiation, diversification, and function in situ.


Asunto(s)
Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Células Dendríticas/inmunología , Células Dendríticas/patología , Animales , Movimiento Celular/inmunología , Células Dendríticas/citología , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/fisiología , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Tejido Linfoide/patología
4.
Immunity ; 55(1): 129-144.e8, 2022 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-34910930

RESUMEN

Dendritic cells (DCs) patrol tissues and transport antigens to lymph nodes to initiate adaptive immune responses. Within tissues, DCs constitute a complex cell population composed of distinct subsets that can exhibit different activation states and functions. How tissue-specific cues orchestrate DC diversification remains elusive. Here, we show that the small intestine included two pools of cDC2s originating from common pre-DC precursors: (1) lamina propria (LP) CD103+CD11b+ cDC2s that were mature-like proinflammatory cells and (2) intraepithelial cDC2s that exhibited an immature-like phenotype as well as tolerogenic properties. These phenotypes resulted from the action of food-derived retinoic acid (ATRA), which enhanced actomyosin contractility and promoted LP cDC2 transmigration into the epithelium. There, cDC2s were imprinted by environmental cues, including ATRA itself and the mucus component Muc2. Hence, by reaching distinct subtissular niches, DCs can exist as immature and mature cells within the same tissue, revealing an additional mechanism of DC functional diversification.


Asunto(s)
Células Dendríticas/inmunología , Inflamación/inmunología , Mucosa Intestinal/patología , Linfocitos T/inmunología , Actomiosina/metabolismo , Animales , Presentación de Antígeno , Antígenos CD/metabolismo , Antígeno CD11b/metabolismo , Diferenciación Celular , Movimiento Celular , Células Cultivadas , Tolerancia Inmunológica , Cadenas alfa de Integrinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mucina 2/inmunología , Tretinoina/metabolismo
5.
Immunity ; 53(2): 335-352.e8, 2020 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-32610077

RESUMEN

Dendritic cells (DCs) are antigen-presenting cells controlling T cell activation. In humans, the diversity, ontogeny, and functional capabilities of DC subsets are not fully understood. Here, we identified circulating CD88-CD1c+CD163+ DCs (called DC3s) as immediate precursors of inflammatory CD88-CD14+CD1c+CD163+FcεRI+ DCs. DC3s develop via a specific pathway activated by GM-CSF, independent of cDC-restricted (CDP) and monocyte-restricted (cMoP) progenitors. Like classical DCs but unlike monocytes, DC3s drove activation of naive T cells. In vitro, DC3s displayed a distinctive ability to prime CD8+ T cells expressing a tissue homing signature and the epithelial homing alpha-E integrin (CD103) through transforming growth factor ß (TGF-ß) signaling. In vivo, DC3s infiltrated luminal breast cancer primary tumors, and DC3 infiltration correlated positively with CD8+CD103+CD69+ tissue-resident memory T cells. Together, these findings define DC3s as a lineage of inflammatory DCs endowed with a strong potential to regulate tumor immunity.


Asunto(s)
Antígenos CD1/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Neoplasias de la Mama/inmunología , Linfocitos T CD8-positivos/citología , Células Dendríticas/inmunología , Glicoproteínas/metabolismo , Cadenas alfa de Integrinas/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Antígenos CD8/metabolismo , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Línea Celular Tumoral , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos NOD , Factor de Crecimiento Transformador beta1/metabolismo , Tirosina Quinasa 3 Similar a fms/metabolismo
7.
Nat Immunol ; 13(9): 888-99, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22797772

RESUMEN

Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8(+), CD103(+), CD11b(+) and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens.


Asunto(s)
Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Células Dendríticas/inmunología , Transcripción Genética , Diferenciación Celular/genética , Células Dendríticas/citología , Perfilación de la Expresión Génica , Humanos
8.
Nat Immunol ; 13(11): 1118-28, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23023392

RESUMEN

We assessed gene expression in tissue macrophages from various mouse organs. The diversity in gene expression among different populations of macrophages was considerable. Only a few hundred mRNA transcripts were selectively expressed by macrophages rather than dendritic cells, and many of these were not present in all macrophages. Nonetheless, well-characterized surface markers, including MerTK and FcγR1 (CD64), along with a cluster of previously unidentified transcripts, were distinctly and universally associated with mature tissue macrophages. TCEF3, C/EBP-α, Bach1 and CREG-1 were among the transcriptional regulators predicted to regulate these core macrophage-associated genes. The mRNA encoding other transcription factors, such as Gata6, was associated with single macrophage populations. We further identified how these transcripts and the proteins they encode facilitated distinguishing macrophages from dendritic cells.


Asunto(s)
Antígenos CD/genética , Macrófagos/metabolismo , ARN Mensajero/genética , Factores de Transcripción/genética , Transcripción Genética , Animales , Antígenos CD/inmunología , Diferenciación Celular , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Variación Genética , Hígado/citología , Hígado/inmunología , Hígado/metabolismo , Pulmón/citología , Pulmón/inmunología , Pulmón/metabolismo , Macrófagos/citología , Macrófagos/inmunología , Ratones , Microglía/citología , Microglía/inmunología , Microglía/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Especificidad de Órganos , ARN Mensajero/inmunología , Bazo/citología , Bazo/inmunología , Bazo/metabolismo , Factores de Transcripción/inmunología
9.
Immunity ; 42(6): 1197-211, 2015 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-26084029

RESUMEN

Dendritic cells (DCs) are key players in the immune system. Much of their biology has been elucidated via culture systems in which hematopoietic precursors differentiate into DCs under the aegis of cytokines. A widely used protocol involves the culture of murine bone marrow (BM) cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) to generate BM-derived DCs (BMDCs). BMDCs express CD11c and MHC class II (MHCII) molecules and share with DCs isolated from tissues the ability to present exogenous antigens to T cells and to respond to microbial stimuli by undergoing maturation. We demonstrate that CD11c(+)MHCII(+) BMDCs are in fact a heterogeneous group of cells that comprises conventional DCs and monocyte-derived macrophages. DCs and macrophages in GM-CSF cultures both undergo maturation upon stimulation with lipopolysaccharide but respond differentially to the stimulus and remain separable entities. These results have important implications for the interpretation of a vast array of data obtained with DC culture systems.


Asunto(s)
Células de la Médula Ósea/inmunología , Células Dendríticas/inmunología , Macrófagos/inmunología , Animales , Presentación de Antígeno , Antígeno CD11c/metabolismo , Diferenciación Celular , Células Cultivadas , Citocinas/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Inmunofenotipificación , Lipopolisacáridos/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Transcriptoma
10.
Immunity ; 38(4): 818-30, 2013 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-23562160

RESUMEN

In comparison to murine dendritic cells (DCs), less is known about the function of human DCs in tissues. Here, we analyzed, by using lung tissues from humans and humanized mice, the role of human CD1c(+) and CD141(+) DCs in determining the type of CD8(+) T cell immunity generated to live-attenuated influenza virus (LAIV) vaccine. We found that both lung DC subsets acquired influenza antigens in vivo and expanded specific cytotoxic CD8(+) T cells in vitro. However, lung-tissue-resident CD1c(+) DCs, but not CD141(+) DCs, were able to drive CD103 expression on CD8(+) T cells and promoted CD8(+) T cell accumulation in lung epithelia in vitro and in vivo. CD1c(+) DCs induction of CD103 expression was dependent on membrane-bound cytokine TGF-ß1. Thus, CD1c(+) and CD141(+) DCs generate CD8(+) T cells with different properties, and CD1c(+) DCs specialize in the regulation of mucosal CD8(+) T cells.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Pulmón/inmunología , Subgrupos de Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos CD1/metabolismo , Antígenos Virales/inmunología , Diferenciación Celular , Células Cultivadas , Citotoxicidad Inmunológica , Glicoproteínas/metabolismo , Humanos , Inmunidad Mucosa , Memoria Inmunológica , Vacunas contra la Influenza/inmunología , Cadenas alfa de Integrinas/metabolismo , Pulmón/virología , Activación de Linfocitos , Ratones , Ratones SCID , Análisis por Micromatrices
11.
Immunity ; 36(6): 1031-46, 2012 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-22749353

RESUMEN

GM-CSF (Csf-2) is a critical cytokine for the in vitro generation of dendritic cells (DCs) and is thought to control the development of inflammatory DCs and resident CD103(+) DCs in some tissues. Here we showed that in contrast to the current understanding, Csf-2 receptor acts in the steady state to promote the survival and homeostasis of nonlymphoid tissue-resident CD103(+) and CD11b(+) DCs. Absence of Csf-2 receptor on lung DCs abrogated the induction of CD8(+) T cell immunity after immunization with particulate antigens. In contrast, Csf-2 receptor was dispensable for the differentiation and innate function of inflammatory DCs during acute injuries. Instead, inflammatory DCs required Csf-1 receptor for their development. Thus, Csf-2 is important in vaccine-induced CD8(+) T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo.


Asunto(s)
Subunidad beta Común de los Receptores de Citocinas/fisiología , Células Dendríticas/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Inflamación/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Linaje de la Célula , Subunidad beta Común de los Receptores de Citocinas/antagonistas & inhibidores , Subunidad beta Común de los Receptores de Citocinas/deficiencia , Subunidad beta Común de los Receptores de Citocinas/genética , Células Dendríticas/clasificación , Células Dendríticas/citología , Encefalomielitis Autoinmune Experimental/inmunología , Endotoxemia/inmunología , Perfilación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/deficiencia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Homeostasis , Lipopolisacáridos/toxicidad , Listeriosis/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/trasplante , Especificidad de Órganos , Infecciones por Orthomyxoviridae/inmunología , Infecciones Neumocócicas/inmunología , Quimera por Radiación , Bazo/inmunología , Tamoxifeno/farmacología
13.
Immunity ; 31(2): 232-44, 2009 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-19699172

RESUMEN

Dendritic cells (DCs) have the striking ability to cross-present exogenous antigens in association with major histocompatibility complex (MHC) class I to CD8(+) T cells. However, the intracellular pathways underlying cross-presentation remain ill defined. Current models involve cytosolic proteolysis of antigens by the proteasome and peptide import into endoplasmic reticulum (ER) or phagosomal lumen by the transporters associated with antigen processing (TAP1 and TAP2). Here, we show that DCs expressed an ER-resident 47 kDa immune-related GTPase, Igtp (Irgm3). Igtp resides on ER and lipid body (LB) membranes where it binds the LB coat component ADFP. Inactivation of genes encoding for either Igtp or ADFP led to defects in LB formation in DCs and severely impaired cross-presentation of phagocytosed antigens to CD8(+) T cells but not antigen presentation to CD4(+) T cells. We thus define a new role for LB organelles in regulating cross-presentation of exogenous antigens to CD8(+) T lymphocytes in DCs.


Asunto(s)
Presentación de Antígeno/inmunología , Reactividad Cruzada , Células Dendríticas/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Lípidos/inmunología , Fagocitosis , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Retículo Endoplásmico/inmunología , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/inmunología , GTP Fosfohidrolasas/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Perilipina-2
14.
Immunity ; 31(3): 513-25, 2009 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-19733489

RESUMEN

CX(3)CR1(+) and CD103(+) dendritic cells (DCs) in intestinal lamina propria play a key role in mucosal immunity. However, the origin and the developmental pathways that regulate their differentiation in the lamina propria remain unclear. We showed that monocytes gave rise exclusively to CD103(-)CX(3)CR1(+) lamina propria DCs under the control of macrophage-colony-stimulating factor receptor (M-CSFR) and Fms-like thyrosine kinase 3 (Flt3) ligands. In contrast, common DC progenitors (CDP) and pre-DCs, which give rise to lymphoid organ DCs but not to monocytes, differentiated exclusively into CD103(+)CX(3)CR1(-) lamina propria DCs under the control of Flt3 and granulocyte-macrophage-colony-stimulating factor receptor (GM-CSFR) ligands. CD103(+)CX(3)CR1(-) DCs but not CD103(-)CX(3)CR1(+) DCs in the lamina propria constitutively expressed CCR7 and were the first DCs to transport pathogenic Salmonella from the intestinal tract to the mesenteric lymph nodes. Altogether, these results underline the diverse origin of the lamina propria DC network and identify mucosal DCs that arise from pre-DCs as key sentinels of the gut immune system.


Asunto(s)
Linaje de la Célula , Células Dendríticas/citología , Células Dendríticas/inmunología , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Animales , Antígenos CD/inmunología , Receptor 1 de Quimiocinas CX3C , Diferenciación Celular , Movimiento Celular , Cadenas alfa de Integrinas/inmunología , Ganglios Linfáticos/inmunología , Ratones , Ratones Noqueados , Fenotipo , Receptor de Factor Estimulante de Colonias de Macrófagos/inmunología , Receptores de Quimiocina/inmunología , Salmonella/inmunología , Salmonella/patogenicidad , Tirosina Quinasa 3 Similar a fms/deficiencia , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/inmunología
15.
J Immunol ; 195(10): 5066-76, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26459350

RESUMEN

Dendritic cells (DCs) are powerful APCs that can induce Ag-specific adaptive immune responses and are increasingly recognized as important players in innate immunity to both infection and malignancy. Interestingly, although there are multiple described hematological malignancies, DC cancers are rarely observed in humans. Whether this is linked to the immunogenic potential of DCs, which might render them uniquely susceptible to immune control upon neoplastic transformation, has not been fully investigated. To address the issue, we generated a genetically engineered mouse model in which expression of Cre recombinase driven by the C-type lectin domain family 9, member a (Clec9a) locus causes expression of the Kirsten rat sarcoma viral oncogene homolog (Kras)(G12D) oncogenic driver and deletion of the tumor suppressor p53 within developing and differentiated DCs. We show that these Clec9a(Kras-G12D) mice rapidly succumb from disease and display massive accumulation of transformed DCs in multiple organs. In bone marrow chimeras, the development of DC cancer could be induced by a small number of transformed cells and was not prevented by the presence of untransformed DCs. Notably, activation of transformed DCs did not happen spontaneously but could be induced upon stimulation. Although Clec9a(Kras-G12D) mice showed altered thymic T cell development, peripheral T cells were largely unaffected during DC cancer development. Interestingly, transformed DCs were rejected upon adoptive transfer into wild-type but not lymphocyte-deficient mice, indicating that immunological control of DC cancer is in principle possible but does not occur during spontaneous generation in Clec9a(Kras-G12D) mice. Our findings suggest that neoplastic transformation of DCs does not by default induce anti-cancer immunity and can develop unhindered by immunological barriers.


Asunto(s)
Transformación Celular Neoplásica/inmunología , Células Dendríticas/inmunología , Neoplasias Experimentales/inmunología , Células Madre/inmunología , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Células Dendríticas/patología , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Ratones , Ratones Transgénicos , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/inmunología , Ratas , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Células Madre/patología
16.
Blood ; 119(7): 1693-701, 2012 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-22174156

RESUMEN

R-Ras is a member of the RAS superfamily of small GTP-binding proteins. The physiologic function of R-Ras has not been fully elucidated. We found that R-Ras is expressed by lymphoid and nonlymphoid tissues and drastically up-regulated when bone marrow progenitors are induced to differentiate into dendritic cells (DCs). To address the role of R-Ras in DC functions, we generated a R-Ras-deficient mouse strain. We found that tumors induced in Rras(-/-) mice formed with shorter latency and attained greater tumor volumes. This finding has prompted the investigation of a role for R-Ras in the immune system. Indeed, Rras(-/-) mice were impaired in their ability to prime allogeneic and antigen-specific T-cell responses. Rras(-/-) DCs expressed lower levels of surface MHC class II and CD86 in response to lipopolysaccharide compared with wild-type DCs. This was correlated with a reduced phosphorylation of p38 and Akt. Consistently, R-Ras-GTP level was increased within 10 minutes of lipopolysaccharide stimulation. Furthermore, Rras(-/-) DCs have attenuated capacity to spread on fibronectin and form stable immunologic synapses with T cells. Altogether, these findings provide the first demonstration of a role for R-Ras in cell-mediated immunity and further expand on the complexity of small G-protein signaling in DCs.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/genética , Células Dendríticas/fisiología , Activación de Linfocitos/genética , Proteínas ras/fisiología , Animales , Presentación de Antígeno/genética , Presentación de Antígeno/inmunología , Linfocitos T CD4-Positivos/metabolismo , Diferenciación Celular/inmunología , Células Cultivadas , Células Dendríticas/metabolismo , Femenino , Inmunidad Celular/genética , Inmunidad Celular/inmunología , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas ras/genética , Proteínas ras/metabolismo
17.
Immunol Rev ; 234(1): 55-75, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20193012

RESUMEN

Dendritic cells (DCs) have been extensively studied in mice lymphoid organs, but less is known about the origin and the mechanisms that regulate DC development and function in non-lymphoid tissues. Here, we discuss recent evidence establishing the contribution of the DC-restricted lineage to the non-lymphoid tissue DC pool and discuss the mechanisms that control the homeostasis of non-lymphoid tissue DCs. We also review recent results underlining the functional specialization of tissue DCs and discuss the potential implications of these findings in tissue immunity and in the development of novel vaccine strategies.


Asunto(s)
Diferenciación Celular , Linaje de la Célula , Células Dendríticas/inmunología , Células Madre Hematopoyéticas/inmunología , Animales , Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Citocinas/inmunología , Células Dendríticas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Homeostasis , Mediadores de Inflamación/inmunología , Ratones , Fenotipo , Factores de Transcripción/metabolismo , Vacunas/inmunología
18.
Methods Mol Biol ; 2618: 83-92, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36905510

RESUMEN

Dendritic cells (DCs) are mononuclear phagocytes of hematopoietic origin residing in lymphoid and nonlymphoid tissues. DCs are often referred as the sentinels of the immune system as they can sense pathogens and danger signals. Upon activation, DCs migrate to the draining lymph nodes and present antigens to naïve T cells to trigger adaptive immunity. Hematopoietic progenitors for DCs reside in the adult bone marrow (BM). Therefore, BM cell culture systems have been developed to generate large amounts of primary DCs in vitro conveniently enabling to analyze their developmental and functional features. Here, we review various protocols enabling to generate DCs in vitro from murine BM cells and discuss the cellular heterogeneity of each culture system.


Asunto(s)
Médula Ósea , Linfocitos T , Animales , Ratones , Células de la Médula Ósea , Diferenciación Celular , Células Cultivadas , Células Dendríticas , Ratones Endogámicos C57BL
19.
Methods Mol Biol ; 2618: 121-132, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36905513

RESUMEN

Dendritic cells (DCs) are professional antigen-presenting cells controlling the activation of T cells and thus regulating adaptive immune response against pathogens or tumors. Modeling human DC differentiation and function is crucial for our understanding of immune response and the development of new therapies. Considering DC rarity in human blood, in vitro systems allowing their faithful generation are needed. This chapter will describe a DC differentiation method based on the co-culture of CD34+ cord blood progenitors together with mesenchymal stromal cells (eMSCs) engineered to deliver growth factors and chemokines.


Asunto(s)
Células Dendríticas , Sangre Fetal , Humanos , Células Cultivadas , Antígenos CD34/metabolismo , Diferenciación Celular , Moléculas de Adhesión Celular
20.
Nat Cell Biol ; 25(12): 1736-1745, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38036749

RESUMEN

Myeloid cell infiltration of solid tumours generally associates with poor patient prognosis and disease severity1-13. Therefore, understanding the regulation of myeloid cell differentiation during cancer is crucial to counteract their pro-tumourigenic role. Bone marrow (BM) haematopoiesis is a tightly regulated process for the production of all immune cells in accordance to tissue needs14. Myeloid cells differentiate during haematopoiesis from multipotent haematopoietic stem and progenitor cells (HSPCs)15-17. HSPCs can sense inflammatory signals from the periphery during infections18-21 or inflammatory disorders22-27. In these settings, HSPC expansion is associated with increased myeloid differentiation28,29. During carcinogenesis, the elevation of haematopoietic growth factors supports the expansion and differentiation of committed myeloid progenitors5,30. However, it is unclear whether cancer-related inflammation also triggers demand-adapted haematopoiesis at the level of multipotent HSPCs. In the BM, HSPCs reside within the haematopoietic niche which delivers HSC maintenance and differentiation cues31-35. Mesenchymal stem cells (MSCs) are a major cellular component of the BM niche and contribute to HSC homeostasis36-41. Modifications of MSCs in systemic disorders have been associated with HSC differentiation towards myeloid cells22,42. It is unknown if MSCs are regulated in the context of solid tumours and if their myeloid supportive activity is impacted by cancer-induced systemic changes. Here, using unbiased transcriptomic analysis and in situ imaging of HSCs and the BM niche during breast cancer, we show that both HSCs and MSCs are transcriptionally and spatially modified. We demonstrate that breast tumour can distantly remodel the cellular cross-talks in the BM niche leading to increased myelopoiesis.


Asunto(s)
Médula Ósea , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Células Madre Hematopoyéticas/metabolismo , Células Madre Multipotentes/metabolismo , Diferenciación Celular , Nicho de Células Madre , Células de la Médula Ósea
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