Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 192
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Nat Immunol ; 24(8): 1281-1294, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37443283

RESUMO

Germinal centers (GCs) require sustained availability of antigens to promote antibody affinity maturation against pathogens and vaccines. A key source of antigens for GC B cells are immune complexes (ICs) displayed on follicular dendritic cells (FDCs). Here we show that FDC spatial organization regulates antigen dynamics in the GC. We identify heterogeneity within the FDC network. While the entire light zone (LZ) FDC network captures ICs initially, only the central cells of the network function as the antigen reservoir, where different antigens arriving from subsequent immunizations colocalize. Mechanistically, central LZ FDCs constitutively express subtly higher CR2 membrane densities than peripheral LZ FDCs, which strongly increases the IC retention half-life. Even though repeated immunizations gradually saturate central FDCs, B cell responses remain efficient because new antigens partially displace old ones. These results reveal the principles shaping antigen display on FDCs during the GC reaction.


Assuntos
Células Dendríticas Foliculares , Centro Germinativo , Antígenos , Linfócitos B , Complexo Antígeno-Anticorpo/metabolismo
2.
Nat Immunol ; 24(7): 1149-1160, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37202489

RESUMO

B cell zone reticular cells (BRCs) form stable microenvironments that direct efficient humoral immunity with B cell priming and memory maintenance being orchestrated across lymphoid organs. However, a comprehensive understanding of systemic humoral immunity is hampered by the lack of knowledge of global BRC sustenance, function and major pathways controlling BRC-immune cell interactions. Here we dissected the BRC landscape and immune cell interactome in human and murine lymphoid organs. In addition to the major BRC subsets underpinning the follicle, including follicular dendritic cells, PI16+ RCs were present across organs and species. As well as BRC-produced niche factors, immune cell-driven BRC differentiation and activation programs governed the convergence of shared BRC subsets, overwriting tissue-specific gene signatures. Our data reveal that a canonical set of immune cell-provided cues enforce bidirectional signaling programs that sustain functional BRC niches across lymphoid organs and species, thereby securing efficient humoral immunity.


Assuntos
Linfócitos B , Células Estromais , Camundongos , Humanos , Animais , Imunidade Humoral , Células Dendríticas Foliculares , Homeostase
3.
Nat Immunol ; 24(7): 1138-1148, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37202490

RESUMO

Fibroblastic reticular cells (FRCs) direct the interaction and activation of immune cells in discrete microenvironments of lymphoid organs. Despite their important role in steering innate and adaptive immunity, the age- and inflammation-associated changes in the molecular identity and functional properties of human FRCs have remained largely unknown. Here, we show that human tonsillar FRCs undergo dynamic reprogramming during life and respond vigorously to inflammatory perturbation in comparison to other stromal cell types. The peptidase inhibitor 16 (PI16)-expressing reticular cell (PI16+ RC) subset of adult tonsils exhibited the strongest inflammation-associated structural remodeling. Interactome analysis combined with ex vivo and in vitro validation revealed that T cell activity within subepithelial niches is controlled by distinct molecular pathways during PI16+ RC-lymphocyte interaction. In sum, the topological and molecular definition of the human tonsillar stromal cell landscape reveals PI16+ RCs as a specialized FRC niche at the core of mucosal immune responses in the oropharynx.


Assuntos
Tonsila Palatina , Linfócitos T , Humanos , Fibroblastos , Linfócitos/metabolismo , Inflamação/metabolismo , Proteínas de Transporte/metabolismo , Glicoproteínas/metabolismo
4.
Nat Immunol ; 23(8): 1246-1255, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35817845

RESUMO

Lymph nodes (LNs) comprise two main structural elements: fibroblastic reticular cells that form dedicated niches for immune cell interaction and capsular fibroblasts that build a shell around the organ. Immunological challenge causes LNs to increase more than tenfold in size within a few days. Here, we characterized the biomechanics of LN swelling on the cellular and organ scale. We identified lymphocyte trapping by influx and proliferation as drivers of an outward pressure force, causing fibroblastic reticular cells of the T-zone (TRCs) and their associated conduits to stretch. After an initial phase of relaxation, TRCs sensed the resulting strain through cell matrix adhesions, which coordinated local growth and remodeling of the stromal network. While the expanded TRC network readopted its typical configuration, a massive fibrotic reaction of the organ capsule set in and countered further organ expansion. Thus, different fibroblast populations mechanically control LN swelling in a multitier fashion.


Assuntos
Linfonodos , Células Estromais , Animais , Fibroblastos , Linfócitos , Camundongos , Camundongos Endogâmicos C57BL
5.
Nat Immunol ; 22(4): 510-519, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33707780

RESUMO

Fibroblastic reticular cells (FRCs) determine the organization of lymphoid organs and control immune cell interactions. While the cellular and molecular mechanisms underlying FRC differentiation in lymph nodes and the splenic white pulp have been elaborated to some extent, in Peyer's patches (PPs) they remain elusive. Using a combination of single-cell transcriptomics and cell fate mapping in advanced mouse models, we found that PP formation in the mouse embryo is initiated by an expansion of perivascular FRC precursors, followed by FRC differentiation from subepithelial progenitors. Single-cell transcriptomics and cell fate mapping confirmed the convergence of perivascular and subepithelial FRC lineages. Furthermore, lineage-specific loss- and gain-of-function approaches revealed that the two FRC lineages synergistically direct PP organization, maintain intestinal microbiome homeostasis and control anticoronavirus immune responses in the gut. Collectively, this study reveals a distinct mosaic patterning program that generates key stromal cell infrastructures for the control of intestinal immunity.


Assuntos
Linhagem da Célula , Fibroblastos/imunologia , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Intestino Delgado/imunologia , Nódulos Linfáticos Agregados/imunologia , Animais , Comunicação Celular , Células Cultivadas , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Fibroblastos/metabolismo , Microbioma Gastrointestinal , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Interações Hospedeiro-Patógeno , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/virologia , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Intestino Delgado/virologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vírus da Hepatite Murina/imunologia , Vírus da Hepatite Murina/patogenicidade , Nódulos Linfáticos Agregados/metabolismo , Nódulos Linfáticos Agregados/microbiologia , Nódulos Linfáticos Agregados/virologia , Fenótipo , Análise de Célula Única , Transcriptoma
6.
Nat Immunol ; 22(8): 1042-1051, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34267375

RESUMO

Pathogens and vaccines that produce persisting antigens can generate expanded pools of effector memory CD8+ T cells, described as memory inflation. While properties of inflating memory CD8+ T cells have been characterized, the specific cell types and tissue factors responsible for their maintenance remain elusive. Here, we show that clinically applied adenovirus vectors preferentially target fibroblastic stromal cells in cultured human tissues. Moreover, we used cell-type-specific antigen targeting to define critical cells and molecules that sustain long-term antigen presentation and T cell activity after adenovirus vector immunization in mice. While antigen targeting to myeloid cells was insufficient to activate antigen-specific CD8+ T cells, genetic activation of antigen expression in Ccl19-cre-expressing fibroblastic stromal cells induced inflating CD8+ T cells. Local ablation of vector-targeted cells revealed that lung fibroblasts support the protective function and metabolic fitness of inflating memory CD8+ T cells in an interleukin (IL)-33-dependent manner. Collectively, these data define a critical fibroblastic niche that underpins robust protective immunity operating in a clinically important vaccine platform.


Assuntos
Adenoviridae/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Interleucina-33/imunologia , Ativação Linfocitária/imunologia , Células Estromais/imunologia , Adenoviridae/genética , Animais , Linhagem Celular Tumoral , Quimiocina CCL19/metabolismo , Quimera/genética , Epitopos de Linfócito T/imunologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Vetores Genéticos/imunologia , Humanos , Pulmão/citologia , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vacinação
7.
Nat Immunol ; 21(6): 649-659, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424359

RESUMO

Efficient generation of germinal center (GC) responses requires directed movement of B cells between distinct microenvironments underpinned by specialized B cell-interacting reticular cells (BRCs). How BRCs are reprogrammed to cater to the developing GC remains unclear, and studying this process is largely hindered by incomplete resolution of the cellular composition of the B cell follicle. Here we used genetic targeting of Cxcl13-expressing cells to define the molecular identity of the BRC landscape. Single-cell transcriptomic analysis revealed that BRC subset specification was predetermined in the primary B cell follicle. Further topological remodeling of light and dark zone follicular dendritic cells required CXCL12-dependent crosstalk with B cells and dictated GC output by retaining B cells in the follicle and steering their interaction with follicular helper T cells. Together, our results reveal that poised BRC-defined microenvironments establish a feed-forward system that determines the efficacy of the GC reaction.


Assuntos
Escuridão , Células Dendríticas Foliculares/imunologia , Células Dendríticas Foliculares/metabolismo , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Imunomodulação/efeitos da radiação , Luz , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Comunicação Celular , Quimiocina CXCL12/metabolismo , Camundongos , Camundongos Transgênicos , Fenótipo , Análise de Célula Única , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
9.
Immunity ; 52(5): 794-807.e7, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32298648

RESUMO

Lymphocyte homeostasis and immune surveillance require that T and B cells continuously recirculate between secondary lymphoid organs. Here, we used intravital microscopy to define lymphocyte trafficking routes within the spleen, an environment of open blood circulation and shear forces unlike other lymphoid organs. Upon release from arterioles into the red pulp sinuses, T cells latched onto perivascular stromal cells in a manner that was independent of the chemokine receptor CCR7 but sensitive to Gi protein-coupled receptor inhibitors. This latching sheltered T cells from blood flow and enabled unidirectional migration to the bridging channels and then to T zones, entry into which required CCR7. Inflammatory responses modified the chemotactic cues along the perivascular homing paths, leading to rapid block of entry. Our findings reveal a role for vascular structures in lymphocyte recirculation through the spleen, indicating the existence of separate entry and exit routes and that of a checkpoint located at the gate to the T zone.


Assuntos
Movimento Celular/imunologia , Receptores CCR7/imunologia , Baço/imunologia , Linfócitos T/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Humanos , Vigilância Imunológica/imunologia , Microscopia Intravital , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Linfócitos/citologia , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores CCR7/genética , Receptores CCR7/metabolismo , Transdução de Sinais/imunologia , Baço/citologia , Baço/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo
10.
Immunity ; 53(5): 1015-1032.e8, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33207209

RESUMO

Solitary intestinal lymphoid tissues such as cryptopatches (CPs) and isolated lymphoid follicles (ILFs) constitute steady-state activation hubs containing group 3 innate lymphoid cells (ILC3) that continuously produce interleukin (IL)-22. The outer surface of CPs and ILFs is demarcated by a poorly characterized population of CD11c+ cells. Using genome-wide single-cell transcriptional profiling of intestinal mononuclear phagocytes and multidimensional flow cytometry, we found that CP- and ILF-associated CD11c+ cells were a transcriptionally distinct subset of intestinal cDCs, which we term CIA-DCs. CIA-DCs required programming by CP- and ILF-resident CCR6+ ILC3 via lymphotoxin-ß receptor signaling in cDCs. CIA-DCs differentially expressed genes associated with immunoregulation and were the major cellular source of IL-22 binding protein (IL-22BP) at steady state. Mice lacking CIA-DC-derived IL-22BP exhibited diminished expression of epithelial lipid transporters, reduced lipid resorption, and changes in body fat homeostasis. Our findings provide insight into the design principles of an immunoregulatory checkpoint controlling nutrient absorption.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologia , Receptores de Interleucina/biossíntese , Animais , Biomarcadores , Expressão Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Imunofenotipagem , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos , Camundongos , Camundongos Transgênicos , RNA Citoplasmático Pequeno/genética , Receptores de Interleucina/genética , Transdução de Sinais
11.
Nat Immunol ; 17(12): 1388-1396, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27798617

RESUMO

Fibroblastic reticular cells (FRCs) of secondary lymphoid organs form distinct niches for interaction with hematopoietic cells. We found here that production of the cytokine IL-15 by FRCs was essential for the maintenance of group 1 innate lymphoid cells (ILCs) in Peyer's patches and mesenteric lymph nodes. Moreover, FRC-specific ablation of the innate immunological sensing adaptor MyD88 unleashed IL-15 production by FRCs during infection with an enteropathogenic virus, which led to hyperactivation of group 1 ILCs and substantially altered the differentiation of helper T cells. Accelerated clearance of virus by group 1 ILCs precipitated severe intestinal inflammatory disease with commensal dysbiosis, loss of intestinal barrier function and diminished resistance to colonization. In sum, FRCs act as an 'on-demand' immunological 'rheostat' by restraining activation of group 1 ILCs and thereby preventing immunopathological damage in the intestine.


Assuntos
Citrobacter rodentium/imunologia , Infecções por Coronavirus/imunologia , Infecções por Enterobacteriaceae/imunologia , Fibroblastos/imunologia , Interleucina-15/metabolismo , Linfócitos/imunologia , Vírus da Hepatite Murina/imunologia , Animais , Células Cultivadas , Imunidade Inata , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Nódulos Linfáticos Agregados/patologia , Células Th1/imunologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo
12.
Immunity ; 50(6): 1467-1481.e6, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31201093

RESUMO

Tissue-resident macrophages are receptive to specific signals concentrated in cellular niches that direct their cell differentiation and maintenance genetic programs. Here, we found that deficiency of the cytokine RANKL in lymphoid tissue organizers and marginal reticular stromal cells of lymph nodes resulted in the loss of the CD169+ sinusoidal macrophages (SMs) comprising the subcapsular and the medullary subtypes. Subcapsular SM differentiation was impaired in mice with targeted RANK deficiency in SMs. Temporally controlled RANK removal in lymphatic endothelial cells (LECs) revealed that lymphatic RANK activation during embryogenesis and shortly after birth was required for the differentiation of both SM subtypes. Moreover, RANK expression by LECs was necessary for SM restoration after inflammation-induced cell loss. Thus, cooperation between mesenchymal cells and LECs shapes a niche environment that supports SM differentiation and reconstitution after inflammation.


Assuntos
Citocinas/metabolismo , Linfonodos/citologia , Macrófagos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Células Estromais/metabolismo , Animais , Biomarcadores , Diferenciação Celular , Microambiente Celular , Imunofenotipagem , Macrófagos/imunologia , Camundongos , Camundongos Transgênicos , Transdução de Sinais
13.
Immunity ; 51(6): 1074-1087.e9, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31784108

RESUMO

Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8+ T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation. VIDEO ABSTRACT.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interferon Tipo I/imunologia , Fígado/metabolismo , Vírus da Coriomeningite Linfocítica/imunologia , Receptor de Interferon alfa e beta/metabolismo , Animais , Arginina/sangue , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Feminino , Hepatócitos/metabolismo , Fígado/imunologia , Fígado/virologia , Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ornitina/sangue , Ornitina Carbamoiltransferase/genética , Transdução de Sinais/imunologia , Ureia/metabolismo , Células Vero
14.
Nat Immunol ; 16(1): 75-84, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25347465

RESUMO

In lymph nodes, fibroblastic reticular cells (FRCs) form a collagen-based reticular network that supports migratory dendritic cells (DCs) and T cells and transports lymph. A hallmark of FRCs is their propensity to contract collagen, yet this function is poorly understood. Here we demonstrate that podoplanin (PDPN) regulates actomyosin contractility in FRCs. Under resting conditions, when FRCs are unlikely to encounter mature DCs expressing the PDPN receptor CLEC-2, PDPN endowed FRCs with contractile function and exerted tension within the reticulum. Upon inflammation, CLEC-2 on mature DCs potently attenuated PDPN-mediated contractility, which resulted in FRC relaxation and reduced tissue stiffness. Disrupting PDPN function altered the homeostasis and spacing of FRCs and T cells, which resulted in an expanded reticular network and enhanced immunity.


Assuntos
Colágeno/metabolismo , Fibroblastos/citologia , Lectinas Tipo C/metabolismo , Linfonodos/citologia , Glicoproteínas de Membrana/metabolismo , Amidas/farmacologia , Animais , Sobrevivência Celular/imunologia , Colágeno/imunologia , Citoesqueleto/imunologia , Citoesqueleto/ultraestrutura , Inibidores Enzimáticos/farmacologia , Feminino , Fibroblastos/imunologia , Fibroblastos/ultraestrutura , Lectinas Tipo C/imunologia , Linfonodos/imunologia , Linfonodos/ultraestrutura , Masculino , Glicoproteínas de Membrana/imunologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Fosforilação , Piridinas/farmacologia , Organismos Livres de Patógenos Específicos
15.
Immunity ; 48(1): 120-132.e8, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29343433

RESUMO

Group 3 innate lymphoid cells (ILC3s) sense environmental signals and are critical for tissue integrity in the intestine. Yet, which signals are sensed and what receptors control ILC3 function remain poorly understood. Here, we show that ILC3s with a lymphoid-tissue-inducer (LTi) phenotype expressed G-protein-coupled receptor 183 (GPR183) and migrated to its oxysterol ligand 7α,25-hydroxycholesterol (7α,25-OHC). In mice lacking Gpr183 or 7α,25-OHC, ILC3s failed to localize to cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Gpr183 deficiency in ILC3s caused a defect in CP and ILF formation in the colon, but not in the small intestine. Localized oxysterol production by fibroblastic stromal cells provided an essential signal for colonic lymphoid tissue development, and inflammation-induced increased oxysterol production caused colitis through GPR183-mediated cell recruitment. Our findings show that GPR183 promotes lymphoid organ development and indicate that oxysterol-GPR183-dependent positioning within tissues controls ILC3 activity and intestinal homeostasis.


Assuntos
Colite/metabolismo , Linfócitos/metabolismo , Tecido Linfoide/metabolismo , Oxisteróis/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Movimento Celular/genética , Colite/imunologia , Colite/patologia , Colo/imunologia , Colo/patologia , Citocinas/metabolismo , Citometria de Fluxo , Imunofluorescência , Ligantes , Linfócitos/patologia , Tecido Linfoide/patologia , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
16.
Nat Immunol ; 15(10): 973-81, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25151489

RESUMO

Fibroblastic reticular cells (FRCs) are known to inhabit T cell-rich areas of lymphoid organs, where they function to facilitate interactions between T cells and dendritic cells. However, in vivo manipulation of FRCs has been limited by a dearth of genetic tools that target this lineage. Here, using a mouse model to conditionally ablate FRCs, we demonstrated their indispensable role in antiviral T cell responses. Unexpectedly, loss of FRCs also attenuated humoral immunity due to impaired B cell viability and follicular organization. Follicle-resident FRCs established a favorable niche for B lymphocytes via production of the cytokine BAFF. Thus, our study indicates that adaptive immunity requires an intact FRC network and identifies a subset of FRCs that control B cell homeostasis and follicle identity.


Assuntos
Linfócitos B/imunologia , Fibroblastos/imunologia , Homeostase/imunologia , Linfócitos T/imunologia , Animais , Fator Ativador de Células B/imunologia , Fator Ativador de Células B/metabolismo , Linfócitos B/metabolismo , Movimento Celular/imunologia , Sobrevivência Celular/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Imunidade Humoral/imunologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Linfócitos T/metabolismo
17.
Immunity ; 47(1): 80-92.e4, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28709801

RESUMO

Lymph nodes (LNs) are strategically situated throughout the body at junctures of the blood vascular and lymphatic systems to direct immune responses against antigens draining from peripheral tissues. The current paradigm describes LN development as a programmed process that is governed through the interaction between mesenchymal lymphoid tissue organizer (LTo) cells and hematopoietic lymphoid tissue inducer (LTi) cells. Using cell-type-specific ablation of key molecules involved in lymphoid organogenesis, we found that initiation of LN development is dependent on LTi-cell-mediated activation of lymphatic endothelial cells (LECs) and that engagement of mesenchymal stromal cells is a succeeding event. LEC activation was mediated mainly by signaling through receptor activator of NF-κB (RANK) and the non-canonical NF-κB pathway and was steered by sphingosine-1-phosphate-receptor-dependent retention of LTi cells in the LN anlage. Finally, the finding that pharmacologically enforced interaction between LTi cells and LECs promotes ectopic LN formation underscores the central LTo function of LECs.


Assuntos
Células Endoteliais/fisiologia , Linfonodos/fisiologia , Células-Tronco Mesenquimais/fisiologia , Organogênese , Animais , Diferenciação Celular , Células Cultivadas , Coristoma , Embrião de Mamíferos , Receptor beta de Linfotoxina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais
18.
Circ Res ; 134(12): 1703-1717, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38843287

RESUMO

Fibroblasts are essential for building and maintaining the structural integrity of all organs. Moreover, fibroblasts can acquire an inflammatory phenotype to accommodate immune cells in specific niches and to provide migration, differentiation, and growth factors. In the heart, balancing of fibroblast activity is critical for cardiac homeostasis and optimal organ function during inflammation. Fibroblasts sustain cardiac homeostasis by generating local niche environments that support housekeeping functions and by actively engaging in intercellular cross talk. During inflammatory perturbations, cardiac fibroblasts rapidly switch to an inflammatory state and actively communicate with infiltrating immune cells to orchestrate immune cell migration and activity. Here, we summarize the current knowledge on the molecular landscape of cardiac fibroblasts, focusing on their dual role in promoting tissue homeostasis and modulating immune cell-cardiomyocyte interaction. In addition, we discuss potential future avenues for manipulating cardiac fibroblast activity during myocardial inflammation.


Assuntos
Fibroblastos , Homeostase , Miocárdio , Humanos , Animais , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibroblastos/imunologia , Miocárdio/patologia , Miocárdio/imunologia , Miocárdio/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Inflamação/imunologia , Miocardite/imunologia , Miocardite/patologia , Miocardite/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Comunicação Celular
19.
Immunol Rev ; 306(1): 108-122, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34866192

RESUMO

Fibroblastic reticular cells (FRCs) are specialized stromal cells of lymphoid organs that generate the structural foundation of the tissue and actively interact with immune cells. Distinct FRC subsets position lymphocytes and myeloid cells in specialized niches where they present processed or native antigen and provide essential growth factors and cytokines for immune cell activation and differentiation. Niche-specific functions of FRC subpopulations have been defined using genetic targeting, high-dimensional transcriptomic analyses, and advanced imaging methods. Here, we review recent findings on FRC-immune cell interaction and the elaboration of FRC development and differentiation. We discuss how imaging approaches have not only shaped our understanding of FRC biology, but have critically advanced the niche concept of immune cell maintenance and control of immune reactivity.


Assuntos
Fibroblastos , Células Estromais , Comunicação Celular , Diferenciação Celular , Perfilação da Expressão Gênica , Humanos , Linfonodos
20.
Eur J Immunol ; 54(10): e2451207, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38980268

RESUMO

Tertiary lymphoid structures (TLS) resemble follicles of secondary lymphoid organs and develop in nonlymphoid tissues during inflammation and cancer. Which cell types and signals drive the development of TLS is largely unknown. To investigate early events of TLS development in the lungs, we repeatedly instilled p(I:C) plus ovalbumin (Ova) intranasally. This induced TLS ranging from lymphocytic aggregates to organized and functional structures containing germinal centers. We found that TLS development is independent of FAP+ fibroblasts, alveolar macrophages, or CCL19 but crucially depends on type I interferon (IFN-I). Mechanistically, IFN-I initiates two synergistic pathways that culminate in the development of TLS. On the one hand, IFN-I induces lymphotoxin (LT)α in lymphoid cells, which stimulate stromal cells to produce the B-cell-attracting chemokine CXCL13 through LTßR-signaling. On the other hand, IFN-I is sensed by stromal cells that produce the T-cell-attracting chemokines CXCL9, CXCL10 as well as CCL19 and CCL21 independently of LTßR. Consequently, B-cell aggregates develop within a week, whereas follicular dendritic cells and germinal centers appear after 3 weeks. Thus, sustained production of IFN-I together with an antigen is essential for the induction of functional TLS in the lungs.


Assuntos
Imunidade Inata , Interferon Tipo I , Estruturas Linfoides Terciárias , Animais , Estruturas Linfoides Terciárias/imunologia , Camundongos , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Imunidade Inata/efeitos dos fármacos , Quimiocina CCL19/metabolismo , Pulmão/imunologia , Quimiocina CCL21/metabolismo , Quimiocina CXCL13/metabolismo , Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Receptor beta de Linfotoxina/metabolismo , Receptor beta de Linfotoxina/imunologia , Camundongos Endogâmicos C57BL , Células Estromais/imunologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Linfotoxina-alfa/metabolismo , Linfotoxina-alfa/imunologia , Centro Germinativo/imunologia , Ovalbumina/imunologia , Ovalbumina/administração & dosagem , Transdução de Sinais/imunologia , Transdução de Sinais/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/efeitos dos fármacos , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/imunologia , Camundongos Knockout , Quimiocina CXCL9/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA