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1.
Annu Rev Immunol ; 34: 93-119, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-26735697

RESUMO

The dendritic cells (DCs) of the immune system function in innate and adaptive responses by directing activity of various effector cells rather than serving as effectors themselves. DCs and closely related myeloid lineages share expression of many surface receptors, presenting a challenge in distinguishing their unique in vivo functions. Recent work has taken advantage of unique transcriptional programs to identify and manipulate murine DCs in vivo. This work has assigned several nonredundant in vivo functions to distinct DC lineages, consisting of plasmacytoid DCs and several subsets of classical DCs that promote different immune effector modules in response to pathogens. In parallel, a correspondence between human and murine DC subsets has emerged, underlying structural similarities for the DC lineages between these species. Recent work has begun to unravel the transcriptional circuitry that controls the development and diversification of DCs from common progenitors in the bone marrow.


Assuntos
Células da Medula Óssea/fisiologia , Células Dendríticas/fisiologia , Regulação da Expressão Gênica , Imunidade Celular , Animais , Diferenciação Celular , Linhagem da Célula , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imunidade Celular/genética , Camundongos , Ativação Transcricional
2.
Nat Immunol ; 20(9): 1174-1185, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406377

RESUMO

Classical type 1 dendritic cells (cDC1s) are required for antiviral and antitumor immunity, which necessitates an understanding of their development. Development of the cDC1 progenitor requires an E-protein-dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor Irf8 (+41-kb Irf8 enhancer), but its maturation instead requires the Batf3-dependent +32-kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2 and Zeb2. Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2hi and Id2lo CDPs to Zeb2lo and Id2hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E-protein activity to exclude plasmacytoid dendritic cell potential and explains the switch in Irf8 enhancer usage during cDC1 development.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Células Dendríticas/citologia , Elementos Facilitadores Genéticos/genética , Proteína 2 Inibidora de Diferenciação/metabolismo , Fatores Reguladores de Interferon/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Repressoras/metabolismo , Células-Tronco/citologia
3.
Nat Immunol ; 20(9): 1161-1173, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406378

RESUMO

Induction of the transcription factor Irf8 in the common dendritic cell progenitor (CDP) is required for classical type 1 dendritic cell (cDC1) fate specification, but the mechanisms controlling this induction are unclear. In the present study Irf8 enhancers were identified via chromatin profiling of dendritic cells and CRISPR/Cas9 genome editing was used to assess their roles in Irf8 regulation. An enhancer 32 kilobases (kb) downstream of the Irf8 transcriptional start site (+32-kb Irf8) that was active in mature cDC1s was required for the development of this lineage, but not for its specification. Instead, a +41-kb Irf8 enhancer, previously thought to be active only in plasmacytoid dendritic cells, was found to also be transiently accessible in cDC1 progenitors, and deleting this enhancer prevented the induction of Irf8 in CDPs and abolished cDC1 specification. Thus, cryptic activation of the +41-kb Irf8 enhancer in dendritic cell progenitors is responsible for cDC1 fate specification.


Assuntos
Células Dendríticas/citologia , Elementos Facilitadores Genéticos/genética , Fatores Reguladores de Interferon/metabolismo , Macrófagos/citologia , Monócitos/citologia , Animais , Sistemas CRISPR-Cas/genética , Diferenciação Celular , Linhagem da Célula , Células Dendríticas/imunologia , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Células-Tronco/citologia , Células Tumorais Cultivadas
4.
Immunity ; 55(6): 1032-1050.e14, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35704993

RESUMO

Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity and maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role in different subsets remains unclear. At homeostasis, only mature CCR7+ cDC1 expressed IDO1 that was dependent on IRF8. Lipopolysaccharide treatment induced maturation and IDO1-dependent tolerogenic activity in isolated immature cDC1, but not isolated cDC2. However, both human and mouse cDC2 could induce IDO1 and acquire tolerogenic function when co-cultured with mature cDC1 through the action of cDC1-derived l-kynurenine. Accordingly, cDC1-specific inactivation of IDO1 in vivo exacerbated disease in experimental autoimmune encephalomyelitis. This study identifies a previously unrecognized metabolic communication in which IDO1-expressing cDC1 cells extend their immunoregulatory capacity to the cDC2 subset through their production of tryptophan metabolite l-kynurenine. This metabolic axis represents a potential therapeutic target in treating autoimmune demyelinating diseases.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase , Cinurenina , Animais , Células Dendríticas , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Cinurenina/metabolismo , Camundongos , Transdução de Sinais , Triptofano/metabolismo
5.
Nat Immunol ; 18(5): 563-572, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28346410

RESUMO

Variable strengths of signaling via the T cell antigen receptor (TCR) can produce divergent outcomes, but the mechanism of this remains obscure. The abundance of the transcription factor IRF4 increases with TCR signal strength, but how this would induce distinct types of responses is unclear. We compared the expression of genes in the TH2 subset of helper T cells to enhancer occupancy by the BATF-IRF4 transcription factor complex at varying strengths of TCR stimulation. Genes dependent on BATF-IRF4 clustered into groups with distinct TCR sensitivities. Enhancers exhibited a spectrum of occupancy by the BATF-IRF4 ternary complex that correlated with the sensitivity of gene expression to TCR signal strength. DNA sequences immediately flanking the previously defined AICE motif controlled the affinity of BATF-IRF4 for direct binding to DNA. Analysis by the chromatin immunoprecipitation-exonuclease (ChIP-exo) method allowed the identification of a previously unknown high-affinity AICE2 motif at a human single-nucleotide polymorphism (SNP) of the gene encoding the immunomodulatory receptor CTLA-4 that was associated with resistance to autoimmunity. Thus, the affinity of different enhancers for the BATF-IRF4 complex might underlie divergent signaling outcomes in response to various strengths of TCR signaling.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Antígeno CTLA-4/genética , Elementos Facilitadores Genéticos/genética , Fatores Reguladores de Interferon/metabolismo , Complexos Multiproteicos/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Células Th2/fisiologia , Animais , Autoimunidade/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , Predisposição Genética para Doença , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Ligação Proteica/genética , Transdução de Sinais/genética
6.
Cell ; 156(6): 1223-1234, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24630724

RESUMO

Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor SPI-C is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80(+)VCAM1(+) bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor BACH1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Furthermore, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insights into iron homeostasis.


Assuntos
Diferenciação Celular , Proteínas de Ligação a DNA/metabolismo , Heme/metabolismo , Ferro/metabolismo , Monócitos/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Proteínas de Ligação a DNA/genética , Feminino , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Células Mieloides/metabolismo , Baço/citologia , Baço/metabolismo
7.
Immunity ; 50(4): 1069-1083.e8, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30926233

RESUMO

Skin conventional dendritic cells (cDCs) exist as two distinct subsets, cDC1s and cDC2s, which maintain the balance of immunity to pathogens and tolerance to self and microbiota. Here, we examined the roles of dermal cDC1s and cDC2s during bacterial infection, notably Propionibacterium acnes (P. acnes). cDC1s, but not cDC2s, regulated the magnitude of the immune response to P. acnes in the murine dermis by controlling neutrophil recruitment to the inflamed site and survival and function therein. Single-cell mRNA sequencing revealed that this regulation relied on secretion of the cytokine vascular endothelial growth factor α (VEGF-α) by a minor subset of activated EpCAM+CD59+Ly-6D+ cDC1s. Neutrophil recruitment by dermal cDC1s was also observed during S. aureus, bacillus Calmette-Guérin (BCG), or E. coli infection, as well as in a model of bacterial insult in human skin. Thus, skin cDC1s are essential regulators of the innate response in cutaneous immunity and have roles beyond classical antigen presentation.


Assuntos
Acne Vulgar/imunologia , Células Dendríticas/classificação , Infecções por Bactérias Gram-Positivas/imunologia , Infiltração de Neutrófilos/imunologia , Fator A de Crescimento do Endotélio Vascular/imunologia , Acne Vulgar/microbiologia , Animais , Apresentação de Antígeno , Quimiotaxia de Leucócito/imunologia , Células Dendríticas/imunologia , Orelha Externa , Regulação da Expressão Gênica , Ontologia Genética , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Injeções Intradérmicas , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Propionibacterium acnes , RNA Mensageiro/biossíntese , Análise de Célula Única , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética
8.
Nat Immunol ; 16(7): 708-17, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26054719

RESUMO

The transcription factors Batf3 and IRF8 are required for the development of CD8α(+) conventional dendritic cells (cDCs), but the basis for their actions has remained unclear. Here we identified two progenitor cells positive for the transcription factor Zbtb46 that separately generated CD8α(+) cDCs and CD4(+) cDCs and arose directly from the common DC progenitor (CDP). Irf8 expression in CDPs required prior autoactivation of Irf8 that was dependent on the transcription factor PU.1. Specification of the clonogenic progenitor of CD8α(+) cDCs (the pre-CD8 DC) required IRF8 but not Batf3. However, after specification of pre-CD8 DCs, autoactivation of Irf8 became Batf3 dependent at a CD8α(+) cDC-specific enhancer with multiple transcription factor AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3(-/-) mice that were specified toward development into pre-CD8 DCs failed to complete their development into CD8α(+) cDCs due to decay of Irf8 autoactivation and diverted to the CD4(+) cDC lineage.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Células Dendríticas/imunologia , Fatores Reguladores de Interferon/imunologia , Proteínas Repressoras/imunologia , Células-Tronco/imunologia , Animais , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Antígeno CD24/imunologia , Antígeno CD24/metabolismo , Antígenos CD8/imunologia , Antígenos CD8/metabolismo , Células Cultivadas , Células Clonais/imunologia , Células Clonais/metabolismo , Células Dendríticas/metabolismo , Citometria de Fluxo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Ligação Proteica , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Homologia de Sequência do Ácido Nucleico , Células-Tronco/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia
9.
Nature ; 584(7822): 624-629, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32788723

RESUMO

Conventional type 1 dendritic cells (cDC1)1 are thought to perform antigen cross-presentation, which is required to prime CD8+ T cells2,3, whereas cDC2 are specialized for priming CD4+ T cells4,5. CD4+ T cells are also considered to help CD8+ T cell responses through a variety of mechanisms6-11, including a process whereby CD4+ T cells 'license' cDC1 for CD8+ T cell priming12. However, this model has not been directly tested in vivo or in the setting of help-dependent tumour rejection. Here we generated an Xcr1Cre mouse strain to evaluate the cellular interactions that mediate tumour rejection in a model requiring CD4+ and CD8+ T cells. As expected, tumour rejection required cDC1 and CD8+ T cell priming required the expression of major histocompatibility class I molecules by cDC1. Unexpectedly, early priming of CD4+ T cells against tumour-derived antigens also required cDC1, and this was not simply because they transport antigens to lymph nodes for processing by cDC2, as selective deletion of major histocompatibility class II molecules in cDC1 also prevented early CD4+ T cell priming. Furthermore, deletion of either major histocompatibility class II or CD40 in cDC1 impaired tumour rejection, consistent with a role for cognate CD4+ T cell interactions and CD40 signalling in cDC1 licensing. Finally, CD40 signalling in cDC1 was critical not only for CD8+ T cell priming, but also for initial CD4+ T cell activation. Thus, in the setting of tumour-derived antigens, cDC1 function as an autonomous platform capable of antigen processing and priming for both CD4+ and CD8+ T cells and of the direct orchestration of their cross-talk that is required for optimal anti-tumour immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Apresentação Cruzada , Células Dendríticas/imunologia , Neoplasias/imunologia , Animais , Apresentação de Antígeno/imunologia , Linfócitos T CD4-Positivos/citologia , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Camundongos , Transdução de Sinais
10.
Proc Natl Acad Sci U S A ; 120(35): e2220853120, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37607223

RESUMO

Ly6Clo monocytes are a myeloid subset that specializes in the surveillance of vascular endothelium. Ly6Clo monocytes have been shown to derive from Ly6Chi monocytes. NOTCH2 signaling has been implicated as a trigger for Ly6Clo monocyte development, but the basis for this effect is unclear. Here, we examined the impact of NOTCH2 signaling of myeloid progenitors on the development of Ly6Clo monocytes in vitro. NOTCH2 signaling induced by delta-like ligand 1 (DLL1) efficiently induced the transition of Ly6Chi TREML4- monocytes into Ly6Clo TREML4+ monocytes. We further identified two additional transcriptional requirements for development of Ly6Clo monocytes. Deletion of BCL6 from myeloid progenitors abrogated development of Ly6Clo monocytes. IRF2 was also required for Ly6Clo monocyte development in a cell-intrinsic manner. DLL1-induced in vitro transition into Ly6Clo TREML4+ monocytes required IRF2 but unexpectedly could occur in the absence of NUR77 or BCL6. These results imply a transcriptional hierarchy for these factors in controlling Ly6Clo monocyte development.


Assuntos
Endotélio Vascular , Monócitos , Hematopoese , Transdução de Sinais
11.
Nat Immunol ; 14(9): 937-48, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23913046

RESUMO

Defense against attaching-and-effacing bacteria requires the sequential generation of interleukin 23 (IL-23) and IL-22 to induce protective mucosal responses. Although CD4(+) and NKp46(+) innate lymphoid cells (ILCs) are the critical source of IL-22 during infection, the precise source of IL-23 is unclear. We used genetic techniques to deplete mice of specific subsets of classical dendritic cells (cDCs) and analyzed immunity to the attaching-and-effacing pathogen Citrobacter rodentium. We found that the signaling receptor Notch2 controlled the terminal stage of cDC differentiation. Notch2-dependent intestinal CD11b(+) cDCs were an obligate source of IL-23 required for survival after infection with C. rodentium, but CD103(+) cDCs dependent on the transcription factor Batf3 were not. Our results demonstrate a nonredundant function for CD11b(+) cDCs in the response to pathogens in vivo.


Assuntos
Citrobacter rodentium/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Receptor Notch2/metabolismo , Animais , Antígenos CD/metabolismo , Antígeno CD11b/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Dendríticas/citologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/mortalidade , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Interleucina-23/metabolismo , Mucosa Intestinal/microbiologia , Lectinas Tipo C/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , Camundongos , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , Receptor Notch2/deficiência , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Baço/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Cicatrização/genética , Cicatrização/imunologia
12.
Proc Natl Acad Sci U S A ; 115(42): 10726-10731, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30279176

RESUMO

CD4+ T follicular helper (TFH) cells support germinal center (GC) reactions promoting humoral immunity. Dendritic cell (DC) diversification into genetically distinct subsets allows for specialization in promoting responses against several types of pathogens. Whether any classical DC (cDC) subset is required for humoral immunity is unknown, however. We tested several genetic models that selectively ablate distinct DC subsets in mice for their impact on splenic GC reactions. We identified a requirement for Notch2-dependent cDC2s, but not Batf3-dependent cDC1s or Klf4-dependent cDC2s, in promoting TFH and GC B cell formation in response to sheep red blood cells and inactivated Listeria monocytogenes This effect was mediated independent of Il2ra and several Notch2-dependent genes expressed in cDC2s, including Stat4 and Havcr2 Notch2 signaling during cDC2 development also substantially reduced the efficiency of cDC2s for presentation of MHC class II-restricted antigens, limiting the strength of CD4 T cell activation. Together, these results demonstrate a nonredundant role for the Notch2-dependent cDC2 subset in supporting humoral immune responses.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Eritrócitos/imunologia , Centro Germinativo/imunologia , Receptor Notch2/fisiologia , Baço/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Apresentação de Antígeno/imunologia , Linfócitos B/metabolismo , Diferenciação Celular , Células Cultivadas , Células Dendríticas/metabolismo , Centro Germinativo/metabolismo , Imunidade Humoral/imunologia , Fator 4 Semelhante a Kruppel , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovinos , Transdução de Sinais , Baço/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
13.
Nature ; 507(7491): 243-7, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24509714

RESUMO

The transcription factors c-Myc and N-Myc--encoded by Myc and Mycn, respectively--regulate cellular growth and are required for embryonic development. A third paralogue, Mycl1, is dispensable for normal embryonic development but its biological function has remained unclear. To examine the in vivo function of Mycl1 in mice, we generated an inactivating Mycl1(gfp) allele that also reports Mycl1 expression. We find that Mycl1 is selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression is initiated in the common DC progenitor concurrent with reduction in c-Myc expression. Mature DCs lack expression of c-Myc and N-Myc but maintain L-Myc expression even in the presence of inflammatory signals such as granulocyte-macrophage colony-stimulating factor. All DC subsets develop in Mycl1-deficient mice, but some subsets such as migratory CD103(+) conventional DCs in the lung and liver are greatly reduced at steady state. Importantly, loss of L-Myc by DCs causes a significant decrease in in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming.


Assuntos
Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Regulação da Expressão Gênica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Linfócitos T/imunologia , Animais , Antígenos CD/metabolismo , Divisão Celular , Células Dendríticas/citologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Cadeias alfa de Integrinas/metabolismo , Fatores Reguladores de Interferon/metabolismo , Listeria monocytogenes/imunologia , Fígado/citologia , Fígado/imunologia , Pulmão/citologia , Pulmão/imunologia , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-myc/deficiência , Transcrição Gênica , Vesiculovirus/imunologia
14.
Proc Natl Acad Sci U S A ; 114(15): 3957-3962, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28348230

RESUMO

RelB is an NF-κB family transcription factor activated in the noncanonical pathway downstream of NF-κB-inducing kinase (NIK) and TNF receptor family members including lymphotoxin-ß receptor (LTßR) and CD40. Early analysis suggested that RelB is required for classical dendritic cell (cDC) development based on a severe reduction of cDCs in Relb-/- mice associated with profound myeloid expansion and perturbations in B and T cells. Subsequent analysis of radiation chimeras generated from wild-type and Relb-/- bone marrow showed that RelB exerts cell-extrinsic actions on some lineages, but it has remained unclear whether the impact of RelB on cDC development is cell-intrinsic or -extrinsic. Here, we reevaluated the role of RelB in cDC and myeloid development using a series of radiation chimeras. We found that there was no cell-intrinsic requirement for RelB for development of most cDC subsets, except for the Notch2- and LTßR-dependent subset of splenic CD4+ cDC2s. These results identify a relatively restricted role of RelB in DC development. Moreover, the myeloid expansion in Relb-/- mice resulted from hematopoietic-extrinsic actions of RelB. This result suggests that there is an unrecognized but critical role for RelB within the nonhematopoietic niche that controls normal myelopoiesis.


Assuntos
Células Dendríticas/fisiologia , Células Mieloides/fisiologia , Fator de Transcrição RelB/genética , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Sistema Hematopoético/citologia , Sistema Hematopoético/metabolismo , Receptor beta de Linfotoxina/metabolismo , Linfotoxina-beta/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas Serina-Treonina Quinases/metabolismo , Baço/citologia , Baço/metabolismo , Fator de Transcrição RelB/metabolismo , Quinase Induzida por NF-kappaB
15.
Proc Natl Acad Sci U S A ; 113(51): 14775-14780, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27930303

RESUMO

Dendritic cells (DCs) and monocytes develop from a series of bone-marrow-resident progenitors in which lineage potential is regulated by distinct transcription factors. Zeb2 is an E-box-binding protein associated with epithelial-mesenchymal transition and is widely expressed among hematopoietic lineages. Previously, we observed that Zeb2 expression is differentially regulated in progenitors committed to classical DC (cDC) subsets in vivo. Using systems for inducible gene deletion, we uncover a requirement for Zeb2 in the development of Ly-6Chi monocytes but not neutrophils, and we show a corresponding requirement for Zeb2 in expression of the M-CSF receptor in the bone marrow. In addition, we confirm a requirement for Zeb2 in development of plasmacytoid DCs but find that Zeb2 is not required for cDC2 development. Instead, Zeb2 may act to repress cDC1 progenitor specification in the context of inflammatory signals.


Assuntos
Células Dendríticas/citologia , Regulação da Expressão Gênica , Monócitos/citologia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/fisiologia , Animais , Medula Óssea/metabolismo , Linfócitos T CD8-Positivos/citologia , Linhagem da Célula , Citoplasma/metabolismo , Feminino , Citometria de Fluxo , Deleção de Genes , Perfilação da Expressão Gênica , Inflamação , Integrases/metabolismo , Masculino , Camundongos , Neutrófilos/citologia , Neutrófilos/metabolismo
16.
J Am Soc Nephrol ; 29(1): 138-154, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29217759

RESUMO

Dendritic cells (DCs) are thought to form a dendritic network across barrier surfaces and throughout organs, including the kidney, to perform an important sentinel function. However, previous studies of DC function used markers, such as CD11c or CX3CR1, that are not unique to DCs. Here, we evaluated the role of DCs in renal inflammation using a CD11c reporter mouse line and two mouse lines with DC-specific reporters, Zbtb46-GFP and Snx22-GFP. Multiphoton microscopy of kidney sections confirmed that most of the dendritically shaped CD11c+ cells forming a network throughout the renal interstitium expressed macrophage-specific markers. In contrast, DCs marked by Zbtb46-GFP or Snx22-GFP were less abundant, concentrated around blood vessels, and round in shape. We confirmed this pattern of localization using imaging mass cytometry. Motility measurements showed that resident macrophages were sessile, whereas DCs were motile before and after inflammation. Although uninflamed glomeruli rarely contained DCs, injury with nephrotoxic antibodies resulted in accumulation of ZBTB46 + cells in the periglomerular region. ZBTB46 identifies all classic DCs, which can be categorized into two functional subsets that express either CD103 or CD11b. Depletion of ZBTB46 + cells attenuated the antibody-induced kidney injury, whereas deficiency of the CD103+ subset accelerated injury through a mechanism that involved increased neutrophil infiltration. RNA sequencing 7 days after nephrotoxic antibody injection showed that CD11b+ DCs expressed the neutrophil-attracting cytokine CXCL2, whereas CD103+ DCs expressed high levels of several anti-inflammatory genes. These results provide new insights into the distinct functions of the two major DC subsets in glomerular inflammation.


Assuntos
Células Dendríticas/fisiologia , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Animais , Antígenos CD/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Antígenos CD11/genética , Antígeno CD11b/genética , Movimento Celular , Quimiocina CXCL2/genética , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/metabolismo , Cadeias alfa de Integrinas/metabolismo , Macrófagos , Masculino , Camundongos , Camundongos Knockout , Neutrófilos/patologia , Neutrófilos/fisiologia , Proteínas Repressoras/genética , Análise de Sequência de RNA , Nexinas de Classificação/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma
17.
Mod Pathol ; 31(9): 1479-1486, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743654

RESUMO

Distinguishing classical dendritic cells from other myeloid cell types is complicated by the shared expression of cell surface markers. ZBTB46 is a zinc finger and BTB domain-containing transcription factor, which is expressed by dendritic cells and committed dendritic cell precursors, but not by plasmacytoid dendritic cells, monocytes, macrophages, or other immune cell populations. In this study, we demonstrate that expression of ZBTB46 identifies human dendritic cell neoplasms. We examined ZBTB46 expression in a range of benign and malignant histiocytic disorders and found that ZBTB46 is able to clearly define the dendritic cell identity of many previously unclassified histiocytic disease subtypes. In particular, all examined cases of Langerhans cell histiocytosis and histiocytic sarcoma expressed ZBTB46, while all cases of blastic plasmacytoid dendritic cell neoplasm, chronic myelomonocytic leukemia, juvenile xanthogranuloma, Rosai-Dorfman disease, and Erdheim-Chester disease failed to demonstrate expression of ZBTB46. Moreover, ZBTB46 expression clarified the identity of diagnostically challenging neoplasms, such as cases of indeterminate cell histiocytosis, classifying a fraction of these entities as dendritic cell malignancies. These findings clarify the lineage origins of human histiocytic disorders and distinguish dendritic cell disorders from all other myeloid neoplasms.


Assuntos
Células Dendríticas/metabolismo , Histiocitose/diagnóstico , Células Mieloides/metabolismo , Fatores de Transcrição/metabolismo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Células Dendríticas/patologia , Diagnóstico Diferencial , Feminino , Histiocitose/metabolismo , Histiocitose/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Células Mieloides/patologia , Adulto Jovem
18.
Blood ; 123(19): 2968-77, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24677539

RESUMO

Runx1 and Cbfß are critical for the establishment of definitive hematopoiesis and are implicated in leukemic transformation. Despite the absolute requirements for these factors in the development of hematopoietic stem cells and lymphocytes, their roles in the development of bone marrow progenitor subsets have not been defined. Here, we demonstrate that Cbfß is essential for the development of Flt3(+) macrophage-dendritic cell (DC) progenitors in the bone marrow and all DC subsets in the periphery. Besides the loss of DC progenitors, pan-hematopoietic Cbfb-deficient mice also lack CD105(+) erythroid progenitors, leading to severe anemia at 3 to 4 months of age. Instead, Cbfb deficiency results in aberrant progenitor differentiation toward granulocyte-macrophage progenitors (GMPs), resulting in a myeloproliferative phenotype with accumulation of GMPs in the periphery and cellular infiltration of the liver. Expression of the transcription factor Irf8 is severely reduced in Cbfb-deficient progenitors, and overexpression of Irf8 restors DC differentiation. These results demonstrate that Runx proteins and Cbfß restrict granulocyte lineage commitment to facilitate multilineage hematopoietic differentiation and thus identify their novel tumor suppressor function in myeloid leukemia.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade beta de Fator de Ligação ao Core/metabolismo , Células Dendríticas/metabolismo , Transtornos Mieloproliferativos/metabolismo , Células-Tronco/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo , Anemia/genética , Anemia/metabolismo , Anemia/patologia , Animais , Células da Medula Óssea/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Subunidade beta de Fator de Ligação ao Core/genética , Citometria de Fluxo , Expressão Gênica , Granulócitos/metabolismo , Hematopoese/genética , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Neurochem Res ; 41(1-2): 316-27, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26700430

RESUMO

Nitric oxide (NO) regulates numerous physiological process and is the main source of reactive nitrogen species (RNS). NO promotes cell survival, but it also induces apoptotic death having been involved in the pathogenesis of several neurodegenerative diseases. NO and superoxide anion react to form peroxynitrite, which accounts for most of the deleterious effects of NO. The mechanisms by which these molecules regulate the apoptotic process are not well understood. In this study, we evaluated the role of NO and peroxynitrite in the apoptotic death of cultured cerebellar granule neurons (CGN), which are known to experience apoptosis by staurosporine (St) or potassium deprivation (K5). We found that CGN treated with the peroxynitrite catalyst, FeTTPs were completely rescued from St-induced death, but not from K5-induced death. On the other hand, the inhibition of the inducible nitric oxide synthase partially protected cell viability in CGN treated with K5, but not with St, while the inhibitor L-NAME further reduced the cell viability in St, but it did not affect K5. Finally, an inhibitor of the soluble guanylate cyclase (sGC) diminished the cell viability in K5, but not in St. Altogether, these results shows that NO promotes cell survival in K5 through sGC-cGMP and promotes cell death by other mechanisms, while in St NO promotes cell survival independently of cGMP and peroxynitrite results critical for St-induced death. Our results suggest that RNS are differentially handled by CGN during cell death depending on the death-inducing conditions.


Assuntos
Apoptose/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Grânulos Citoplasmáticos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ácido Peroxinitroso/farmacologia , Potássio/metabolismo , Estaurosporina/farmacologia , Animais , Caspase 3/efeitos dos fármacos , Cerebelo/citologia , Neurônios/citologia , Óxido Nítrico/antagonistas & inibidores , Ratos
20.
J Immunol ; 187(6): 3353-61, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21849679

RESUMO

CD93 is emerging as a novel regulator of inflammation; however, its molecular function is unknown. CD93 exists as a membrane-associated glycoprotein on the surface of cells involved in the inflammatory cascade, including endothelial and myeloid cells. A soluble form (sCD93) is detectable in blood and is elevated with inflammation. In this study, we demonstrate heightened susceptibility to thioglycollate-induced peritonitis in CD93(-/-) mice. CD93(-/-) mice showed a 1.6-1.8-fold increase in leukocyte infiltration during thioglycollate-induced peritonitis between 3 and 24 h that returned to wild type levels by 96 h. Impaired vascular integrity in CD93(-/-) mice during peritonitis was demonstrated using fluorescence multiphoton intravital microscopy; however, no differences in cytokine or chemokine levels were detected with Luminex Multiplex or ELISA analysis. C1q-hemolytic activity in CD93(-/-) mice was decreased by 22% at time zero and by 46% 3 h after thioglycollate injection, suggesting a defect in the classical complement pathway. Leukocyte recruitment and C1q-hemolytic activity was restored to wild type levels when CD93 was expressed on either hematopoietic cells or nonhematopoietic cells in bone marrow chimeric mice. However, elevated levels of sCD93 in inflammatory fluid were observed only when CD93 was expressed on nonhematopoietic cells. Because cell-associated CD93 was sufficient to restore a normal inflammatory response, these data suggest that cell-associated CD93, and not sCD93, regulates leukocyte recruitment and complement activation during murine peritonitis.


Assuntos
Quimiotaxia de Leucócito/imunologia , Complemento C1q/metabolismo , Hemólise/imunologia , Glicoproteínas de Membrana/metabolismo , Peritonite/metabolismo , Receptores de Complemento/metabolismo , Animais , Membrana Celular/imunologia , Membrana Celular/metabolismo , Complemento C1q/imunologia , Ensaio de Imunoadsorção Enzimática , Células HEK293 , Humanos , Imuno-Histoquímica , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peritonite/imunologia , Receptores de Complemento/imunologia , Transfecção
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