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1.
Nature ; 628(8007): 400-407, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38480882

RESUMO

AIRE is an unconventional transcription factor that enhances the expression of thousands of genes in medullary thymic epithelial cells and promotes clonal deletion or phenotypic diversion of self-reactive T cells1-4. The biological logic of AIRE's target specificity remains largely unclear as, in contrast to many transcription factors, it does not bind to a particular DNA sequence motif. Here we implemented two orthogonal approaches to investigate AIRE's cis-regulatory mechanisms: construction of a convolutional neural network and leveraging natural genetic variation through analysis of F1 hybrid mice5. Both approaches nominated Z-DNA and NFE2-MAF as putative positive influences on AIRE's target choices. Genome-wide mapping studies revealed that Z-DNA-forming and NFE2L2-binding motifs were positively associated with the inherent ability of a gene's promoter to generate DNA double-stranded breaks, and promoters showing strong double-stranded break generation were more likely to enter a poised state with accessible chromatin and already-assembled transcriptional machinery. Consequently, AIRE preferentially targets genes with poised promoters. We propose a model in which Z-DNA anchors the AIRE-mediated transcriptional program by enhancing double-stranded break generation and promoter poising. Beyond resolving a long-standing mechanistic conundrum, these findings suggest routes for manipulating T cell tolerance.


Assuntos
Proteína AIRE , DNA Forma Z , Tolerância Imunológica , Linfócitos T , Timo , Animais , Camundongos , Proteína AIRE/metabolismo , Cromatina/genética , Cromatina/metabolismo , Quebras de DNA de Cadeia Dupla , DNA Forma Z/química , DNA Forma Z/genética , DNA Forma Z/metabolismo , Células Epiteliais/metabolismo , Variação Genética , Redes Neurais de Computação , Fator 2 Relacionado a NF-E2/metabolismo , Regiões Promotoras Genéticas , Linfócitos T/citologia , Linfócitos T/imunologia , Timo/citologia , Transcrição Gênica , Feminino
2.
Nat Immunol ; 18(3): 263-273, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28135252

RESUMO

Aire is a transcription factor that controls T cell tolerance by inducing the expression of a large repertoire of genes specifically in thymic stromal cells. It interacts with scores of protein partners of diverse functional classes. We found that Aire and some of its partners, notably those implicated in the DNA-damage response, preferentially localized to and activated long chromatin stretches that were overloaded with transcriptional regulators, known as super-enhancers. We also identified topoisomerase 1 as a cardinal Aire partner that colocalized on super-enhancers and was required for the interaction of Aire with all of its other associates. We propose a model that entails looping of super-enhancers to efficiently deliver Aire-containing complexes to local and distal transcriptional start sites.


Assuntos
Montagem e Desmontagem da Cromatina , DNA Topoisomerases Tipo I/metabolismo , Elementos Facilitadores Genéticos/fisiologia , Linfócitos T/fisiologia , Timo/fisiologia , Fatores de Transcrição/metabolismo , Ativação Transcricional , Animais , Autoimunidade , Dano ao DNA/genética , Reparo do DNA/genética , DNA Topoisomerases Tipo I/genética , Epigênese Genética , Redes Reguladoras de Genes , Células HEK293 , Humanos , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Fatores de Transcrição/genética , Proteína AIRE
3.
Immunity ; 53(6): 1202-1214.e6, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33086036

RESUMO

The mechanisms by which regulatory T (Treg) cells differentially control allergic and autoimmune responses remain unclear. We show that Treg cells in food allergy (FA) had decreased expression of transforming growth factor beta 1 (TGF-ß1) because of interleukin-4 (IL-4)- and signal transducer and activator of transciription-6 (STAT6)-dependent inhibition of Tgfb1 transcription. These changes were modeled by Treg cell-specific Tgfb1 monoallelic inactivation, which induced allergic dysregulation by impairing microbiota-dependent retinoic acid receptor-related orphan receptor gamma t (ROR-γt)+ Treg cell differentiation. This dysregulation was rescued by treatment with Clostridiales species, which upregulated Tgfb1 expression in Treg cells. Biallelic deficiency precipitated fatal autoimmunity with intense autoantibody production and dysregulated T follicular helper and B cell responses. These results identify a privileged role of Treg cell-derived TGF-ß1 in regulating allergy and autoimmunity at distinct checkpoints in a Tgfb1 gene dose- and microbiota-dependent manner.


Assuntos
Autoimunidade/imunologia , Hipersensibilidade/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/imunologia , Adolescente , Animais , Autoimunidade/genética , Linfócitos B/imunologia , Diferenciação Celular , Criança , Pré-Escolar , Hipersensibilidade Alimentar/imunologia , Dosagem de Genes , Humanos , Hipersensibilidade/genética , Imunoglobulina G/imunologia , Lactente , Mastócitos/imunologia , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Células T Auxiliares Foliculares/imunologia , Linfócitos T Reguladores/metabolismo , Transcrição Gênica , Fator de Crescimento Transformador beta1/genética , Adulto Jovem
4.
Immunity ; 45(5): 999-1012, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27851927

RESUMO

Aire's primary mechanism of action is to regulate transcription of a battery of genes in medullary thymic epithelial cells (mTECs) and, consequently, negative selection of effector T cells and positive selection of regulatory T cells. We found that Aire-deficient mice had expanded thymic and peripheral populations of perinatally generated IL-17A+Vγ6+Vδ1+ T cells, considered to be "early responders" to tissue stress and drivers of inflammatory reactions. Aire-dependent control of Il7 expression in mTECs regulated the size of thymic IL-17A+Vγ6+Vδ1+ compartments. In mice lacking Aire and γδ T cells, certain tissues typically targeted in the "Aire-less" disease, notably the retina, were only minimally infiltrated. IL-17A+Vγ6+Vδ1+ cells were present in the retina of wild-type mice and expanded very early in Aire-deficient mice. A putatively parallel population of IL-17A+Vγ9+Vδ2+ T cells was increased in humans lacking Aire. Thus, Aire exerts multi-faceted autoimmune control that extends to a population of innate-like T cells.


Assuntos
Tolerância Imunológica/imunologia , Poliendocrinopatias Autoimunes/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Fatores de Transcrição/imunologia , Adolescente , Adulto , Animais , Criança , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Interleucina-17/biossíntese , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase , Subpopulações de Linfócitos T/metabolismo , Transcriptoma , Adulto Jovem , Proteína AIRE
5.
J Immunol ; 210(2): 126-133, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36596219

RESUMO

DNA topoisomerases (TOPs) are complex enzymatic machines with extraordinary capacity to maintain DNA topology during torsion-intensive steps of replication and transcription. Recently, TOPs have gained significant attention for their tissue-specific function, and the vital role of TOPs in immune homeostasis and dysfunction is beginning to emerge. TOPs have been implicated in various immunological disorders such as autoimmunity, B cell immunodeficiencies, and sepsis, underscoring their importance in immune regulation. However, much remains unknown about immunological underpinnings of TOPs, and a deeper understanding of the role of TOPs in the immune system will be critical for yielding significant insights into the etiology of immunological disorders. In this review, we first discuss the recent literature highlighting the contribution of TOPs in the development of immune cells, and we further provide an overview of their importance in immune cell responses.


Assuntos
DNA , Síndromes de Imunodeficiência , Humanos , Autoimunidade
7.
Proc Natl Acad Sci U S A ; 118(38)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34518235

RESUMO

Aire controls immunological tolerance by driving promiscuous expression of a large swath of the genome in medullary thymic epithelial cells (mTECs). Its molecular mechanism remains enigmatic. High-resolution chromosome-conformation capture (Hi-C) experiments on ex vivo mTECs revealed Aire to have a widespread impact on higher-order chromatin structure, disfavoring architectural loops while favoring transcriptional loops. In the presence of Aire, cohesin complexes concentrated on superenhancers together with mediator complexes, while the CCCTC-binding factor (CTCF) was relatively depleted from structural domain boundaries. In particular, Aire associated with the cohesin loader, NIPBL, strengthening this factor's affiliation with cohesin's enzymatic subunits. mTEC transcripts up-regulated in the presence of Aire corresponded closely to those down-regulated in the absence of one of the cohesin subunits, SA-2. A mechanistic model incorporating these findings explains many of the unusual features of Aire's impact on mTEC transcription, providing molecular insight into tolerance induction.


Assuntos
Fator de Ligação a CCCTC/genética , Cromatina/genética , Animais , Proteínas de Ciclo Celular/genética , Regulação para Baixo/genética , Células Epiteliais/fisiologia , Genoma/genética , Células HEK293 , Humanos , Tolerância Imunológica/genética , Camundongos , Timo/fisiologia , Fatores de Transcrição , Proteína AIRE
8.
Subcell Biochem ; 100: 201-237, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36301496

RESUMO

Nucleic acid methylation is a fundamental epigenetic mechanism that impinges upon several cellular attributes, including metabolism and energy production. The dysregulation of deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) methylation can lead to metabolic rewiring in the cell, which in turn facilitates tumor development. Here, we review the current knowledge on the interplay between DNA/RNA methylation and metabolic programs in cancer cells. We also discuss the mechanistic role of these pathways in tumor development and progression.


Assuntos
Neoplasias , RNA , Humanos , RNA/genética , RNA/metabolismo , Metilação de DNA , Neoplasias/genética , Neoplasias/metabolismo , DNA/metabolismo , Homeostase
9.
Proc Natl Acad Sci U S A ; 112(32): E4448-57, 2015 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-26216992

RESUMO

Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA polymerase II paused just downstream of transcriptional start sites. We explored Aire's collaboration with the bromodomain-containing protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire:Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire's caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire:Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers.


Assuntos
Regulação da Expressão Gênica , Proteínas Nucleares/metabolismo , Fator B de Elongação Transcricional Positiva/metabolismo , Timo/citologia , Elongação da Transcrição Genética , Fatores de Transcrição/metabolismo , Acetilação/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/genética , Lisina/metabolismo , Camundongos , Modelos Biológicos , Dados de Sequência Molecular , Mutação , Proteínas Nucleares/química , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Mapeamento de Interação de Proteínas , Estrutura Terciária de Proteína , Splicing de RNA/efeitos dos fármacos , Splicing de RNA/genética , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Elongação da Transcrição Genética/efeitos dos fármacos , Fatores de Transcrição/química , Fatores de Transcrição/genética , Transcriptoma/genética , Proteína AIRE
11.
Proc Natl Acad Sci U S A ; 110(5): 1833-8, 2013 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-23319629

RESUMO

Aire impacts immunological tolerance by regulating the expression of a large set of genes in thymic medullary epithelial cells, thereby controlling the repertoire of self-antigens encountered by differentiating thymocytes. Both humans and mice lacking Aire develop multiorgan autoimmunity. Currently, there are few molecular details on how Aire performs this crucial function. The more amino-terminal of its two plant homeodomains (PHDs), PHD1, helps Aire target poorly transcribed loci by "reading" the methylation status of a particular lysine residue of histone-3, a process that does not depend on the more carboxyl-terminal PHD-2. This study addresses the role of PHD2 in Aire function by comparing the behavior of wild-type and PHD2-deleted Aire in both transfected cells and transgenic mice. PHD2 was required for Aire to interact with sets of protein partners involved in chromatin structure/binding or transcription but not with those implicated in pre-mRNA processing; it also was not required for Aire's nuclear translocation or regional distribution. PHD2 strongly influenced the ability of Aire to regulate the medullary epithelial cell transcriptome and so was crucial for effective central tolerance induction. Thus, Aire's two PHDs seem to play distinct roles in the scenario by which it assures immunological tolerance.


Assuntos
Células Epiteliais/imunologia , Tolerância Imunológica/imunologia , Fatores de Transcrição/imunologia , Transcriptoma/imunologia , Animais , Sítios de Ligação/genética , Sítios de Ligação/imunologia , Células Cultivadas , Células Epiteliais/metabolismo , Feminino , Células HEK293 , Humanos , Tolerância Imunológica/genética , Immunoblotting , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Análise de Sequência com Séries de Oligonucleotídeos , Ligação Proteica/imunologia , Timo/citologia , Timo/imunologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma/genética , Proteína AIRE
14.
Infect Immun ; 82(8): 3141-53, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24818666

RESUMO

In Aspergillus fumigatus, the conidial surface contains dihydroxynaphthalene (DHN)-melanin. Six-clustered gene products have been identified that mediate sequential catalysis of DHN-melanin biosynthesis. Melanin thus produced is known to be a virulence factor, protecting the fungus from the host defense mechanisms. In the present study, individual deletion of the genes involved in the initial three steps of melanin biosynthesis resulted in an altered conidial surface with masked surface rodlet layer, leaky cell wall allowing the deposition of proteins on the cell surface and exposing the otherwise-masked cell wall polysaccharides at the surface. Melanin as such was immunologically inert; however, deletion mutant conidia with modified surfaces could activate human dendritic cells and the subsequent cytokine production in contrast to the wild-type conidia. Cell surface defects were rectified in the conidia mutated in downstream melanin biosynthetic pathway, and maximum immune inertness was observed upon synthesis of vermelone onward. These observations suggest that although melanin as such is an immunologically inert material, it confers virulence by facilitating proper formation of the A. fumigatus conidial surface.


Assuntos
Aspergillus fumigatus/química , Aspergillus fumigatus/imunologia , Deleção de Genes , Melaninas/biossíntese , Esporos Fúngicos/química , Esporos Fúngicos/imunologia , Propriedades de Superfície , Aspergillus fumigatus/genética , Vias Biossintéticas/genética , Citocinas/metabolismo , Células Dendríticas/imunologia , Humanos , Imunidade Celular , Esporos Fúngicos/genética
15.
Mol Cancer ; 13: 210, 2014 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-25208737

RESUMO

BACKGROUND: Increased incidence of lung cancer among pulmonary tuberculosis patients suggests mycobacteria-induced tumorigenic response in the host. The alveolar epithelial cells, candidate cells that form lung adenocarcinoma, constitute a niche for mycobacterial replication and infection. We thus explored the possible mechanism of M. bovis Bacillus Calmette-Guérin (BCG)-assisted tumorigenicity in type II epithelial cells, human lung adenocarcinoma A549 and other cancer cells. METHODS: Cancer cell lines originating from lung, colon, bladder, liver, breast, skin and cervix were treated with tumor necrosis factor (TNF)-α in presence or absence of BCG infection. p53, COP1 and sonic hedgehog (SHH) signaling markers were determined by immunoblotting and luciferase assays, and quantitative real time PCR was done for p53-responsive pro-apoptotic genes and SHH signaling markers. MTT assays and Annexin V staining were utilized to study apoptosis. Gain- and loss-of-function approaches were used to investigate the role for SHH and COP1 signaling during apoptosis. A549 xenografted mice were used to validate the contribution of BCG during TNF-α treatment. RESULTS: Here, we show that BCG inhibits TNF-α-mediated apoptosis in A549 cells via downregulation of p53 expression. Substantiating this observation, BCG rescued A549 xenografts from TNF-α-mediated tumor clearance in nude mice. Furthermore, activation of SHH signaling by BCG induced the expression of an E3 ubiquitin ligase, COP1. SHH-driven COP1 targeted p53, thereby facilitating downregulation of p53-responsive pro-apoptotic genes and inhibition of apoptosis. Similar effects of BCG could be shown for HCT116, T24, MNT-1, HepG2 and HELA cells but not for HCT116 p53(-/-) and MDA-MB-231 cells. CONCLUSION: Our results not only highlight possible explanations for the coexistence of pulmonary tuberculosis and lung cancer but also address probable reasons for failure of BCG immunotherapy of cancers.


Assuntos
Apoptose , Mycobacterium bovis/fisiologia , Neoplasias/patologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Células HeLa , Células Hep G2 , Humanos , Camundongos , Camundongos Nus , Neoplasias/microbiologia , Neoplasias Experimentais , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Biol Chem ; 286(7): 5823-35, 2011 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-21156799

RESUMO

Intracellular pathogen sensor, NOD2, has been implicated in regulation of wide range of anti-inflammatory responses critical during development of a diverse array of inflammatory diseases; however, underlying molecular details are still imprecisely understood. In this study, we demonstrate that NOD2 programs macrophages to trigger Notch1 signaling. Signaling perturbations or genetic approaches suggest signaling integration through cross-talk between Notch1-PI3K during the NOD2-triggered expression of a multitude of immunological parameters including COX-2/PGE(2) and IL-10. NOD2 stimulation enhanced active recruitment of CSL/RBP-Jk on the COX-2 promoter in vivo. Intriguingly, nitric oxide assumes critical importance in NOD2-mediated activation of Notch1 signaling as iNOS(-/-) macrophages exhibited compromised ability to execute NOD2-triggered Notch1 signaling responses. Correlative evidence demonstrates that this mechanism operates in vivo in brain and splenocytes derived from wild type, but not from iNOS(-/-) mice. Importantly, NOD2-driven activation of the Notch1-PI3K signaling axis contributes to its capacity to impart survival of macrophages against TNF-α or IFN-γ-mediated apoptosis and resolution of inflammation. Current investigation identifies Notch1-PI3K as signaling cohorts involved in the NOD2-triggered expression of a battery of genes associated with anti-inflammatory functions. These findings serve as a paradigm to understand the pathogenesis of NOD2-associated inflammatory diseases and clearly pave a way toward development of novel therapeutics.


Assuntos
Macrófagos Peritoneais/metabolismo , Proteína Adaptadora de Sinalização NOD2/metabolismo , Receptor Notch1/metabolismo , Transdução de Sinais , Animais , Apoptose/genética , Linhagem Celular , Sobrevivência Celular/genética , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/genética , Dinoprostona/metabolismo , Inflamação/genética , Inflamação/metabolismo , Inflamação/terapia , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Receptor Notch1/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
17.
J Biol Chem ; 286(42): 37032-44, 2011 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-21862586

RESUMO

Innate immunity recognizes and resists various pathogens; however, the mechanisms regulating pathogen versus nonpathogen discrimination are still imprecisely understood. Here, we demonstrate that pathogen-specific activation of TLR2 upon infection with Mycobacterium bovis BCG, in comparison with other pathogenic microbes, including Salmonella typhimurium and Staphylococcus aureus, programs macrophages for robust up-regulation of signaling cohorts of Wnt-ß-catenin signaling. Signaling perturbations or genetic approaches suggest that infection-mediated stimulation of Wnt-ß-catenin is vital for activation of Notch1 signaling. Interestingly, inducible NOS (iNOS) activity is pivotal for TLR2-mediated activation of Wnt-ß-catenin signaling as iNOS(-/-) mice demonstrated compromised ability to trigger activation of Wnt-ß-catenin signaling as well as Notch1-mediated cellular responses. Intriguingly, TLR2-driven integration of iNOS/NO, Wnt-ß-catenin, and Notch1 signaling contributes to its capacity to regulate the battery of genes associated with T(Reg) cell lineage commitment. These findings reveal a role for differential stimulation of TLR2 in deciding the strength of Wnt-ß-catenin signaling, which together with signals from Notch1 contributes toward the modulation of a defined set of effector functions in macrophages and thus establishes a conceptual framework for the development of novel therapeutics.


Assuntos
Bactérias/imunologia , Infecções Bacterianas/imunologia , Macrófagos Peritoneais/imunologia , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/imunologia , Proteínas Wnt/imunologia , beta Catenina/imunologia , Animais , Bactérias/metabolismo , Infecções Bacterianas/genética , Infecções Bacterianas/metabolismo , Linhagem Celular , Macrófagos Peritoneais/metabolismo , Macrófagos Peritoneais/microbiologia , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Receptor Notch1/genética , Receptor Notch1/imunologia , Receptor Notch1/metabolismo , Transdução de Sinais/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologia , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Regulação para Cima/genética , Regulação para Cima/imunologia , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
18.
J Immunol ; 184(7): 3495-504, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20176745

RESUMO

Mycobacterium tuberculosis, the causative agent of pulmonary tuberculosis, infects one-third of the world's population. Activation of host immune responses for containment of mycobacterial infections involves participation of innate immune cells, such as dendritic cells (DCs). DCs are sentinels of the immune system and are important for eliciting both primary and secondary immune responses to pathogens. In this context, to understand the molecular pathogenesis of tuberculosis and host response to mycobacteria and to conceive prospective vaccine candidates, it is important to understand how cell wall Ags of M. tuberculosis and, in particular, the proline-glutamic acid_polymorphic guanine-cytosine-rich sequence (PE_PGRS) family of proteins modulate DC maturation and function. In this study, we demonstrate that two cell wall-associated/secretory PE_PGRS proteins, PE_PGRS 17 (Rv0978c) and PE_PGRS 11 (Rv0754), recognize TLR2, induce maturation and activation of human DCs, and enhance the ability of DCs to stimulate CD4(+) T cells. We further found that PE_PGRS protein-mediated activation of DCs involves participation of ERK1/2, p38 MAPK, and NF-kappaB signaling pathways. Priming of human DCs with IFN-gamma further augmented PE_PGRS 17 or PE_PGRS 11 Ag-induced DC maturation and secretion of key proinflammatory cytokines. Our results suggest that by activating DCs, PE_PGRS proteins, important mycobacterial cell wall Ags, could potentially contribute in the initiation of innate immune responses during tuberculosis infection and hence regulate the clinical course of tuberculosis.


Assuntos
Antígenos de Bactérias/imunologia , Células Dendríticas/imunologia , Transdução de Sinais/imunologia , Tuberculose/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Separação Celular , Parede Celular/imunologia , Citocinas/biossíntese , Citometria de Fluxo , Imunofluorescência , Humanos , Immunoblotting , Imunoprecipitação , Mycobacterium tuberculosis/imunologia , Proteínas Recombinantes/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção
19.
Front Immunol ; 13: 866937, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35493450

RESUMO

Immunological tolerance plays a critical role during pregnancy as semi-allogeneic fetus must be protected from immune responses during the gestational period. Regulatory T cells (Tregs), a subpopulation of CD4+ T cells that express transcription factor Foxp3, are central to the maintenance of immunological tolerance and prevention of autoimmunity. Tregs are also known to accumulate at placenta in uterus during pregnancy, and they confer immunological tolerance at maternal-fetal interface by controlling the immune responses against alloantigens. Thus, uterine Tregs help in maintaining an environment conducive for survival of the fetus during gestation, and low frequency or dysfunction of Tregs is associated with recurrent spontaneous abortions and other pregnancy-related complications such as preeclampsia. Interestingly, there are many parallels in the development of placenta and solid tumours, and the tumour microenvironment is considered to be somewhat similar to that at maternal-fetal interface. Moreover, Tregs play a largely similar role in tumour immunity as they do at placenta- they create a tolerogenic system and suppress the immune responses against the cells within tumour and at maternal-fetal interface. In this review, we discuss the role of Tregs in supporting the proper growth of the embryo during pregnancy. We also highlight the similarities and differences between Tregs at maternal-fetal interface and tumour Tregs, in an attempt to draw a comparison between their roles in these two physiologic and pathologic states.


Assuntos
Neoplasias , Complicações na Gravidez , Feminino , Humanos , Tolerância Imunológica , Isoantígenos , Neoplasias/patologia , Placenta , Gravidez , Linfócitos T Reguladores , Microambiente Tumoral
20.
J Biol Chem ; 285(47): 36511-22, 2010 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-20837474

RESUMO

Mycobacterium tuberculosis, an etiological agent of pulmonary tuberculosis, causes significant morbidity and mortality worldwide. Pathogenic mycobacteria survive in the host by subverting host innate immunity. Dendritic cells (DCs) are professional antigen-presenting cells that are vital for eliciting immune responses to infectious agents, including pathogenic mycobacteria. DCs orchestrate distinct Th responses based on the signals they receive. In this perspective, deciphering the interactions of the proline-glutamic acid/proline-proline-glutamic acid (PE/PPE) family of proteins of M. tuberculosis with DCs assumes significant pathophysiological attributes. In this study, we demonstrate that Rv1917c (PPE34), a representative member of the proline-proline-glutamic-major polymorphic tandem repeat family, interacts with TLR2 and triggers functional maturation of human DCs. Signaling perturbations implicated a critical role for integrated cross-talk among PI3K-MAPK and NF-κB signaling cascades in Rv1917c-induced maturation of DCs. However, this maturation of DCs was associated with a secretion of high amounts of anti-inflammatory cytokine IL-10, whereas Th1-polarizing cytokine IL-12 was not induced. Consistent with these results, Rv1917c-matured DCs favored secretion of IL-4, IL-5, and IL-10 from CD4(+) T cells and contributed to Th2-skewed cytokine balance ex vivo in healthy individuals and in patients with pulmonary tuberculosis. Interestingly, the Rv1917c-skewed Th2 immune response involved induced expression of cyclooxygenase-2 (COX-2) in DCs. Taken together, these results indicate that Rv1917c facilitates a shift in the ensuing immunity toward the Th2 phenotype and could aid in immune evasion by mycobacteria.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Mycobacterium tuberculosis/metabolismo , NF-kappa B/metabolismo , Células Th2/imunologia , Tuberculose/metabolismo , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Western Blotting , Células Cultivadas , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Ensaio de Imunoadsorção Enzimática , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Imunofluorescência , Regulação da Expressão Gênica , Humanos , Mycobacterium tuberculosis/imunologia , NF-kappa B/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T , Células Th2/metabolismo , Tuberculose/imunologia , Tuberculose/microbiologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Domínios de Homologia de src
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