RESUMO
Asthma, the most prevalent respiratory disease, affects more than 300 million people and causes more than 250,000 deaths annually. Type 2-high asthma is characterized by interleukin (IL)-5-driven eosinophilia, along with airway inflammation and remodeling caused by IL-4 and IL-13. Here we utilize IL-5 as the targeting domain and deplete BCOR and ZC3H12A to engineer long-lived chimeric antigen receptor (CAR) T cells that can eradicate eosinophils. We call these cells immortal-like and functional IL-5 CAR T cells (5TIF) cells. 5TIF cells were further modified to secrete an IL-4 mutein that blocks IL-4 and IL-13 signaling, designated as 5TIF4 cells. In asthma models, a single infusion of 5TIF4 cells in fully immunocompetent mice, without any conditioning regimen, led to sustained repression of lung inflammation and alleviation of asthmatic symptoms. These data show that asthma, a common chronic disease, can be pushed into long-term remission with a single dose of long-lived CAR T cells.
Assuntos
Asma , Receptores de Antígenos Quiméricos , Animais , Asma/imunologia , Asma/terapia , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva/métodos , Linfócitos T/imunologia , Interleucina-5/imunologia , Interleucina-5/metabolismo , Modelos Animais de Doenças , Humanos , Interleucina-4/imunologia , Interleucina-4/metabolismo , Camundongos Endogâmicos C57BL , Eosinófilos/imunologia , Feminino , Interleucina-13/metabolismo , Interleucina-13/imunologiaRESUMO
In many asthmatics, chronic airway inflammation is driven by IL-4-, IL-5-, and IL-13-producing Th2 cells or ILC2s. Type 2 cytokines promote hallmark features of the disease such as eosinophilia, mucus hypersecretion, bronchial hyperresponsiveness (BHR), IgE production, and susceptibility to exacerbations. However, only half the asthmatics have this "type 2-high" signature, and "type 2-low" asthma is more associated with obesity, presence of neutrophils, and unresponsiveness to corticosteroids, the mainstay asthma therapy. Here, we review the underlying immunological basis of various asthma endotypes by discussing results obtained from animal studies as well as results generated in clinical studies targeting specific immune pathways.
Assuntos
Asma/imunologia , Imunidade Adaptativa , Células Epiteliais Alveolares/patologia , Animais , Asma/fisiopatologia , Asma/terapia , Asma/virologia , Linfócitos B/imunologia , Terapia Biológica , Humanos , Imunoglobulina E/imunologiaRESUMO
Lung dendritic cells (DCs) bridge innate and adaptive immunity, and depending on context, they also induce a Th1, Th2, or Th17 response to optimally clear infectious threats. Conversely, lung DCs can also mount maladaptive Th2 immune responses to harmless allergens and, in this way, contribute to immunopathology. It is now clear that the various aspects of DC biology can be understood only if we take into account the functional specializations of different DC subsets that are present in the lung in homeostasis or are attracted to the lung as part of the inflammatory response to inhaled noxious stimuli. Lung DCs are heavily influenced by the nearby epithelial cells, and a model is emerging whereby direct communication between DCs and epithelial cells determines the outcome of the pulmonary immune response. Here, we have approached DC biology from the perspective of viral infection and allergy to illustrate these emerging concepts.
Assuntos
Asma/imunologia , Células Dendríticas/imunologia , Influenza Humana/imunologia , Pulmão/imunologia , Imunidade Adaptativa , Alérgenos/imunologia , Animais , Asma/prevenção & controle , Células Dendríticas/metabolismo , Humanos , Pulmão/patologia , Pulmão/virologia , Camundongos , Pneumonia/imunologia , Pneumonia/patologiaRESUMO
Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I. PGE2-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE2 metabolites correlate with serum sST2. In mice, PGE2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP)2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE2 or ST2 expression by MCs back to control levels. PGE2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE2 states.
Assuntos
Dinoprostona , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Pulmão , Mastócitos , Camundongos Knockout , Animais , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Mastócitos/imunologia , Mastócitos/metabolismo , Dinoprostona/metabolismo , Camundongos , Interleucina-33/metabolismo , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Asma/imunologia , Asma/metabolismo , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Camundongos Endogâmicos C57BL , Inflamação/imunologia , Feminino , Masculino , Transdução de Sinais , Pneumonia/imunologia , Pneumonia/metabolismoRESUMO
Antibiotic use in early life disrupts microbial colonization and increases the risk of developing allergies and asthma. We report that mice given antibiotics in early life (EL-Abx), but not in adulthood, were more susceptible to house dust mite (HDM)-induced allergic airway inflammation. This susceptibility was maintained even after normalization of the gut microbiome. EL-Abx decreased systemic levels of indole-3-propionic acid (IPA), which induced long-term changes to cellular stress, metabolism, and mitochondrial respiration in the lung epithelium. IPA reduced mitochondrial respiration and superoxide production and altered chemokine and cytokine production. Consequently, early-life IPA supplementation protected EL-Abx mice against exacerbated HDM-induced allergic airway inflammation in adulthood. These results reveal a mechanism through which EL-Abx can predispose the lung to allergic airway inflammation and highlight a possible preventative approach to mitigate the detrimental consequences of EL-Abx.
Assuntos
Antibacterianos , Asma , Disbiose , Microbioma Gastrointestinal , Indóis , Pyroglyphidae , Animais , Camundongos , Disbiose/imunologia , Indóis/farmacologia , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/imunologia , Asma/imunologia , Pyroglyphidae/imunologia , Pulmão/imunologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Feminino , Inflamação/imunologia , Modelos Animais de Doenças , Mitocôndrias/metabolismo , Citocinas/metabolismo , Hipersensibilidade/imunologia , PropionatosRESUMO
The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1-FPR2-IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces.
Assuntos
Asma/imunologia , Rinite Alérgica/imunologia , Proteína Amiloide A Sérica/metabolismo , Transdução de Sinais/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alérgenos/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Asma/patologia , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais , Proteínas de Ligação a Ácido Graxo/imunologia , Feminino , Humanos , Imunidade Humoral , Imunidade Inata , Interleucina-33/metabolismo , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Cultura Primária de Células , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Rinite Alérgica/patologia , Proteína Amiloide A Sérica/genética , Regulação para Cima , Adulto JovemAssuntos
Asma , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Asma/imunologia , Humanos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Imunoterapia Adotiva/métodos , Animais , Linfócitos T/imunologia , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.
Assuntos
Asma/imunologia , Redes Reguladoras de Genes/imunologia , Transcriptoma/imunologia , Viroses/imunologia , Adolescente , Asma/genética , Asma/virologia , Estudos de Casos e Controles , Criança , Resfriado Comum/genética , Resfriado Comum/imunologia , Resfriado Comum/virologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Viroses/genética , Viroses/virologiaRESUMO
Low exposure to microbial products, respiratory viral infections and air pollution are major risk factors for allergic asthma, yet the mechanistic links between such conditions and host susceptibility to type 2 allergic disorders remain unclear. Through the use of single-cell RNA sequencing, we characterized lung neutrophils in mice exposed to a pro-allergic low dose of lipopolysaccharide (LPS) or a protective high dose of LPS before exposure to house dust mites. Unlike exposure to a high dose of LPS, exposure to a low dose of LPS instructed recruited neutrophils to upregulate their expression of the chemokine receptor CXCR4 and to release neutrophil extracellular traps. Low-dose LPS-induced neutrophils and neutrophil extracellular traps potentiated the uptake of house dust mites by CD11b+Ly-6C+ dendritic cells and type 2 allergic airway inflammation in response to house dust mites. Neutrophil extracellular traps derived from CXCR4hi neutrophils were also needed to mediate allergic asthma triggered by infection with influenza virus or exposure to ozone. Our study indicates that apparently unrelated environmental risk factors can shape recruited lung neutrophils to promote the initiation of allergic asthma.
Assuntos
Poluentes Atmosféricos/imunologia , Alérgenos/imunologia , Asma/imunologia , Armadilhas Extracelulares/metabolismo , Neutrófilos/imunologia , Animais , Células Dendríticas/imunologia , Modelos Animais de Doenças , Exposição Ambiental/efeitos adversos , Armadilhas Extracelulares/imunologia , Feminino , Humanos , Lipopolissacarídeos/imunologia , Pulmão/citologia , Pulmão/imunologia , Camundongos , Neutrófilos/metabolismo , Orthomyxoviridae/imunologia , Ozônio/imunologia , Pyroglyphidae/imunologia , Receptores CXCR4/imunologia , Receptores CXCR4/metabolismo , Regulação para CimaRESUMO
Childhood asthma is typically associated with a polarized Th2 response to inhaled allergens and is influenced by genetics. Yang et al. show that the asthma susceptibility gene DENND1B controls cytokine production in Th2 lymphocytes by controlling the rate of TCR internalization and routing to endosomes, providing a molecular basis for how DENND1B contributes to asthma pathogenesis.
Assuntos
Asma/imunologia , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Células Th2/imunologia , Animais , Feminino , HumanosRESUMO
The DENN domain is an evolutionary conserved protein module found in all eukaryotes and serves as an exchange factor for Rab-GTPases to regulate diverse cellular functions. Variants in DENND1B are associated with development of childhood asthma and other immune disorders. To understand how DENND1B may contribute to human disease, Dennd1b(-/-) mice were generated and exhibit hyper-allergic responses following antigen challenge. Dennd1b(-/-) TH2, but not other TH cells, exhibit delayed receptor-induced T cell receptor (TCR) downmodulation, enhanced TCR signaling, and increased production of effector cytokines. As DENND1B interacts with AP-2 and Rab35, TH2 cells deficient in AP-2 or Rab35 also exhibit enhanced TCR-mediated effector functions. Moreover, human TH2 cells carrying asthma-associated DENND1B variants express less DENND1B and phenocopy Dennd1b(-/-) TH2 cells. These results provide a molecular basis for how DENND1B, a previously unrecognized regulator of TCR downmodulation in TH2 cells, contributes to asthma pathogenesis and how DENN-domain-containing proteins may contribute to other human disorders.
Assuntos
Asma/imunologia , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Células Th2/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/imunologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Hipersensibilidade/imunologia , Ativação Linfocitária , Camundongos , Polimorfismo de Nucleotídeo Único , Células Th2/metabolismo , Proteínas rab de Ligação ao GTP/genéticaRESUMO
Allergic airway inflammation is driven by type-2 CD4+ T cell inflammatory responses. We uncover an immunoregulatory role for the nucleotide release channel, Panx1, in T cell crosstalk during airway disease. Inverse correlations between Panx1 and asthmatics and our mouse models revealed the necessity, specificity, and sufficiency of Panx1 in T cells to restrict inflammation. Global Panx1-/- mice experienced exacerbated airway inflammation, and T-cell-specific deletion phenocopied Panx1-/- mice. A transgenic designed to re-express Panx1 in T cells reversed disease severity in global Panx1-/- mice. Panx1 activation occurred in pro-inflammatory T effector (Teff) and inhibitory T regulatory (Treg) cells and mediated the extracellular-nucleotide-based Treg-Teff crosstalk required for suppression of Teff cell proliferation. Mechanistic studies identified a Salt-inducible kinase-dependent phosphorylation of Panx1 serine 205 important for channel activation. A genetically targeted mouse expressing non-phosphorylatable Panx1S205A phenocopied the exacerbated inflammation in Panx1-/- mice. These data identify Panx1-dependent Treg:Teff cell communication in restricting airway disease.
Assuntos
Asma/imunologia , Comunicação Celular/imunologia , Conexinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linhagem Celular , Proliferação de Células/fisiologia , Conexinas/genética , Modelos Animais de Doenças , Células HEK293 , Humanos , Células Jurkat , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Sistema Respiratório/imunologiaRESUMO
Exaggerated airway constriction triggered by repeated exposure to allergen, also called hyperreactivity, is a hallmark of asthma. Whereas vagal sensory neurons are known to function in allergen-induced hyperreactivity1-3, the identity of downstream nodes remains poorly understood. Here we mapped a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA sequencing, followed by RNAscope assay at baseline and allergen challenges, showed that a Dbh+ nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh+ nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh+ nTS and NA. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. This knowledge informs how neural modulation could be used to control allergen-induced airway hyperreactivity.
Assuntos
Alérgenos , Tronco Encefálico , Hiper-Reatividade Brônquica , Dopamina beta-Hidroxilase , Pulmão , Neurônios , Animais , Feminino , Masculino , Camundongos , Alérgenos/imunologia , Asma/imunologia , Asma/fisiopatologia , Tronco Encefálico/citologia , Tronco Encefálico/fisiologia , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Interleucina-4/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/inervação , Pulmão/fisiopatologia , Mastócitos/imunologia , Neurônios/enzimologia , Neurônios/fisiologia , Norepinefrina/antagonistas & inibidores , Norepinefrina/metabolismo , Núcleo Solitário/citologia , Núcleo Solitário/fisiologia , Nervo Vago/citologia , Nervo Vago/fisiologia , Bulbo/citologia , Bulbo/efeitos dos fármacos , Gânglios Autônomos/citologia , Dopamina beta-Hidroxilase/metabolismoRESUMO
The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. We found that murid herpesvirus 4 (MuHV-4) inhibited the development of house dust mite (HDM)-induced experimental asthma by modulating lung innate immune cells. Specifically, infection with MuHV-4 caused the replacement of resident alveolar macrophages (AMs) by monocytes with regulatory functions. Monocyte-derived AMs blocked the ability of dendritic cells to trigger a HDM-specific response by the TH2 subset of helper T cells. Our results indicate that replacement of embryonic AMs by regulatory monocytes is a major mechanism underlying the long-term training of lung immunity after infection.
Assuntos
Asma/terapia , Macrófagos Alveolares/imunologia , Monócitos/imunologia , Pyroglyphidae/imunologia , Rhadinovirus/imunologia , Células Th2/imunologia , Transferência Adotiva , Animais , Asma/imunologia , Linhagem Celular , Cricetinae , Células Dendríticas/imunologia , Feminino , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Macrófagos Alveolares/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Th2/transplanteRESUMO
CD4+ T helper (Th) cells are fundamental players in immunity. Based on the expression of signature cytokines and transcription factors, several Th subsets have been defined. Th cells are thought to be far more heterogeneous and multifunctional than originally believed, but characterization of the full diversity has been hindered by technical limitations. Here, we employ mass cytometry to analyze the diversity of Th cell responses generated in vitro and in animal disease models, revealing a vast heterogeneity of effector states with distinct cytokine footprints. The diversities of cytokine responses established during primary antigen encounters in Th1- and Th2-cell-polarizing conditions are largely maintained after secondary challenge, regardless of the new inflammatory environment, highlighting many of the identified states as stable Th cell sublineages. We also find that Th17 cells tend to upregulate Th2-cell-associated cytokines upon challenge, indicating a closer developmental connection between Th17 and Th2 cells than previously anticipated.
Assuntos
Citocinas/metabolismo , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Animais , Asma/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Humanos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pyroglyphidae/imunologia , Células Th1/citologia , Células Th17/citologia , Células Th2/citologiaRESUMO
Asthma is a common chronic respiratory disease affecting more than 300 million people worldwide. Clinical features of asthma and its immunological and molecular etiology vary significantly among patients. An understanding of the complexities of asthma has evolved to the point where precision medicine approaches, including microbiome analysis, are being increasingly recognized as an important part of disease management. Lung and gut microbiota play several important roles in the development, regulation, and maintenance of healthy immune responses. Dysbiosis and subsequent dysregulation of microbiota-related immunological processes affect the onset of the disease, its clinical characteristics, and responses to treatment. Bacteria and viruses are the most extensively studied microorganisms relating to asthma pathogenesis, but other microbes, including fungi and even archaea, can potently influence airway inflammation. This review focuses on recently discovered connections between lung and gut microbiota, including bacteria, fungi, viruses, and archaea, and their influence on asthma.
Assuntos
Asma/imunologia , Asma/microbiologia , Trato Gastrointestinal , Pulmão , Microbiota/imunologia , Animais , Asma/patologia , Asma/fisiopatologia , Disbiose/imunologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/parasitologia , Trato Gastrointestinal/virologia , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/parasitologia , Pulmão/virologia , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Sistema Respiratório/parasitologia , Sistema Respiratório/virologiaRESUMO
Innate lymphoid cells (ILCs) play an important role in the control and maintenance of barrier immunity. However, chronic activation of ILCs results in immune-mediated pathology. Here, we show that tissue-resident type 2 ILCs (ILC2s) display a distinct metabolic signature upon chronic activation. In the context of allergen-driven airway inflammation, ILC2s increase their uptake of both external lipids and glucose. Externally acquired fatty acids are transiently stored in lipid droplets and converted into phospholipids to promote the proliferation of ILC2s. This metabolic program is imprinted by interleukin-33 (IL-33) and regulated by the genes Pparg and Dgat1, which are both controlled by glucose availability and mTOR signaling. Restricting dietary glucose by feeding mice a ketogenic diet largely ablated ILC2-mediated airway inflammation by impairing fatty acid metabolism and the formation of lipid droplets. Together, these results reveal that pathogenic ILC2 responses require lipid metabolism and identify ketogenic diet as a potent intervention strategy to treat airway inflammation.
Assuntos
Alérgenos/administração & dosagem , Asma/dietoterapia , Diacilglicerol O-Aciltransferase/imunologia , Dieta Cetogênica/métodos , Interleucina-33/imunologia , Gotículas Lipídicas/metabolismo , Subpopulações de Linfócitos T/imunologia , Alternaria/química , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Citocinas/administração & dosagem , Diacilglicerol O-Aciltransferase/genética , Modelos Animais de Doenças , Ácidos Graxos/imunologia , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Glucose/imunologia , Glucose/metabolismo , Imunidade Inata , Interleucina-33/administração & dosagem , Interleucina-33/genética , Interleucinas/administração & dosagem , Gotículas Lipídicas/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR gama/genética , PPAR gama/imunologia , Papaína/administração & dosagem , Fosfolipídeos/imunologia , Fosfolipídeos/metabolismo , Cultura Primária de Células , Subpopulações de Linfócitos T/classificação , Subpopulações de Linfócitos T/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/imunologia , Linfopoietina do Estroma do TimoRESUMO
Inflammation induced during infection can both promote and suppress immunity. This contradiction suggests that inflammatory cytokines affect the immune system in a context-dependent manner. Here we show that nonspecific bystander inflammation conditions naive CD4(+) T cells for enhanced peripheral Foxp3 induction and reduced effector differentiation. This results in inhibition of immune responses in vivo via a Foxp3-dependent effect on antigen-specific naive CD4(+) T cell precursors. Such conditioning may have evolved to allow immunity to infection while limiting subsequent autoimmunity caused by release of self-antigens in the wake of infection. Furthermore, this phenomenon suggests a mechanistic explanation for the idea that early tuning of the immune system by infection affects the long-term quality of immune regulation.
Assuntos
Asma/imunologia , Autoimunidade/imunologia , Efeito Espectador/imunologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Diabetes Mellitus/imunologia , Fatores de Transcrição Forkhead/imunologia , Inflamação , Tolerância a Antígenos Próprios/imunologia , Animais , Autoantígenos , Efeito Espectador/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/efeitos dos fármacos , Citocinas/farmacologia , Metilação de DNA , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Perfilação da Expressão Gênica , Indutores de Interferon/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Tolerância Periférica/imunologia , Poli I-C/farmacologia , Regiões Promotoras Genéticas , Linfopoietina do Estroma do TimoRESUMO
Asthma is a chronic inflammatory airway disease associated with type 2 cytokines interleukin-4 (IL-4), IL-5, and IL-13, which promote airway eosinophilia, mucus overproduction, bronchial hyperresponsiveness (BHR), and immunogloubulin E (IgE) synthesis. However, only half of asthma patients exhibit signs of an exacerbated Type 2 response. "Type 2-low" asthma has different immune features: airway neutrophilia, obesity-related systemic inflammation, or in some cases, few signs of immune activation. Here, we review the cytokine networks driving asthma, placing these in cellular context and incorporating insights from cytokine-targeting therapies in the clinic. We discuss established and emerging paradigms in the context of the growing appreciation of disease heterogeneity and argue that the development of new and improved therapeutics will require understanding the diverse mechanisms underlying the spectrum of asthma pathologies.
Assuntos
Asma/imunologia , Citocinas/imunologia , Imunidade Adaptativa , Corticosteroides/uso terapêutico , Alérgenos/imunologia , Animais , Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Asma/classificação , Asma/tratamento farmacológico , Asma/fisiopatologia , Ensaios Clínicos como Assunto , Citocinas/antagonistas & inibidores , Células Epiteliais/imunologia , Humanos , Inflamação/imunologia , Interferons/imunologia , Camundongos , Camundongos Knockout , Modelos Imunológicos , Células Th2/imunologiaRESUMO
Naive CD4+ T cells differentiate into functionally diverse T helper (Th) cell subsets. Th2 cells play a pathogenic role in asthma, yet a clear picture of their transcriptional profile is lacking. We performed single-cell RNA sequencing (scRNA-seq) of T helper cells from lymph node, lung, and airways in the house dust mite (HDM) model of allergic airway disease. scRNA-seq resolved transcriptional profiles of naive CD4+ T, Th1, Th2, regulatory T (Treg) cells, and a CD4+ T cell population responsive to type I interferons. Th2 cells in the airways were enriched for transcription of many genes, including Cd200r1, Il6, Plac8, and Igfbp7, and their mRNA profile was supported by analysis of chromatin accessibility and flow cytometry. Pathways associated with lipid metabolism were enriched in Th2 cells, and experiments with inhibitors of key metabolic pathways supported roles for glucose and lipid metabolism. These findings provide insight into the differentiation of pathogenic Th2 cells in the context of allergy.