RESUMO
A principal purpose of type 2 immunity was thought to be defense against large parasites, but it also functions in the restoration of homeostasis, such as toxin clearance following snake bites. In other cases, like allergy, the type 2 T helper (Th2) cytokines and cells present in the environment are detrimental and cause diseases. In recent years, the recognition of cell heterogeneity within Th2-associated cell populations has revealed specific functions of cells with a particular phenotype or gene signature. In addition, here we discuss the recent data regarding heterogeneity of type 2 immunity-related cells, as well as their newly identified role in a variety of processes ranging from involvement in respiratory viral infections [especially in the context of the recent COVID-19 (coronavirus disease 2019) pandemic] to control of cancer development or of metabolic homeostasis.
Assuntos
COVID-19 , Hipersensibilidade , Animais , Citocinas/metabolismo , Homeostase , Humanos , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th2RESUMO
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/patologiaAssuntos
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
The causal signals and the relevance of group 2 innate lymphoid cell (ILC2) dynamic redistribution during inflammation remain unknown. In this issue of Immunity, Cautivo et al. show that type 2 immunity drives ILC2 accumulation at non-adventitial "parenchymal" sites, allowing balanced responses in inflamed tissues.
Assuntos
Imunidade Inata , Linfócitos , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Linfócitos/imunologiaRESUMO
In the version of this article initially published, the accession code for the RNA-seq data set deposited in the NCBI public repository Sequence Read Archive was missing from the 'Data availability' subsection of the Methods section. The accession code is SRP125477.
RESUMO
The immunology of the hygiene hypothesis of allergy is complex and involves the loss of cellular and humoral immunoregulatory pathways as a result of the adoption of a Western lifestyle and the disappearance of chronic infectious diseases. The influence of diet and reduced microbiome diversity now forms the foundation of scientific thinking on how the allergy epidemic occurred, although clear mechanistic insights into the process in humans are still lacking. Here we propose that barrier epithelial cells are heavily influenced by environmental factors and by microbiome-derived danger signals and metabolites, and thus act as important rheostats for immunoregulation, particularly during early postnatal development. Preventive strategies based on this new knowledge could exploit the diversity of the microbial world and the way humans react to it, and possibly restore old symbiotic relationships that have been lost in recent times, without causing disease or requiring a return to an unhygienic life style.
Assuntos
Epiderme/imunologia , Hipótese da Higiene , Hipersensibilidade/imunologia , Imunidade Adaptativa , Fatores Etários , Alérgenos/imunologia , Animais , Epiderme/metabolismo , Epiderme/microbiologia , Epitélio/imunologia , Epitélio/metabolismo , Epitélio/microbiologia , Humanos , Estilo de Vida , MicrobiotaRESUMO
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
Notch2 and B cell antigen receptor (BCR) signaling determine whether transitional B cells become marginal zone B (MZB) or follicular B (FoB) cells in the spleen, but it is unknown how these pathways are related. We generated Taok3-/- mice, lacking the serine/threonine kinase Taok3, and found cell-intrinsic defects in the development of MZB but not FoB cells. Type 1 transitional (T1) B cells required Taok3 to rapidly respond to ligation by the Notch ligand Delta-like 1. BCR ligation by endogenous or exogenous ligands induced the surface expression of the metalloproteinase ADAM10 on T1 B cells in a Taok3-dependent manner. T1 B cells expressing surface ADAM10 were committed to becoming MZB cells in vivo, whereas T1 B cells lacking expression of ADAM10 were not. Thus, during positive selection in the spleen, BCR signaling causes immature T1 B cells to become receptive to Notch ligands via Taok3-mediated surface expression of ADAM10.
Assuntos
Proteína ADAM10/metabolismo , Imunidade Adaptativa , Secretases da Proteína Precursora do Amiloide/metabolismo , Linfócitos B/fisiologia , Diferenciação Celular , Linhagem da Célula , Centro Germinativo/imunologia , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína ADAM10/genética , Secretases da Proteína Precursora do Amiloide/genética , Animais , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Regulação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética , Receptor Notch2/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de SinaisRESUMO
The initial molecular events and the cell type(s) responsible for the development of fibrosis are unclear. Fukushima, Satoh, et al. find that increased expression of the nuclear exosome targeting complex component Rbm7 in lung epithelial cells promotes the degradation of the long non-coding RNA NEAT1, impairs DNA repair, and triggers apoptosis. Dying epithelial cells release chemokines that recruit atypical monocytes, which drive tissue fibrosis.
Assuntos
Exossomos , RNA Longo não Codificante , Núcleo Celular , Fibrose , Humanos , Proteínas de Ligação a RNARESUMO
The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs.
Assuntos
Plasticidade Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunidade , Macrófagos/imunologia , Macrófagos/metabolismo , Infecções por Respirovirus/etiologia , Apresentação de Antígeno , Biomarcadores , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Imunofenotipagem , Interferon Tipo I/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Especificidade de Órgãos/imunologia , Receptores Fc/metabolismo , Infecções por Respirovirus/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fatores de Transcrição , Viroses/genética , Viroses/imunologia , Viroses/metabolismo , Viroses/virologiaRESUMO
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.
Assuntos
Asma/imunologia , Hipersensibilidade Respiratória/imunologia , Sistema Respiratório/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th2/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Modelos Animais de Doenças , Humanos , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Orexina/genética , Pyroglyphidae/imunologia , Análise de Sequência de RNA , Análise de Célula Única , TranscriptomaRESUMO
Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2 (TH2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the TH17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma.
Assuntos
Asma/imunologia , Animais , Asma/tratamento farmacológico , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Eosinófilos/citologia , Eosinófilos/imunologia , Humanos , Células Th17/citologia , Células Th17/imunologia , Células Th2/imunologiaRESUMO
Despite the lack of endogenous chitin synthesis, mammalian genomes encode two enzymatically active true chitinases (chitotriosidase and acidic mammalian chitinase) and a variable number of chitinase-like proteins (CLPs) that have no enzyme activity but bind chitin. Chitinases and CLPs are prominent components of type-2 immune response-mediated respiratory diseases. However, despite extensive research into their role in allergic airway disease, there is still no agreement on whether they are mere biomarkers of disease or actual disease drivers. Functions ascribed to chitinases and CLPs include, but are not limited to host defense against chitin-containing pathogens, directly promoting inflammation, and modulating tissue remodeling and fibrosis. Here, we discuss in detail the chitin-dependent and -independent roles of chitinases and CLPs in the context of allergic airway disease, and recent advances and emerging concepts in the field that might identify opportunities for new therapies.
Assuntos
Asma , Quitinases , Hipersensibilidade , Animais , Humanos , Quitinases/metabolismo , Inflamação , Quitina/metabolismo , Mamíferos/metabolismoRESUMO
Allergic disease originates in early life and polymorphisms in interleukin-33 gene (IL33) and IL1RL1, coding for IL-33R and decoy receptor sST2, confer allergy risk. Early life T helper 2 (Th2) cell skewing and allergy susceptibility are often seen as remnants of feto-maternal symbiosis. Here we report that shortly after birth, innate lymphoid type 2 cells (ILC2s), eosinophils, basophils, and mast cells spontaneously accumulated in developing lungs in an IL-33-dependent manner. During the phase of postnatal lung alveolarization, house dust mite exposure further increased IL-33, which boosted cytokine production in ILC2s and activated CD11b+ dendritic cells (DCs). IL-33 suppressed IL-12p35 and induced OX40L in neonatal DCs, thus promoting Th2 cell skewing. Decoy sST2 had a strong preventive effect on asthma in the neonatal period, less so in adulthood. Thus, enhanced neonatal Th2 cell skewing to inhaled allergens results from postnatal hyperactivity of the IL-33 axis during a period of maximal lung remodeling.
Assuntos
Asma/imunologia , Interleucina-33/imunologia , Pulmão/crescimento & desenvolvimento , Pulmão/imunologia , Células Th2/imunologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Hipersensibilidade/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pyroglyphidae/imunologia , Transdução de Sinais/imunologiaRESUMO
Interferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated "terminal selectors." Using BM chimeras, conditional Irf8(fl/fl) mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs.
Assuntos
Diferenciação Celular/fisiologia , Células Dendríticas/metabolismo , Células Dendríticas/fisiologia , Fatores Reguladores de Interferon/metabolismo , Fatores de Transcrição/metabolismo , Animais , Interferon Tipo I/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Monócitos/fisiologia , Regiões Promotoras Genéticas/fisiologia , Linfócitos T/metabolismo , Linfócitos T/fisiologiaRESUMO
BACKGROUND: Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5 and IL-13 cytokines produced by TH2 lymphocytes or type 2 innate lymphoid cells (ILC2s). Interleukin-2 family cytokines play a key role in the differentiation, homeostasis and effector function of innate and adaptive lymphocytes. OBJECTIVE: IL-9 and IL-21 boost the activation and proliferation of TH2 and ILC2s, but the relative importance and potential synergism between these γc cytokines is currently unknown. METHODS: Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination, in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human allergic asthmatics in comparison to non-asthmatic controls. Here, we also measured IL-21 in both groups. RESULTS: IL-9 played a central role in controlling innate IL-33 induced lung inflammation by promoting proliferation and activation of ILC2s, in an IL-21 independent manner. Conversely, chronic house dust mite induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, that controlled TH2 activation, eosinophilia, total serum IgE and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, since combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage (BAL) samples we measured elevated IL-21 protein within the allergic asthmatic group, compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets. CONCLUSION: IL-9 and IL-21 play important and non-redundant roles in allergic asthma by boosting ILC2s and TH2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.