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Metastasis constitutes the primary cause of cancer-related deaths, with the lung being a commonly affected organ. We found that activation of lung-resident group 2 innate lymphoid cells (ILC2s) orchestrated suppression of natural killer (NK) cell-mediated innate antitumor immunity, leading to increased lung metastases and mortality. Using multiple models of lung metastasis, we show that interleukin (IL)-33-dependent ILC2 activation in the lung is involved centrally in promoting tumor burden. ILC2-driven innate type 2 inflammation is accompanied by profound local suppression of interferon-γ production and cytotoxic function of lung NK cells. ILC2-dependent suppression of NK cells is elaborated via an innate regulatory mechanism, which is reliant on IL-5-induced lung eosinophilia, ultimately limiting the metabolic fitness of NK cells. Therapeutic targeting of IL-33 or IL-5 reversed NK cell suppression and alleviated cancer burden. Thus, we reveal an important function of IL-33 and ILC2s in promoting tumor metastasis via their capacity to suppress innate type 1 immunity.
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Eosinófilos/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Pulmão/imunologia , Linfócitos/imunologia , Animais , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Humanos , Tolerância Imunológica , Imunidade Inata , Interleucina-33/metabolismo , Interleucina-5/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Células Th2/imunologiaRESUMO
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
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.
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Asthma is a T helper 2 (Th2)-cell-mediated disease; however, recent findings implicate Th17 and innate lymphoid cells also in regulating airway inflammation. Herein, we have demonstrated profound interleukin-21 (IL-21) production after house dust mite (HDM)-driven asthma by using T cell receptor (TCR) transgenic mice reactive to Dermatophagoides pteronyssinus 1 and an IL-21GFP reporter mouse. IL-21-producing cells in the mediastinal lymph node (mLN) bore characteristics of T follicular helper (Tfh) cells, whereas IL-21(+) cells in the lung did not express CXCR5 (a chemokine receptor expressed by Tfh cells) and were distinct from effector Th2 or Th17 cells. Il21r(-/-) mice developed reduced type 2 responses and the IL-21 receptor (IL-21R) enhanced Th2 cell function in a cell-intrinsic manner. Finally, administration of recombinant IL-21 and IL-25 synergistically promoted airway eosinophilia primarily via effects on CD4(+) lymphocytes. This highlights an important Th2-cell-amplifying function of IL-21-producing CD4(+) T cells in allergic airway inflammation.
Assuntos
Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Eosinofilia/imunologia , Eosinófilos/efeitos dos fármacos , Pulmão/imunologia , Receptores de Interleucina-21/administração & dosagem , Células Th2/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Células Cultivadas , Cisteína Endopeptidases/imunologia , Eosinófilos/imunologia , Imunidade Celular , Interleucinas/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pyroglyphidae/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores CXCR5/metabolismo , Receptores de Interleucina-21/genéticaRESUMO
Dendritic cells (DCs) are critical for the activation of naïve CD4+ T cells and are considered professional antigen-presenting cells (APCs), as are macrophages and B cells. Recently, several innate type 2 immune cells, such as basophils, mast cells (MCs), eosinophils, and innate type 2 lymphocytes (ILC2), have also emerged as harboring APC behavior. Through surface expression or transfer of peptide-loaded MHCII, expression of costimulatory and co-inhibitory molecules, as well as the secretion of polarizing cytokines, these innate cells can extensively communicate with effector and regulatory CD4+ T cells. An exciting new concept is that the complementary tasks of these 'amateur' APCs contribute to shaping and regulating adaptive immunity to allergens and helminths, often in collaboration with professional APCs.
Assuntos
Imunidade Adaptativa/imunologia , Células Apresentadoras de Antígenos/imunologia , Linfócitos/imunologia , Alérgenos/imunologia , Animais , Células Dendríticas/imunologia , HumanosRESUMO
Rationale: Emerging evidence supports a crucial role for tertiary lymphoid organs (TLOs) in chronic obstructive pulmonary disease (COPD) progression. However, mechanisms of immune cell activation leading to TLOs in COPD remain to be defined.Objectives: To examine the role of lung dendritic cells (DCs) in T follicular helper (Tfh)-cell induction, a T-cell subset critically implicated in lymphoid organ formation, in COPD.Methods: Myeloid cell heterogeneity and phenotype were studied in an unbiased manner via single-cell RNA sequencing on HLA-DR+ cells sorted from human lungs. We measured the in vitro capability of control and COPD lung DC subsets, sorted using a fluorescence-activated cell sorter, to polarize IL-21+CXCL13+ (IL-21-positive and C-X-C chemokine ligand type 13-positive) Tfh-like cells. In situ imaging analysis was performed on Global Initiative for Chronic Obstructive Lung Disease stage IV COPD lungs with TLOs.Measurements and Main Results: Single-cell RNA-sequencing analysis revealed a high degree of heterogeneity among human lung myeloid cells. Among these, conventional dendritic type 2 cells (cDC2s) showed increased induction of IL-21+CXCL13+ Tfh-like cells. Importantly, the capacity to induce IL-21+ Tfh-like cells was higher in cDC2s from patients with COPD than in those from control patients. Increased Tfh-cell induction by COPD cDC2s correlated with increased presence of Tfh-like cells in COPD lungs as compared with those in control lungs, and cDC2s colocalized with Tfh-like cells in TLOs of COPD lungs. Mechanistically, cDC2s exhibited a unique migratory signature and (transcriptional) expression of several pathways and genes related to DC-induced Tfh-cell priming. Importantly, blocking the costimulatory OX40L (OX40 ligand)-OX40 axis reduced Tfh-cell induction by control lung cDC2s.Conclusions: In COPD lungs, we found lung EBI2+ (Epstein-Barr virus-induced gene 2-positive) OX-40L-expressing cDC2s that induced IL-21+ Tfh-like cells, suggesting an involvement of these cells in TLO formation.
Assuntos
Células Dendríticas/imunologia , Pulmão/citologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/imunologia , Estruturas Linfoides Terciárias/etiologia , Idoso , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
BACKGROUND: The emergence of IL-33 as a key molecular player in the development and propagation of widespread inflammatory diseases, including asthma and atopic dermatitis, has established the need for effective IL-33-neutralizing biologics. OBJECTIVE: Here we describe the development and validation of a new antagonist of IL-33, termed IL-33trap, which combines the extracellular domains of the IL-33 receptor (ST2) and its coreceptor, IL-1 receptor accessory protein, into a single fusion protein. METHODS: We produced and purified recombinant IL-33trap from human cells and analyzed its IL-33-binding affinity and IL-33 antagonistic activity in cultured cells and mice. IL-33trap activity was also benchmarked with a recombinant soluble ST2 corresponding to the naturally occurring IL-33 decoy receptor. Finally, we studied the effect of IL-33trap in the Alternaria alternata mouse model of allergic airway inflammation. RESULTS: In vitro IL-33trap binds IL-33 and inhibits IL-33 activity to a much stronger degree than soluble ST2. Furthermore, IL-33trap inhibits eosinophil infiltration, splenomegaly, and production of signature cytokines in splenic lymphocytes and lung tissue on IL-33 injection. Finally, administration of IL-33trap at the time of allergen challenge inhibits inflammatory responses in a preclinical mouse model of acute allergic airway inflammation. CONCLUSIONS: IL-33trap is a novel IL-33 antagonist that outperforms the natural IL-33 decoy receptor and shows anti-inflammatory activities in a preclinical mouse model of acute allergic airway inflammation when administered at the time of allergen challenge.
Assuntos
Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Interleucina-33/antagonistas & inibidores , Alternaria/imunologia , Animais , Asma/imunologia , Produtos Biológicos/farmacologia , Células Cultivadas , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Células HEK293 , Humanos , Interleucina-33/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
BACKGROUND: It is currently unknown why allergen exposure or environmental triggers in patients with mild-to-moderate asthma result in TH2-mediated eosinophilic inflammation, whereas patients with severe asthma often present with TH17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both TH2 and TH17 cell differentiation and is mediated through nuclear factor κB activation. Ablation of TNF-α-induced protein 3 (TNFAIP3), one of the crucial negative regulators of nuclear factor κB activation in myeloid cells and DCs, was shown to control DC activation. OBJECTIVE: In this study we investigated the precise role of TNFAIP3 in myeloid cells for the development of TH2- and TH17-cell mediated asthma. METHODS: We exposed mice with conditional deletion of the Tnfaip3 gene in either myeloid cells (by using the lysozyme M [LysM] promotor) or specifically in DCs (by using the Cd11c promotor) to acute and chronic house dust mite (HDM)-driven asthma models. RESULTS: We demonstrated that reduced Tnfaip3 gene expression in DCs in either Tnfaip3CD11c or Tnfaip3LysM mice dose-dependently controlled development of TH17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wild-type mice had a purely TH2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific TH17 cell differentiation through increased expression of the TH17-instructing cytokines IL-1ß, IL-6, and IL-23, whereas HDM-specific TH2 cell differentiation was hampered by increased IL-12 and IL-6 production. CONCLUSIONS: These data show that the extent of TNFAIP3 expression in DCs controls TH2/TH17 cell differentiation. This implies that reducing DC activation could be a new pharmacologic intervention to treat patients with severe asthma who present with TH17-mediated neutrophilic inflammation.
Assuntos
Asma/metabolismo , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Pulmão/imunologia , Células Th17/imunologia , Células Th2/imunologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/imunologia , Alérgenos/imunologia , Animais , Citocinas/imunologia , Eosinófilos/imunologia , Feminino , Inflamação/imunologia , Mediadores da Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Neutrófilos/imunologia , Pyroglyphidae/imunologia , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A20 negatively regulates multiple inflammatory signalling pathways. We here addressed the role of A20 in club cells (also known as Clara cells) of the bronchial epithelium in their response to influenza A virus infection. Club cells provide a niche for influenza virus replication, but little is known about the functions of these cells in antiviral immunity. Using airway epithelial cell-specific A20 knockout (A20AEC-KO) mice, we show that A20 in club cells critically controls innate immune responses upon TNF or double stranded RNA stimulation. Surprisingly, A20AEC-KO mice are better protected against influenza A virus challenge than their wild type littermates. This phenotype is not due to decreased viral replication. Instead host innate and adaptive immune responses and lung damage are reduced in A20AEC-KO mice. These attenuated responses correlate with a dampened cytotoxic T cell (CTL) response at later stages during infection, indicating that A20AEC-KO mice are better equipped to tolerate Influenza A virus infection. Expression of the chemokine CCL2 (also named MCP-1) is particularly suppressed in the lungs of A20AEC-KO mice during later stages of infection. When A20AEC-KO mice were treated with recombinant CCL2 the protective effect was abrogated demonstrating the crucial contribution of this chemokine to the protection of A20AEC-KO mice to Influenza A virus infection. Taken together, we propose a mechanism of action by which A20 expression in club cells controls inflammation and antiviral CTL responses in response to influenza virus infection.
Assuntos
Cisteína Endopeptidases/imunologia , Citotoxicidade Imunológica/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Infecções por Orthomyxoviridae/imunologia , Mucosa Respiratória/imunologia , Animais , Cisteína Endopeptidases/deficiência , Citometria de Fluxo , Imunidade Inata/imunologia , Immunoblotting , Imuno-Histoquímica , Vírus da Influenza A , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase , Linfócitos T Citotóxicos/imunologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfaRESUMO
Chronic helminth infection with Schistosoma (S.) mansoni protects against allergic airway inflammation (AAI) in mice and is associated with reduced Th2 responses to inhaled allergens in humans, despite the presence of schistosome-specific Th2 immunity. Schistosome eggs strongly induce type 2 immunity and allow to study the dynamics of Th2 versus regulatory responses in the absence of worms. Treatment with isolated S. mansoni eggs by i.p. injection prior to induction of AAI to ovalbumin (OVA)/alum led to significantly reduced AAI as assessed by less BAL and lung eosinophilia, less cellular influx into lung tissue, less OVA-specific Th2 cytokines in lungs and lung-draining mediastinal lymph nodes and less circulating allergen-specific IgG1 and IgE antibodies. While OVA-specific Th2 responses were inhibited, treatment induced a strong systemic Th2 response to the eggs. The protective effect of S. mansoni eggs was unaltered in µMT mice lacking mature (B2) B cells and unaffected by Treg cell depletion using anti-CD25 blocking antibodies during egg treatment and allergic sensitization. Notably, prophylactic egg treatment resulted in a reduced influx of pro-inflammatory, monocyte-derived dendritic cells into lung tissue of allergic mice following challenge. Altogether, S. mansoni eggs can protect against the development of AAI, despite strong egg-specific Th2 responses.
Assuntos
Anticorpos Antiprotozoários/sangue , Asma/prevenção & controle , Óvulo/imunologia , Schistosoma mansoni/imunologia , Alérgenos/imunologia , Compostos de Alúmen/farmacologia , Animais , Anticorpos Antiprotozoários/imunologia , Asma/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Eosinofilia/prevenção & controle , Feminino , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Inflamação/patologia , Subunidade alfa de Receptor de Interleucina-2 , Pulmão/imunologia , Pulmão/parasitologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Ovalbumina/farmacologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologiaRESUMO
BACKGROUND: Allergic asthma is a CD4 TH2-lymphocyte driven disease characterized by airway hyperresponsiveness and eosinophilia. B cells can present antigens to CD4 T cells and produce IgE immunoglobulins that arm effector cells; however, mouse models are inconclusive on whether B cells are necessary for asthma development. OBJECTIVES: We sought to address the role of B cells in a house dust mite (HDM)-driven TH2-high asthma mouse model. METHODS: Wild-type and B cell-deficient muMT mice were sensitized and challenged through the airways with HDM extracts. The antigen-presenting capacities of B cells were studied by using new T-cell receptor transgenic 1-DER mice specific for the Der p 1 allergen. RESULTS: In vitro-activated B cells from HDM-exposed mice presented antigen to 1-DER T cells and induced a TH2 phenotype. In vivo B cells were dispensable for activation of naive 1-DER T cells but necessary for full expansion of primed 1-DER T cells. At high HDM challenge doses, B cells were not required for development of pulmonary asthmatic features yet contributed to TH2 expansion in the mediastinal lymph nodes but not in the lungs. When the amount of challenge allergen was decreased, muMT mice had reduced asthma features. Under these limiting conditions, B cells contributed also to expansion of TH2 effector cells in the lungs and central memory T cells in the mediastinal lymph nodes. CONCLUSION: B cells are a major part of the adaptive immune response to inhaled HDM allergen, particularly when the amount of inhaled allergen is low, by expanding allergen-specific T cells.
Assuntos
Antígenos de Dermatophagoides/imunologia , Asma/imunologia , Linfócitos B/imunologia , Células Th2/imunologia , Animais , Apresentação de Antígeno , Citocinas/imunologia , Linfonodos/citologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pyroglyphidae/imunologia , Baço/citologiaRESUMO
Immunotherapy advances have been hindered by difficulties in tracking the behaviors of lymphocytes after antigen signaling. Here, we assessed the behavior of T cells active within tumors through the development of the antigen receptor signaling reporter (AgRSR) mouse, fate-mapping lymphocytes responding to antigens at specific times and locations. Contrary to reports describing the ready egress of T cells out of the tumor, we find that intratumoral antigen signaling traps CD8+ T cells in the tumor. These clonal populations expand and become increasingly exhausted over time. By contrast, antigen-signaled regulatory T cell (Treg) clonal populations readily recirculate out of the tumor. Consequently, intratumoral antigen signaling acts as a gatekeeper to compartmentalize CD8+ T cell responses, even within the same clonotype, thus enabling exhausted T cells to remain confined to a specific tumor tissue site.
Assuntos
Linfócitos T CD8-Positivos , Transdução de Sinais , Animais , Linfócitos T CD8-Positivos/imunologia , Camundongos , Transdução de Sinais/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Antígenos de Neoplasias/imunologia , Neoplasias/imunologiaRESUMO
Regulatory T cells (Tregs) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident Tregs and group 2 innate lymphoid cells (ILC2s); however, how Tregs locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of Treg function. Using spatial, cellular, and molecular profiling of the type 2 inflamed niche, we found that ILC2s and Tregs engage in a direct (OX40L-OX40) and chemotaxis-dependent (CCL1-CCR8) cellular dialogue that enforces the local accumulation of Gata3high Tregs, which are transcriptionally and functionally adapted to the type 2 environment. Genetic interruption of ILC2-Treg communication resulted in uncontrolled type 2 lung inflammation after allergen exposure. Mechanistically, we found that Gata3high Tregs can modulate the local bioavailability of the costimulatory molecule OX40L, which subsequently controlled effector memory T helper 2 cell numbers. Hence, ILC2-Treg interactions represent a critical feedback mechanism to control adaptive type 2 immunity.
Assuntos
Imunidade Adaptativa , Fator de Transcrição GATA3 , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Fator de Transcrição GATA3/imunologia , Fator de Transcrição GATA3/metabolismo , Camundongos , Imunidade Adaptativa/imunologia , Linfócitos/imunologia , Imunidade Inata/imunologia , Camundongos Knockout , Células Th2/imunologia , FemininoRESUMO
The prevalence of allergic disease has increased significantly over the past decades. Although allergies are inherently multifactorial and heterogenous; environmental, maternal, and early-life microbial exposures could strongly modify disease risk. The effects of environmental microbiota are illustrated by the "farm effect", showing protection against asthma when children grow up on traditional farms. Recent studies have further revealed an important role for early-life exposure to a microbe-rich environment imposing lung and gut microbiome maturation and immune education, preventing allergic disease in childhood. Advances are made in the field of immunology and microbiome research, which identified entire microbial taxa, as well as specific microbial metabolites and bacterial products associated with reducing disease risk. Here we discuss the cross-talk between the microbiota and the pathogenesis of allergic disease, including bacterial products as lipopolysaccharide and CpG, in the farm effect.
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An elevated neutrophil-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.
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Natural killer (NK) cells are critical to immune surveillance against infections and cancer. Their role in immune surveillance requires that NK cells are present within tissues in a quiescent state. Mechanisms by which NK cells remain quiescent in tissues are incompletely elucidated. The transcriptional repressor BACH2 plays a critical role within the adaptive immune system, but its function within innate lymphocytes has been unclear. Here, we show that BACH2 acts as an intrinsic negative regulator of NK cell maturation and function. BACH2 is expressed within developing and mature NK cells and promotes the maintenance of immature NK cells by restricting their maturation in the presence of weak stimulatory signals. Loss of BACH2 within NK cells results in accumulation of activated NK cells with unrestrained cytotoxic function within tissues, which mediate augmented immune surveillance to pulmonary cancer metastasis. These findings establish a critical function of BACH2 as a global negative regulator of innate cytotoxic function and tumor immune surveillance by NK cells.
Assuntos
Antineoplásicos , Neoplasias , Fatores de Transcrição de Zíper de Leucina Básica/genética , Humanos , Imunidade Inata , Células Matadoras NaturaisRESUMO
Eosinophils are typically a minority population of circulating granulocytes being released from the bone-marrow as terminally differentiated cells. Besides their function in the defense against parasites and in promoting allergic airway inflammation, regulatory functions have now been attributed to eosinophils in various organs. Although eosinophils are involved in the inflammatory response to allergens, it remains unclear whether they are drivers of the asthma pathology or merely recruited effector cells. Recent findings highlight the homeostatic and pro-resolving capacity of eosinophils and raise the question at what point in time their function is regulated. Similarly, eosinophils from different physical locations display phenotypic and functional diversity. However, it remains unclear whether eosinophil plasticity remains as they develop and travel from the bone marrow to the tissue, in homeostasis or during inflammation. In the tissue, eosinophils of different ages and origin along the inflammatory trajectory may exhibit functional diversity as circumstances change. Herein, we outline the inflammatory time line of allergic airway inflammation from acute, late, adaptive to chronic processes. We summarize the function of the eosinophils in regards to their resident localization and time of recruitment to the lung, in all stages of the inflammatory response. In all, we argue that immunological differences in eosinophils are a function of time and space as the allergic inflammatory response is initiated and resolved.
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Eosinófilos/imunologia , Hipersensibilidade/imunologia , Pulmão/citologia , Animais , Humanos , Inflamação/imunologia , Pulmão/imunologia , Células Th2/imunologiaRESUMO
Group 2 innate lymphoid cells (ILC2) are innate immune cells that respond rapidly to their environment through soluble inflammatory mediators and cell-to-cell interactions. As tissue-resident sentinels, ILC2 help orchestrate localized type 2 immune responses. These ILC2-driven type 2 responses are now recognized in diverse immune processes, different anatomical locations, and homeostatic or pathological settings. ILC2-derived cytokines and cell surface signaling molecules function as key regulators of innate and adaptive immunity. Conversely, ILC2 are governed by their environment. As such, ILC2 form an important nexus of the immune system and may present an attractive target for immune modulation in disease.
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Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Subpopulações de Linfócitos/imunologia , Animais , Diferenciação Celular , Citocinas/imunologia , Hormônios/imunologia , Humanos , Interleucinas/imunologia , Lipídeos/imunologia , Ativação Linfocitária , Subpopulações de Linfócitos/classificação , Subpopulações de Linfócitos/citologia , Camundongos , Modelos Imunológicos , Neuroimunomodulação , Especificidade de Órgãos , Receptores Imunológicos/imunologia , Linfopoietina do Estroma do TimoRESUMO
Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease.
Assuntos
Cistatinas/imunologia , Proteínas de Helminto/imunologia , Inflamação/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Linfócitos T Reguladores/imunologia , Animais , Bronquiolite/complicações , Bronquiolite/imunologia , Bronquiolite/prevenção & controle , Linhagem Celular Tumoral , Cistatinas/farmacologia , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Helminto/farmacologia , Humanos , Fatores Imunológicos/farmacologia , Inflamação/complicações , Inflamação/prevenção & controle , Interleucina-10/imunologia , Interleucina-10/metabolismo , Camundongos , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/fisiologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismoRESUMO
Nanomaterials hold potential of altering the interaction between therapeutic molecules and target cells or tissues. High aspect ratio nanomaterials in particular have been reported to possess unprecedented properties and are intensively investigated for their interaction with biological systems. Graphene oxide (GOx) is a water-soluble graphene derivative that combines high aspect ratio dimension with functional groups that can be exploited for bioconjugation. Here, we demonstrate that GOx nanosheets can spontaneously adsorb proteins by a combination of interactions. This property is then explored for intracellular protein vaccine delivery, in view of the potential of GOx nanosheets to destabilize lipid membranes such as those of intracellular vesicles. Using a series of in vitro experiments, we show that GOx nanosheet adsorbed proteins are efficiently internalized by dendritic cells (DCs: the most potent class of antigen presenting cells of the immune system) and promote antigen cross-presentation to CD8 T cells. The latter is a hallmark in the induction of potent cellular antigen-specific immune responses against intracellular pathogens and cancer.