RESUMO
Anemia is a major comorbidity in aging, chronic kidney and inflammatory diseases, and hematologic malignancies. However, the transcriptomic networks governing hematopoietic differentiation in blood cell development remain incompletely defined. Here we report that the atypical kinase RIOK2 (right open reading frame kinase 2) is a master transcription factor (TF) that not only drives erythroid differentiation, but also simultaneously suppresses megakaryopoiesis and myelopoiesis in primary human stem and progenitor cells. Our study reveals the previously uncharacterized winged helix-turn-helix DNA-binding domain and two transactivation domains of RIOK2 that are critical to regulate key hematopoietic TFs GATA1, GATA2, SPI1, RUNX3 and KLF1. This establishes RIOK2 as an integral component of the transcriptional regulatory network governing human hematopoietic differentiation. Importantly, RIOK2 mRNA expression significantly correlates with these TFs and other hematopoietic genes in myelodysplastic syndromes, acute myeloid leukemia and chronic kidney disease. Further investigation of RIOK2-mediated transcriptional pathways should yield therapeutic approaches to correct defective hematopoiesis in hematologic disorders.
Assuntos
Células Sanguíneas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Sequência de Aminoácidos , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Eritropoese/fisiologia , Regulação da Expressão Gênica/fisiologia , Células HEK293 , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células K562 , Leucemia Mieloide Aguda/metabolismo , Síndromes Mielodisplásicas/metabolismo , Mielopoese/fisiologia , Fatores de Transcrição/metabolismo , Transcrição Gênica/fisiologiaRESUMO
Patients with myelodysplastic syndromes (MDSs) display severe anemia but the mechanisms underlying this phenotype are incompletely understood. Right open-reading-frame kinase 2 (RIOK2) encodes a protein kinase located at 5q15, a region frequently lost in patients with MDS del(5q). Here we show that hematopoietic cell-specific haploinsufficient deletion of Riok2 (Riok2f/+Vav1cre) led to reduced erythroid precursor frequency leading to anemia. Proteomic analysis of Riok2f/+Vav1cre erythroid precursors suggested immune system activation, and transcriptomic analysis revealed an increase in p53-dependent interleukin (IL)-22 in Riok2f/+Vav1cre CD4+ T cells (TH22). Further, we discovered that the IL-22 receptor, IL-22RA1, was unexpectedly present on erythroid precursors. Blockade of IL-22 signaling alleviated anemia not only in Riok2f/+Vav1cre mice but also in wild-type mice. Serum concentrations of IL-22 were increased in the subset of patients with del(5q) MDS as well as patients with anemia secondary to chronic kidney disease. This work reveals a possible therapeutic opportunity for reversing many stress-induced anemias by targeting IL-22 signaling.
Assuntos
Anemia/metabolismo , Anticorpos Neutralizantes/farmacologia , Células Eritroides/metabolismo , Eritropoese/efeitos dos fármacos , Interleucinas/antagonistas & inibidores , Síndromes Mielodisplásicas/tratamento farmacológico , Receptores de Interleucina/metabolismo , Anemia/sangue , Anemia/imunologia , Anemia/prevenção & controle , Animais , Células Cultivadas , Microambiente Celular , Modelos Animais de Doenças , Células Eritroides/imunologia , Humanos , Interleucinas/imunologia , Interleucinas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Receptores de Interleucina/genética , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Interleucina 22RESUMO
Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function1-4. However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies5-8-induces endoplasmic reticulum stress and activates the IRE1α-XBP1 arm of the unfolded protein response9,10 in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1α-XBP1 activation that suppressed mitochondrial activity and IFNγ production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1α-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.
Assuntos
Endorribonucleases/metabolismo , Mitocôndrias/metabolismo , Neoplasias Ovarianas/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Proteína 1 de Ligação a X-Box/metabolismo , Sistemas de Transporte de Aminoácidos Básicos , Animais , Ascite/metabolismo , Respiração Celular , Progressão da Doença , Estresse do Retículo Endoplasmático , Feminino , Regulação Neoplásica da Expressão Gênica , Glucose/metabolismo , Glutamina/metabolismo , Glicosilação , Humanos , Interferon gama/biossíntese , Interferon gama/genética , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Neoplasias Ovarianas/patologia , Transdução de Sinais , Taxa de Sobrevida , Linfócitos T/metabolismo , Evasão Tumoral/imunologia , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box/biossíntese , Proteína 1 de Ligação a X-Box/deficiênciaRESUMO
The respiratory tract maintains immune homeostasis despite constant provocation by environmental Ags. Failure to induce tolerogenic responses to allergens incites allergic inflammation. Despite the understanding that APCs have a crucial role in maintaining immune tolerance, the underlying mechanisms are poorly understood. Using mice with a conditional deletion of peroxisome proliferator-activated receptor γ (PPARγ) in CD11c(+) cells, we show that PPARγ performs two critical functions in CD11c(+) cells to induce tolerance, thereby preserving immune homeostasis. First, PPARγ was crucial for the induction of retinaldehyde dehydrogenase (aldh1a2) selectively in CD103(+) dendritic cells, which we recently showed promotes Foxp3 expression in naive CD4(+) T cells. Second, in all CD11c(+) cells, PPARγ was required to suppress expression of the Th17-skewing cytokines IL-6 and IL-23p19. Also, lack of PPARγ in CD11c(+) cells induced p38 MAPK activity, which was recently linked to Th17 development. Thus, PPARγ favors immune tolerance by promoting regulatory T cell generation and blocking Th17 differentiation.
Assuntos
Hipersensibilidade/imunologia , Tolerância Imunológica , PPAR gama/imunologia , Sistema Respiratório/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/imunologia , Família Aldeído Desidrogenase 1 , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígeno CD11c/genética , Antígeno CD11c/imunologia , Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/patologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Homeostase , Hipersensibilidade/genética , Hipersensibilidade/patologia , Imunidade Inata , Cadeias alfa de Integrinas/genética , Cadeias alfa de Integrinas/imunologia , Subunidade p19 da Interleucina-23/genética , Subunidade p19 da Interleucina-23/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , Camundongos Knockout , PPAR gama/genética , Sistema Respiratório/patologia , Retinal Desidrogenase , Transdução de Sinais , Linfócitos T Reguladores/patologia , Células Th17/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologiaRESUMO
We reported previously that c-kit ligation by membrane-bound stem cell factor (mSCF) boosts IL-6 production in dendritic cells (DCs) and a Th17-immune response. However, Th17 establishment also requires heterodimeric IL-23, but the mechanisms that regulate IL-23 gene expression in DCs are not fully understood. We show that IL-23p19 gene expression in lung DCs is dependent on mSCF, which is regulated by the metalloproteinase MMP-9. Th1-inducing conditions enhanced MMP-9 activity, causing cleavage of mSCF, whereas the opposite was true for Th17-promoting conditions. In MMP-9(-/-) mice, a Th1-inducing condition could maintain mSCF and enhance IL-23p19 in DCs, promoting IL-17-producing CD4(+) T cells in the lung. Conversely, mSCF cleavage from bone marrow DCs in vitro by rMMP-9 led to reduced IL-23p19 expression under Th17-inducing conditions, with dampening of intracellular AKT phosphorylation. Collectively, these results show that the c-kit/mSCF/MMP-9 axis regulates IL-23 gene expression in DCs to control IL-17 production in the lung.
Assuntos
Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Interleucina-17/imunologia , Subunidade p19 da Interleucina-23/imunologia , Pulmão/imunologia , Metaloproteinase 9 da Matriz/imunologia , Fator de Células-Tronco/imunologia , Animais , Membrana Celular/genética , Membrana Celular/imunologia , Membrana Celular/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Regulação da Expressão Gênica/genética , Interleucina-17/genética , Interleucina-17/metabolismo , Subunidade p19 da Interleucina-23/biossíntese , Subunidade p19 da Interleucina-23/genética , Pulmão/citologia , Pulmão/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Fosforilação/genética , Fosforilação/imunologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Células-Tronco/genética , Fator de Células-Tronco/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismoRESUMO
As its central immunomodulatory effects, CD40 induces interleukin (IL)-12-dependent antitumor immune responses; as its local protumor effects, CD40 induces the expression of vascular endothelial growth factor (VEGF) that promotes tumor angiogenesis and growth. Therefore, using a previously established tumor model in mouse, we examined if the antitumor functions of CD40 are self-limited by VEGF induction. We observed that as the tumor mass grew during day 6 to day 18, VEGF expression in the tumor peaked with concomitant decrease in expressions of CD40 and IL-12 but not of IL-10. Among the angiogenic factors, VEGF-B, VEGFR-1, VEGFR-2, angiopoietin-1 and Tie2 expressions decreased, whereas the expressions of angiopoietin-2 and angiopoietin-3 increased with tumor growth. As significant changes in the expressions of these factors were observed on day 6, we treated the tumor-bearing mice with the agonistic anti-CD40 antibody or neutralizing anti-VEGF antibody-alone or in combination-from the fifth day after the injection of tumor cells. The anti-VEGF antibody significantly enhanced the antitumor effects of the anti-CD40 antibody, as observed through increased survival of the mice, accompanied by reduced angiogenesis and angiopoietin-2 expression but higher T-cell proliferation in response to tumor antigens, increased interferon-γ production and tumor cell cytotoxicity and higher levels of tumor antigen-specific serum IgM, IgG1 and IgG2a, indicating B-cell activation. Thus, our data show for the first time that the combined treatment with an agonistic anti-CD40 antibody and a neutralizing anti-VEGF antibody, which increases antitumor immune response or reduces local angiogenesis, respectively, is a novel antitumor strategy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígenos CD40/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anticorpos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígenos CD40/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/efeitos dos fármacos , Linfócitos T/fisiologia , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Respiratory syncytial virus (RSV) infects almost all infants by 2 years of age, and severe bronchiolitis resulting from RSV infection is the primary cause of hospitalization in the first year of life. Among infants hospitalized due to RSV-induced bronchiolitis, those with a specific mutation in the chemokine receptor CX3CR1, which severely compromises binding of its ligand CX3CL1, were at a higher risk for more severe viral bronchiolitis than those without the mutation. Here, we show that RSV infection of newborn mice deficient in CX3CR1 leads to significantly greater neutrophilic inflammation in the lungs, accompanied by an increase in mucus production compared with that induced in WT mice. Analysis of innate and adaptive immune responses revealed an early increase in the number of IL-17+ γδ T cells in CX3CR1-deficient mice that outnumbered IFN-γ+ γδ T cells as well as IFN-γ+ NK cells, IFN-γ being host protective in the context of RSV infection. This bias toward IL-17+ γδ T cells persisted at a later time. The lungs of CX3CR1-deficient mice expressed higher levels of IL-1ß mRNA and protein, and blockade of IL-1ß signaling using IL-1 receptor antagonist significantly reduced the number of IL-17+ γδ T cells in the lungs of infected mice. Blockade of IL-17RC abolished RSV-induced lung pathology in infected CX3CR1-deficient mice. We propose that, in infants harboring mutant CX3CR1, targeting the IL-17R may minimize disease severity and hospitalization in early life.
Assuntos
Animais Recém-Nascidos , Receptor 1 de Quimiocina CX3C/genética , Imunidade Inata , Pulmão/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Animais , Interleucina-17/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos , RNA Mensageiro/metabolismo , Transdução de SinaisRESUMO
We previously showed that Th1/type 1 inflammation marked by increased IFN-γ levels in the airways can be appreciated in 50% of patients with severe asthma, despite high dose corticosteroid (CS) treatment. We hypothesized that a downstream target of IFN-γ, CXCL10, which recruits Th1 cells via the cognate receptor CXCR3, is an important contributor to Th1high asthma and CS unresponsiveness. We show high levels of CXCL10 mRNA closely associated with IFNG levels in the BAL cells of 50% of severe asthmatics and also in the airways of mice subjected to a severe asthma model, both in the context of high-dose CS treatment. The inability of CS to dampen IFNG or CXCL10 expression was not because of impaired nuclear translocation of the glucocorticoid receptor (GR) or its transactivational functions. Rather, in the presence of CS and IFN-γ, STAT1 and GR were recruited on critical regulatory elements in the endogenous CXCL10 promoter in monocytes, albeit without any abatement of CXCL10 gene expression. High CXCL10 gene expression was also associated with a mast cell signature in both humans and mice, CXCR3 being also expressed by mast cells. These findings suggest that the IFN-γ-CXCL10 axis plays a central role in persistent type 1 inflammation that may be facilitated by CS therapy through GR-STAT1 cooperation converging on the CXCL10 promoter.
RESUMO
Severe asthma (SA) is a significant problem both clinically and economically, given its poor response to corticosteroids (CS). We recently reported a complex type 1-dominated (IFN-γ-dominated) immune response in more than 50% of severe asthmatics despite high-dose CS treatment. Also, IFN-γ was found to be critical for increased airway hyperreactivity (AHR) in our model of SA. The transcription factor IRF5 expressed in M1 macrophages can induce a Th1/Th17 response in cocultured human T cells. Here we show markedly higher expression of IRF5 in bronchoalveolar lavage (BAL) cells of severe asthmatics as compared with that in cells from milder asthmatics or healthy controls. Using our SA mouse model, we demonstrate that lack of IRF5 in lymph node migratory DCs severely limits their ability to stimulate the generation of IFN-γ- and IL-17-producing CD4+ T cells and IRF5-/- mice subjected to the SA model displayed significantly lower IFN-γ and IL-17 responses, albeit showing a reciprocal increase in Th2 response. However, the absence of IRF5 rendered the mice responsive to CS with suppression of the heightened Th2 response. These data support the notion that IRF5 inhibition in combination with CS may be a viable approach to manage disease in a subset of severe asthmatics.
RESUMO
Bacterial pneumonia is a significant healthcare burden worldwide. Failure to resolve inflammation after infection precipitates lung injury and an increase in morbidity and mortality. Gram-negative bacteria are common in pneumonia and increased levels of the mito-damage-associated molecular pattern (DAMP) cardiolipin can be detected in the lungs. Here we show that mice infected with Klebsiella pneumoniae develop lung injury with accumulation of cardiolipin. Cardiolipin inhibits resolution of inflammation by suppressing production of anti-inflammatory IL-10 by lung CD11b+Ly6GintLy6CloF4/80+ cells. Cardiolipin induces PPARγ SUMOylation, which causes recruitment of a repressive NCOR/HDAC3 complex to the IL-10 promoter, but not the TNF promoter, thereby tipping the balance towards inflammation rather than resolution. Inhibition of HDAC activity by sodium butyrate enhances recruitment of acetylated histone 3 to the IL-10 promoter and increases the concentration of IL-10 in the lungs. These findings identify a mechanism of persistent inflammation during pneumonia and indicate the potential of HDAC inhibition as a therapy.
Assuntos
Cardiolipinas/fisiologia , Inflamação/metabolismo , Interleucina-10/biossíntese , Infecções por Klebsiella/fisiopatologia , Klebsiella pneumoniae/isolamento & purificação , Pneumonia Bacteriana/metabolismo , Animais , Cardiolipinas/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Interleucina-10/genética , Interleucina-10/metabolismo , Infecções por Klebsiella/microbiologia , Lipopolissacarídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Supressoras Mieloides/imunologia , Oxirredução , PPAR gama/agonistas , PPAR gama/metabolismo , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/patologia , Regiões Promotoras Genéticas , Células RAW 264.7 , Sumoilação , Fator de Necrose Tumoral alfa/genéticaRESUMO
The term asthma encompasses a disease spectrum with mild to very severe disease phenotypes whose traditional common characteristic is reversible airflow limitation. Unlike milder disease, severe asthma is poorly controlled by the current standard of care. Ongoing studies using advanced molecular and immunological tools along with improved clinical classification show that severe asthma does not identify a specific patient phenotype, but rather includes patients with constant medical needs, whose pathobiologic and clinical characteristics vary widely. Accordingly, in recent clinical trials, therapies guided by specific patient characteristics have had better outcomes than previous therapies directed to any subject with a diagnosis of severe asthma. However, there are still significant gaps in our understanding of the full scope of this disease that hinder the development of effective treatments for all severe asthmatics. In this Review, we discuss our current state of knowledge regarding severe asthma, highlighting different molecular and immunological pathways that can be targeted for future therapeutic development.
Assuntos
Asma/imunologia , Interferon gama/imunologia , Animais , Antiasmáticos/uso terapêutico , Asma/sangue , Asma/terapia , Exposição Ambiental , Humanos , Sistema Imunitário , Inflamação , Fenótipo , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Inhalation of environmental antigens such as allergens does not always induce inflammation in the respiratory tract. While antigen-presenting cells (APCs), including dendritic cells and macrophages, take up inhaled antigens, the cell-intrinsic molecular mechanisms that prevent an inflammatory response during this process, such as activation of the transcription factor NF-κB, are not well understood. Here, we show that the nuclear receptor PPARγ plays a critical role in blocking NF-κB activation in response to inhaled antigens to preserve immune tolerance. Tolerance induction promoted mitochondrial respiration, generation of H2O2, and suppression of NF-κB activation in WT, but not PPARγ-deficient, APCs. Forced restoration of H2O2 in PPARγ-deficient cells suppressed IκBα degradation and NF-κB activation. Conversely, scavenging reactive oxygen species from mitochondria promoted IκBα degradation with loss of regulatory and promotion of inflammatory T cell responses in vivo. Thus, communication between PPARγ and the mitochondria maintains immune quiescence in the airways.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Peróxido de Hidrogênio/metabolismo , Pulmão/citologia , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Animais , Antígeno CD11c/metabolismo , Proliferação de Células , Citocinas/genética , Células Dendríticas/metabolismo , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Tolerância Imunológica , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos C57BL , PPAR gama/deficiência , PPAR gama/metabolismo , Regiões Promotoras Genéticas/genética , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/citologiaRESUMO
Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng-/- mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra-/- mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.
Assuntos
Asma/imunologia , Regulação da Expressão Gênica/imunologia , Interferon gama/imunologia , Inibidor Secretado de Peptidases Leucocitárias/imunologia , Células Th2/imunologia , Adolescente , Adulto , Animais , Asma/genética , Asma/patologia , Lavagem Broncoalveolar , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Interferon gama/genética , Interleucina-17/genética , Interleucina-17/imunologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Pessoa de Meia-Idade , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologia , Inibidor Secretado de Peptidases Leucocitárias/genética , Índice de Gravidade de Doença , Células Th1/imunologia , Células Th1/patologia , Células Th2/patologiaRESUMO
Immune tolerance is instituted early in life, during which time regulatory T (T(reg)) cells have an important role. Recurrent infections with respiratory syncytial virus (RSV) in early life increase the risk for asthma in adult life. Repeated infection of infant mice tolerized to ovalbumin (OVA) through their mother's milk with RSV induced allergic airway disease in response to OVA sensitization and challenge, including airway inflammation, hyper-reactivity and higher OVA-specific IgE, as compared to uninfected tolerized control mice. Virus infection induced GATA-3 expression and T helper type 2 (T(H)2) cytokine production in forkhead box P3 (FOXP3)(+) T(reg) cells and compromised the suppressive function of pulmonary T(reg) cells in a manner that was dependent on interleukin-4 receptor α (IL-4Rα) expression in the host. Thus, by promoting a T(H)2-type inflammatory response in the lung, RSV induced a T(H)2-like effector phenotype in T(reg) cells and attenuated tolerance to an unrelated antigen (allergen). Our findings highlight a mechanism by which viral infection targets a host-protective mechanism in early life and increases susceptibility to allergic disease.