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Tissue macrophages self-renew during homeostasis and produce inflammatory mediators upon microbial infection. We examined the relationship between proliferative and inflammatory properties of tissue macrophages by defining the impact of the Wnt/ß-catenin pathway, a central regulator of self-renewal, in alveolar macrophages (AMs). Activation of ß-catenin by Wnt ligand inhibited AM proliferation and stemness, but promoted inflammatory activity. In a murine influenza viral pneumonia model, ß-catenin-mediated AM inflammatory activity promoted acute host morbidity; in contrast, AM proliferation enabled repopulation of reparative AMs and tissue recovery following viral clearance. Mechanistically, Wnt treatment promoted ß-catenin-HIF-1α interaction and glycolysis-dependent inflammation while suppressing mitochondrial metabolism and thereby, AM proliferation. Differential HIF-1α activities distinguished proliferative and inflammatory AMs in vivo. This ß-catenin-HIF-1α axis was conserved in human AMs and enhanced HIF-1α expression associated with macrophage inflammation in COVID-19 patients. Thus, inflammatory and reparative activities of lung macrophages are regulated by ß-catenin-HIF-1α signaling, with implications for the treatment of severe respiratory diseases.
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COVID-19/inmunología , COVID-19/virología , Autorrenovación de las Células/inmunología , Interacciones Huésped-Patógeno/inmunología , Macrófagos/inmunología , SARS-CoV-2/inmunología , Biomarcadores , COVID-19/metabolismo , Citocinas/metabolismo , Susceptibilidad a Enfermedades/inmunología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Mediadores de Inflamación/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Transducción de SeñalRESUMEN
A key effector route of the Sugar Code involves lectins that exert crucial regulatory controls by targeting distinct cellular glycans. We demonstrate that a single amino-acid substitution in a banana lectin, replacing histidine 84 with a threonine, significantly reduces its mitogenicity, while preserving its broad-spectrum antiviral potency. X-ray crystallography, NMR spectroscopy, and glycocluster assays reveal that loss of mitogenicity is strongly correlated with loss of pi-pi stacking between aromatic amino acids H84 and Y83, which removes a wall separating two carbohydrate binding sites, thus diminishing multivalent interactions. On the other hand, monovalent interactions and antiviral activity are preserved by retaining other wild-type conformational features and possibly through unique contacts involving the T84 side chain. Through such fine-tuning, target selection and downstream effects of a lectin can be modulated so as to knock down one activity, while preserving another, thus providing tools for therapeutics and for understanding the Sugar Code.
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Lectinas de Plantas/química , Lectinas de Plantas/genética , Fármacos Anti-VIH/química , Secuencia de Carbohidratos , Ingeniería Genética , Mitógenos/química , Modelos Moleculares , Simulación de Dinámica Molecular , Musa/químicaRESUMEN
Tissue-resident memory CD8+ T (Trm) cells share core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic, and epigenetic regulation of Trm cell and TIL development and function is largely undefined. Here, we found that the transcription factor Bhlhe40 was specifically required for Trm cell and TIL development and polyfunctionality. Local PD-1 signaling inhibited TIL Bhlhe40 expression, and Bhlhe40 was critical for TIL reinvigoration following anti-PD-L1 blockade. Mechanistically, Bhlhe40 sustained Trm cell and TIL mitochondrial fitness and a functional epigenetic state. Building on these findings, we identified an epigenetic and metabolic regimen that promoted Trm cell and TIL gene signatures associated with tissue residency and polyfunctionality. This regimen empowered the anti-tumor activity of CD8+ T cells and possessed therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights into the local regulation of Trm cell and TIL function.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Linfocitos T CD8-positivos/inmunología , Proteínas de Homeodominio/inmunología , Mitocondrias/inmunología , Animales , Epigénesis Genética/inmunología , Regulación de la Expresión Génica/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/inmunologíaRESUMEN
Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. To define whether STAT4 is required for intrinsic signaling in mature DC function, we used conditional mutant mice in the EAE model. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the central nervous system. EAE susceptibility was recovered following adoptive transfer of wild-type bone marrow-derived DCs to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single-cell RNA-sequencing (RNA-seq) identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define an IL-23-STAT4 pathway in DCs that is key to DC function during inflammatory disease.
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Células Dendríticas , Encefalomielitis Autoinmune Experimental , Interleucina-23 , Factor de Transcripción STAT4 , Transducción de Señal , Animales , Factor de Transcripción STAT4/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Interleucina-23/metabolismo , Interleucina-23/inmunología , Ratones , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Ratones Noqueados , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/inmunología , Inflamación/metabolismo , Inflamación/inmunología , Traslado Adoptivo , Ratones Endogámicos C57BL , Humanos , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
The development of Th subsets results from cellular and cytokine cues that are present in the inflammatory environment. The developing T cell integrates multiple signals from the environment that sculpt the cytokine-producing capacity of the effector T cell. Importantly, T cells can discriminate similar cytokine signals to generate distinct outcomes, and that discrimination is critical in Th subset development. IL-9-secreting Th9 cells regulate multiple immune responses, including immunity to pathogens and tumors, allergic inflammation, and autoimmunity. In combination with IL-4, TGF-ß or activin A promotes IL-9 production; yet, it is not clear if both TGF-ß family members generate Th9 cells with identical phenotype and function. We observed that in contrast to TGF-ß that efficiently represses Th2 cytokines in murine Th9 cultures, differentiation with activin A produced a multicytokine T cell phenotype with secretion of IL-4, IL-5, IL-13, and IL-10 in addition to IL-9. Moreover, multicytokine secreting cells are more effective at promoting allergic inflammation. These observations suggest that although TGF-ß and IL-4 were identified as cytokines that stimulate optimal IL-9 production, they might not be the only cytokines that generate optimal function from IL-9-producing T cells in immunity and disease.
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Atopic dermatitis results in diminished barrier function and altered production of antimicrobial peptides. Dendritic epidermal T cells (DETCs) play an important role in the wound repair and inflammation process. Our previous work identified an IL-4-dependent loss of DETCs in Stat6VT mice and in the MC903-induced skin inflammation mouse model. However, the mechanisms through which IL-4 mediates the loss of DETCs are unclear. In this study, we show that IL-4Rα germline knockout mice (Il4ra-/-) have increased DETCs, faster wound healing, and increased epidermal differentiation complex gene and fibronectin expression. The absence of IL-4Rα minimized the MC903-induced loss of DETCs, and reciprocal bone marrow chimera experiments in Il4ra-/- and wild-type mice demonstrated structural nonhematopoietic IL-4-responsive cell-mediated DETC homeostasis. Skin keratinocyte-derived IL-15 decreased dramatically in the MC903 model, while injection of IL-15 rescued DETC loss by promoting DETC proliferation and limiting apoptosis. Conditional deletion of IL-4Rα from keratinocytes using Il4rafl/fl K14-Cre mice showed an increase of DETCs, increased IL-15 production, and diminished skin inflammation following wounding. These results suggest that IL-4-dependent effects on DETCs in allergic skin inflammation are mediated by the IL-4Rα receptor of keratinocytes.
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Dermatitis Atópica , Queratinocitos , Receptores de Superficie Celular , Transducción de Señal , Animales , Ratones , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Inflamación/inmunología , Interleucina-4/inmunología , Queratinocitos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Piel/inmunología , Piel/patologíaRESUMEN
Despite >80 years of clinical experience with coagulation factor VIII (FVIII) inhibitors, surprisingly little is known about the in vivo mechanism of this most serious complication of replacement therapy for hemophilia A. These neutralizing antidrug alloantibodies arise in â¼30% of patients. Inhibitor formation is T-cell dependent, but events leading up to helper T-cell activation have been elusive because of, in part, the complex anatomy and cellular makeup of the spleen. Here, we show that FVIII antigen presentation to CD4+ T cells critically depends on a select set of several anatomically distinct antigen-presenting cells, whereby marginal zone B cells and marginal zone and marginal metallophilic macrophages but not red pulp macrophages (RPMFs) participate in shuttling FVIII to the white pulp in which conventional dendritic cells (DCs) prime helper T cells, which then differentiate into follicular helper T (Tfh) cells. Toll-like receptor 9 stimulation accelerated Tfh cell responses and germinal center and inhibitor formation, whereas systemic administration of FVIII alone in hemophilia A mice increased frequencies of monocyte-derived and plasmacytoid DCs. Moreover, FVIII enhanced T-cell proliferation to another protein antigen (ovalbumin), and inflammatory signaling-deficient mice were less likely to develop inhibitors, indicating that FVIII may have intrinsic immunostimulatory properties. Ovalbumin, which, unlike FVIII, is absorbed into the RPMF compartment, fails to elicit T-cell proliferative and antibody responses when administered at the same dose as FVIII. Altogether, we propose that an antigen trafficking pattern that results in efficient in vivo delivery to DCs and inflammatory signaling, shape the immunogenicity of FVIII.
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Linfocitos T CD4-Positivos , Factor VIII , Hemofilia A , Hemostáticos , Animales , Ratones , Células Dendríticas/metabolismo , Factor VIII/inmunología , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Hemostáticos/inmunología , Hemostáticos/uso terapéutico , Ovalbúmina/inmunologíaRESUMEN
Among the cytokines regulating immune cells, IL-9 has gained considerable attention for its ability to act on multiple cell types as a regulator of beneficial and pathologic immune responses. Yet, it is still not clearly defined how IL-9 impacts immune responses. IL-9 demonstrates a remarkable degree of tissue-specific functionality and has cellular sources that vary by tissue site and the context of the inflammatory milieu. Here, we provide perspective to summarize the biological activities of IL-9 and highlight cell type-specific roles in the immune pathogenesis of diseases. This perspective will be important in defining the diseases where targeting IL-9 as a therapeutic strategy would be beneficial and where it has the potential to complicate clinical outcomes.
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Citocinas , Interleucina-9 , Citocinas/metabolismoRESUMEN
CD4+ TH cells develop into subsets that are specialized in the secretion of particular cytokines to mediate restricted types of inflammation and immune responses. Among the subsets that promote development of allergic inflammatory responses, IL-9-producing TH9 cells are regulated by a number of transcription factors. We have previously shown that the E26 transformation-specific (Ets) family members PU.1 and Ets translocation variant 5 (ETV5) function in parallel to regulate IL-9. In this study we identified a third member of the Ets family of transcription factors, Ets-related gene (ERG), that mediates IL-9 production in TH9 cells in the absence of PU.1 and ETV5. Chromatin immunoprecipitation assays revealed that ERG interaction at the Il9 promoter region is restricted to the TH9 lineage and is sustained during murine TH9 polarization. Knockdown or knockout of ERG during murine or human TH9 polarization in vitro led to a decrease in IL-9 production in TH9 cells. Deletion of ERG in vivo had modest effects on IL-9 production in vitro or in vivo. However, in the absence of PU.1 and ETV5, ERG was required for residual IL-9 production in vitro and for IL-9 production by lung-derived CD4 T cells in a mouse model of chronic allergic airway disease. Thus, ERG contributes to IL-9 regulation in TH9 cells.
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Alveolitis Alérgica Extrínseca , Asma , Hipersensibilidad , Neumonía , Animales , Humanos , Ratones , Linfocitos T CD4-Positivos , Diferenciación Celular , Interleucina-9 , Neumonía/metabolismo , Linfocitos T Colaboradores-Inductores , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulador Transcripcional ERG/metabolismoRESUMEN
Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.
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Diferenciación Celular/genética , Fibroblastos/metabolismo , Fibroblastos/patología , Fibrosis/genética , Fibrosis/patología , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Animales , Secuencia de Bases , Epigénesis Genética , Femenino , Humanos , Inflamación/genética , Inflamación/patología , Masculino , Ratones , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Transactivadores/antagonistas & inhibidoresRESUMEN
The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclin T1 and Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity.
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Inmunidad Adaptativa , Diferenciación Celular , Cromatina/enzimología , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Nucleares/metabolismo , Células Th17/enzimología , Factores de Transcripción/metabolismo , Transcripción Genética , Acetilación , Animales , Factor de Unión a CCCTC , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Cromatina/genética , Proteínas Cromosómicas no Histona/química , Proteínas Cromosómicas no Histona/genética , Ciclina T/genética , Ciclina T/metabolismo , Quinasa 9 Dependiente de la Ciclina/genética , Quinasa 9 Dependiente de la Ciclina/metabolismo , Regulación de la Expresión Génica , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Ratones Endogámicos C57BL , Modelos Moleculares , Proteínas Nucleares/genética , Fenotipo , Fosforilación , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Interferencia de ARN , ARN Polimerasa II/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Relación Estructura-Actividad , Células Th17/inmunología , Factores de Transcripción/genética , Transfección , CohesinasRESUMEN
SignificanceSTAT3 (signal transducer and activator of transcription 3) is a master transcription factor that organizes cellular responses to cytokines and growth factors and is implicated in inflammatory disorders. STAT3 is a well-recognized therapeutic target for human cancer and inflammatory disorders, but how its function is regulated in a cell type-specific manner has been a major outstanding question. We discovered that Stat3 imposes self-directed regulation through controlling transcription of its own regulator homeodomain-interacting protein kinase 2 (Hipk2) in a T helper 17 (Th17) cell-specific manner. Our validation of the functional importance of the Stat3-Hipk2 axis in Th17 cell development in the pathogenesis of T cell-induced colitis in mice suggests an approach to therapeutically treat inflammatory bowel diseases that currently lack a safe and effective therapy.
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Colitis , Factor de Transcripción STAT3 , Animales , Diferenciación Celular/genética , Colitis/genética , Colitis/metabolismo , Activación de Linfocitos , Ratones , Proteínas Serina-Treonina Quinasas/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Células Th17RESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1010103.].
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INTRODUCTION: Hypertension is a growing pandemic affecting over 1 billion people worldwide; about 46% of people with hypertension are unaware. METHOD: Data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 were analyzed to assess the relationship between access to a routine place of care and undiagnosed hypertension in adults aged 18 to 64 years old. We defined undiagnosed hypertension as those meeting the 2017 American Heart Association's guidelines for stage 1 or 2 hypertension who reported not being told by their healthcare provider that they had hypertension. We used a multivariable Poisson regression model to assess the relationship between access to a routine place of care and undiagnosed hypertension. RESULT: The final analytic sample was 5345 hypertensive American adults, with 56% unaware of their status. The results indicate that lack of awareness of hypertension status was highest among those without a routine place of care [PR = 1.20, CI = (1.12-1.29), p < 0.001] compared to those with access to a routine place of care, after adjustment for sociodemographic and clinical characteristics. CONCLUSION: Access to a routine place of care in a non-emergency department setting is essential to reduce the rate of undiagnosed hypertension among American adults. Policymakers should implement policies to address the shortage of primary care providers and increase access to a routine place of care.
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Hipertensión , Adulto , Humanos , Estados Unidos , Adolescente , Adulto Joven , Persona de Mediana Edad , Encuestas Nutricionales , Factores de Riesgo , Hipertensión/diagnóstico , Hipertensión/epidemiología , Atención a la SaludRESUMEN
Yersinia pseudotuberculosis is a foodborne pathogen that subverts immune function by translocation of Yersinia outer protein (Yop) effectors into host cells. As adaptive γδ T cells protect the intestinal mucosa from pathogen invasion, we assessed whether Y. pseudotuberculosis subverts these cells in mice and humans. Tracking Yop translocation revealed that the preferential delivery of Yop effectors directly into murine Vγ4 and human Vδ2+ T cells inhibited anti-microbial IFNγ production. Subversion was mediated by the adhesin YadA, injectisome component YopB, and translocated YopJ effector. A broad anti-pathogen gene signature and STAT4 phosphorylation levels were inhibited by translocated YopJ. Thus, Y. pseudotuberculosis attachment and translocation of YopJ directly into adaptive γδ T cells is a major mechanism of immune subversion in mice and humans. This study uncovered a conserved Y. pseudotuberculosis pathway that subverts adaptive γδ T cell function to promote pathogenicity.
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Proteínas Bacterianas/inmunología , Evasión Inmune/inmunología , Interferón gamma/biosíntesis , Linfocitos Intraepiteliales/inmunología , Infecciones por Yersinia pseudotuberculosis/inmunología , Animales , Humanos , Ratones , Yersinia pseudotuberculosis/inmunologíaRESUMEN
Gamma delta (γδ) T cells are a subset of T lymphocytes that express T cell receptor γ and 5 chains and display structural and functional heterogeneity. γδ T cells are typically of low abundance in the body and account for 1-5% of the blood lymphocytes and peripheral lymphoid tissues. As a bridge between innate and adaptive immunity, γδ T cells are uniquely poised to rapidly respond to stimulation and can regulate immune responses in peripheral tissues. The dendritic epidermal T cells in the skin epidermis can secrete growth factors to regulate skin homeostasis and re-epithelization and release inflammatory factors to mediate wound healing during skin inflammatory responses. Dermal γδ T cells can regulate the inflammatory process by producing interleukin-17 and other cytokines or chemokines. Here, we offer a review of the immune functions of γδ T cells, intending to understand their role in regulating skin barrier integrity and skin wound healing, which may be crucial for the development of novel therapeutics in skin diseases like atopic dermatitis and psoriasis.
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Piel , Linfocitos T , Humanos , Piel/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Citocinas/metabolismo , Inflamación/metabolismoRESUMEN
Preserving appropriate function and metabolism in regulatory T (Treg) cells is crucial for controlling immune tolerance and inflammatory responses. Yet how Treg cells coordinate cellular metabolic programs to support their functional specification remains elusive. In this study, we report that BATF couples the TH2-suppressive function and triglyceride (TG) metabolism in Treg cells for controlling allergic airway inflammation and IgE responses. Mice with Treg-specific ablation of BATF developed an inflammatory disorder characterized by TH2-type dominant responses and were predisposed to house dust mite-induced airway inflammation. Loss of BATF enabled Treg cells to acquire TH2 cell-like characteristics. Moreover, BATF-deficient Treg cells displayed elevated levels of cellular TGs, and repressing or elevating TGs, respectively, restored or exacerbated their defects. Mechanistically, TCR/CD28 costimulation enhanced expression and function of BATF, which sustained IRF4 activity to preserve Treg cell functionality. Thus, our studies reveal that BATF links Treg cell functional specification and fitness of cellular TGs to control allergic responses, and suggest that therapeutic targeting of TG metabolism could be used for the treatment of allergic disease.
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Hipersensibilidad , Linfocitos T Reguladores , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Ratones , Ratones Noqueados , Pyroglyphidae , TriglicéridosRESUMEN
Infection with parasitic worms (helminths) alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6-signaling. We examined the importance of intact T cell Stat6 signaling on helminth-induced suppression of murine colitis that results from T cell transfer into immune-deficient mice. Colonization with the intestinal nematode Heligmosomoides polygyrus bakeri resolves WT T cell transfer colitis. However, if the transferred T cells lack intact Stat6 then helminth exposure failed to attenuate colitis or suppress MLN T cell IFN-γ or IL17 production. Loss of Stat6 signaling resulted in decreased IL10 and increased IFN-γ co-expression by IL-17+ T cells. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that also was not attenuated by helminth infection. These results show that T cell expression of intact but regulated Stat6 signaling is required for helminth infection-associated regulation of pathogenic intestinal inflammation.
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Colitis/inmunología , Nematospiroides dubius/inmunología , Factor de Transcripción STAT6/inmunología , Transducción de Señal/inmunología , Infecciones por Strongylida/inmunología , Linfocitos T Reguladores/inmunología , Animales , Colitis/parasitología , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-17/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/parasitología , Ratones , Ratones Endogámicos C57BL , Células TH1/inmunología , Células TH1/parasitología , Células Th17/inmunología , Células Th17/parasitología , Células Th2/inmunología , Células Th2/parasitologíaRESUMEN
CD4(+) helper T cells acquire effector phenotypes that promote specialized inflammatory responses. We show that the ETS-family transcription factor PU.1 was required for the development of an interleukin 9 (IL-9)-secreting subset of helper T cells. Decreasing PU.1 expression either by conditional deletion in mouse T cells or the use of small interfering RNA in human T cells impaired IL-9 production, whereas ectopic PU.1 expression promoted IL-9 production. Mice with PU.1-deficient T cells developed normal T helper type 2 (T(H)2) responses in vivo but showed attenuated allergic pulmonary inflammation that corresponded to lower expression of Il9 and chemokines in peripheral T cells and in lungs than that of wild-type mice. Together our data suggest a critical role for PU.1 in generating the IL-9-producing (T(H)9) phenotype and in the development of allergic inflammation.