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2.
Nat Immunol ; 21(11): 1359-1370, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32929274

RESUMEN

Elucidating the mechanisms that sustain asthmatic inflammation is critical for precision therapies. We found that interleukin-6- and STAT3 transcription factor-dependent upregulation of Notch4 receptor on lung tissue regulatory T (Treg) cells is necessary for allergens and particulate matter pollutants to promote airway inflammation. Notch4 subverted Treg cells into the type 2 and type 17 helper (TH2 and TH17) effector T cells by Wnt and Hippo pathway-dependent mechanisms. Wnt activation induced growth and differentiation factor 15 expression in Treg cells, which activated group 2 innate lymphoid cells to provide a feed-forward mechanism for aggravated inflammation. Notch4, Wnt and Hippo were upregulated in circulating Treg cells of individuals with asthma as a function of disease severity, in association with reduced Treg cell-mediated suppression. Our studies thus identify Notch4-mediated immune tolerance subversion as a fundamental mechanism that licenses tissue inflammation in asthma.


Asunto(s)
Asma/etiología , Asma/metabolismo , Factor 15 de Diferenciación de Crecimiento/metabolismo , Receptor Notch4/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Alérgenos/inmunología , Análisis de Varianza , Asma/diagnóstico , Biomarcadores , Susceptibilidad a Enfermedades , Expresión Génica , Vía de Señalización Hippo , Humanos , Tolerancia Inmunológica , Inmunofenotipificación , Proteínas Serina-Treonina Quinasas/metabolismo , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Vía de Señalización Wnt
3.
Nat Immunol ; 20(9): 1208-1219, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31384057

RESUMEN

Regulatory T cells (Treg cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (Teff) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient Treg cells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency re-established a subset of Treg cell genetic circuits and suppressed the Teff cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of Treg cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their Teff cell-like program and restored suppressive function. Thus, regulatory function can be re-established in Foxp3-deficient Treg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in Treg cell disorders.


Asunto(s)
Reprogramación Celular/inmunología , Factores de Transcripción Forkhead/genética , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Proteína Asociada al mTOR Insensible a la Rapamicina/genética , Linfocitos T Reguladores/inmunología , Animales , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Glucólisis/fisiología , Humanos , Masculino , Diana Mecanicista del Complejo 2 de la Rapamicina/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación Oxidativa , Transducción de Señal , Linfocitos T Reguladores/citología
4.
Immunity ; 55(11): 1978-1980, 2022 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-36351372

RESUMEN

RORγt+ regulatory T (Treg) cells are critical toward maintaining gut immune tolerance. In recent studies published in Nature, Kedmi et al., Lyu et al., and Akagbosu et al. describe MHCII+RORγt+ antigen-presenting cells that mediate RORγt+ Treg cell differentiation but propose disparate identities for these cells.


Asunto(s)
Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Tolerancia Periférica , Desconcierto , Linfocitos T Reguladores , Células Presentadoras de Antígenos , Células Th17 , Factores de Transcripción Forkhead , Tolerancia Inmunológica
5.
Immunity ; 54(6): 1186-1199.e7, 2021 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-33915108

RESUMEN

A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.


Asunto(s)
Interacciones Huésped-Patógeno , Inmunidad Celular , Neumonía Viral/etiología , Neumonía Viral/metabolismo , Receptor Notch4/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Anfirregulina/farmacología , Animales , Biomarcadores , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunohistoquímica , Inmunomodulación/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Virus de la Influenza A/fisiología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Ratones , Ratones Transgénicos , Neumonía Viral/patología , Receptor Notch4/antagonistas & inhibidores , Receptor Notch4/genética , Índice de Severidad de la Enfermedad
6.
Immunity ; 53(2): 277-289, 2020 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-32814026

RESUMEN

The steep rise in food allergy (FA) has evoked environmental factors involved in disease pathogenesis, including the gut microbiota, diet, and their metabolites. Early introduction of solid foods synchronizes with the "weaning reaction," a time during which the microbiota imprints durable oral tolerance. Recent work has shown that children with FA manifest an early onset dysbiosis with the loss of Clostridiales species, which promotes the differentiation of ROR-γt+ regulatory T cells to suppress FA. This process can be reversed in pre-clinical mouse models by targeted bacteriotherapy. Here, we review the dominant tolerance mechanisms enforced by the microbiota to suppress FA and discuss therapeutic intervention strategies that act to recapitulate the early life window of opportunity in stemming the FA epidemic.


Asunto(s)
Dieta , Disbiosis/microbiología , Hipersensibilidad a los Alimentos/inmunología , Microbioma Gastrointestinal/fisiología , Animales , Clostridiales/aislamiento & purificación , Desensibilización Inmunológica/métodos , Humanos , Tolerancia Inmunológica/inmunología , Inmunoglobulina E/inmunología , Ratones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología
7.
Immunity ; 53(6): 1202-1214.e6, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33086036

RESUMEN

The mechanisms by which regulatory T (Treg) cells differentially control allergic and autoimmune responses remain unclear. We show that Treg cells in food allergy (FA) had decreased expression of transforming growth factor beta 1 (TGF-ß1) because of interleukin-4 (IL-4)- and signal transducer and activator of transciription-6 (STAT6)-dependent inhibition of Tgfb1 transcription. These changes were modeled by Treg cell-specific Tgfb1 monoallelic inactivation, which induced allergic dysregulation by impairing microbiota-dependent retinoic acid receptor-related orphan receptor gamma t (ROR-γt)+ Treg cell differentiation. This dysregulation was rescued by treatment with Clostridiales species, which upregulated Tgfb1 expression in Treg cells. Biallelic deficiency precipitated fatal autoimmunity with intense autoantibody production and dysregulated T follicular helper and B cell responses. These results identify a privileged role of Treg cell-derived TGF-ß1 in regulating allergy and autoimmunity at distinct checkpoints in a Tgfb1 gene dose- and microbiota-dependent manner.


Asunto(s)
Autoinmunidad/inmunología , Hipersensibilidad/inmunología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta1/inmunología , Adolescente , Animales , Autoinmunidad/genética , Linfocitos B/inmunología , Diferenciación Celular , Niño , Preescolar , Hipersensibilidad a los Alimentos/inmunología , Dosificación de Gen , Humanos , Hipersensibilidad/genética , Inmunoglobulina G/inmunología , Lactante , Mastocitos/inmunología , Ratones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Células T Auxiliares Foliculares/inmunología , Linfocitos T Reguladores/metabolismo , Transcripción Genética , Factor de Crecimiento Transformador beta1/genética , Adulto Joven
11.
J Allergy Clin Immunol ; 147(3): 808-813, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33347905

RESUMEN

Food allergy (FA) is a significant public health issue, propelled by its rapidly increasing prevalence. Its sharp rise into prominence has focused attention on causative environmental factors and their interplay with the immune system in disease pathogenesis. In that regard, there is now substantial evidence that alterations in the gut microbiome early in life imprint the host gut mucosal immunity and may play a critical role in precipitating FA. These changes may impact key steps in the development of the infant gut microbiome, including its shaping by maternal factors and upon the introduction of solid food (the weaning reaction). These early-life changes may have long-range effects on host immunity that manifest later in time as disease pathology. Experimental studies have shown that resetting the host intestinal immune responses by treatment with either a healthy fecal microbiota transplantation or defined commensal bacterial taxa can prevent or treat FA. The mechanisms by which these interventions suppress FA include restoration of gut immune regulatory checkpoints, notably the retinoic orphan receptor gamma T+ regulatory T cells, the epithelial barrier, and healthy immunoglobulin A responses to the gut commensals. These findings inform human studies currently in progress that evaluate the role of microbial therapies in FA.


Asunto(s)
Disbiosis/inmunología , Hipersensibilidad a los Alimentos/inmunología , Microbioma Gastrointestinal/inmunología , Modelos Inmunológicos , Linfocitos T Reguladores/inmunología , Animales , Disbiosis/microbiología , Disbiosis/terapia , Trasplante de Microbiota Fecal , Hipersensibilidad a los Alimentos/microbiología , Hipersensibilidad a los Alimentos/terapia , Humanos , Inmunidad Mucosa , Inmunoglobulina A/metabolismo , Inmunoglobulina E/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo
12.
Indian J Microbiol ; 61(4): 524-529, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34744208

RESUMEN

Bacillus licheniformis is a multi-metal tolerant bacteria, isolated from the paddy rhizospheric soil sample. Upon the multiple metal toxicity, B. licheniformis altered their phenotypic/morphogenesis. Here we examined the effects of cadmium (Cd2+), chromium (Cr2+), and mercury (Hg2+) on the morphogenesis of B. licheniformis in comparison to control. We found that the ability of bacteria to grow effectively in presence of cadmium and chromium comes at a cost of acquiring cell density-driven mobility and reformation of filamentous to donut shape respectively. In particular, when bacteria grown on mercury it showed the bacteriostatic strategy to resist mercury. Furthermore, the findings suggest a large variation in the production of exo-polysaccharides (EPS) and suggest the possible role of EPS in gaining resistance to cadmium and chromium. Together this study identifies previously unknown characteristics of B. licheniformis to participate in bioremediation and provides the first evidence on positive effects of bacterial morphogenesis and the involvement of EPS in bacteria to resisting metal toxicity.

13.
J Allergy Clin Immunol ; 144(2): 524-535.e8, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30529242

RESUMEN

BACKGROUND: Therapeutic normal IgG or intravenous immunoglobulin (IVIG) exerts anti-inflammatory effects through several mutually nonexclusive mechanisms. Recent data in mouse models of autoimmune disease suggest that IVIG induces IL-4 in basophils by enhancing IL-33 in SIGN-related 1-positive innate cells. However, translational insight on these data is lacking. OBJECTIVE: We sought to investigate the effect of IVIG on human basophil functions. METHODS: Isolated circulating basophils from healthy donors were cultured in the presence of IL-3, IL-33, GM-CSF, thymic stromal lymphopoietin, or IL-25. The effect of IVIG and F(ab')2 and Fc IVIG fragments was examined based on expression of various surface molecules, phosphorylation of spleen tyrosine kinase, induction of cytokines, and histamine release. Basophil phenotypes were also analyzed from IVIG-treated patients with myopathy. Approaches, such as depletion of anti-IgE reactivity from IVIG, blocking antibodies, or inhibitors, were used to investigate the mechanisms. RESULTS: We report that IVIG directly induces activation of IL-3-primed human basophils, but IL-33 and other cytokines were dispensable for this effect. Activation of basophils by IVIG led to enhanced expression of CD69 and secretion of IL-4, IL-6, and IL-8. IVIG-treated patients with myopathy displayed enhanced expression of CD69 on basophils. The spleen tyrosine kinase pathway is implicated in these functions of IVIG and were mediated by F(ab')2 fragments. Mechanistically, IVIG induced IL-4 in human basophils by interacting with basophil surface-bound IgE but independent of FcγRII, type II Fc receptors, C-type lectin receptors, and sialic acid-binding immunoglobulin-like lectins. CONCLUSION: These results uncovered a pathway of promoting the TH2 response by IVIG through direct interaction of IgG with human basophils.


Asunto(s)
Antiinflamatorios/farmacología , Basófilos/inmunología , Fragmentos Fc de Inmunoglobulinas/farmacología , Inmunoglobulinas Intravenosas/farmacología , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Basófilos/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Liberación de Histamina , Humanos , Inmunoglobulina E/metabolismo , Interleucina-3/metabolismo , Lectinas Tipo C/metabolismo , Ratones , Quinasa Syk/metabolismo , Regulación hacia Arriba
15.
Cell Microbiol ; 19(6)2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28382773

RESUMEN

CD4+ CD25+ FoxP3+ regulatory T cells (Tregs) are key players for maintaining immune tolerance and for reducing the inflammation-mediated tissue damage following infection. However, Tregs also suppress protective immune responses to pathogens (including virus, bacteria, parasites, and fungi) and vaccines and enhance pathogen persistence by inhibiting the activation and functions of both innate and adaptive immune cells such as dendritic cells, macrophages, and T and B lymphocytes and by promoting immunosuppressive environment. Therefore, equilibrium in the Treg number and function is important to ensure pathogen clearance and protection from infection-associated immunopathologies. Recent advances in understanding of Treg influence on the outcome of infection opened new avenues to target them. Various small molecules, pharmacological inhibitors, monoclonal antibodies that target Tregs provided proof of concept in experimental models. The field also benefits from advances in other subjects, particularly oncology and autoimmunity, where Treg-targeted therapies are exploited in the clinic to a greater extent. The future research should aim at translating this preclinical success to human application.


Asunto(s)
Infecciones Bacterianas/inmunología , Tolerancia Inmunológica/inmunología , Micosis/inmunología , Enfermedades Parasitarias/inmunología , Linfocitos T Reguladores/inmunología , Virosis/inmunología , Linfocitos B/inmunología , Células Dendríticas/inmunología , Humanos , Macrófagos/inmunología
16.
J Infect Dis ; 216(10): 1281-1294, 2017 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-28968869

RESUMEN

Background: Human dendritic cell (DC) response to α-(1,3)-glucan polysaccharide of Aspergillus fumigatus and ensuing CD4+ T-cell polarization are poorly characterized. Methods: α-(1,3)-Glucan was isolated from A. fumigatus conidia and mycelia cell wall. For the analysis of polarization, DCs and autologous naive CD4+ T cells were cocultured. Phenotype of immune cells was analyzed by flow cytometry, and cytokines by enzyme-linked immunosorbent assay (ELISA). Blocking antibodies were used to dissect the role of Toll-like receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) in regulating α-(1,3)-glucan-mediated DC activation and T-cell responses. DCs from TLR2-deficient mice were additionally used to consolidate the findings. Results: α-(1,3)-Glucan induced the maturation of DCs and was dependent in part on TLR2. "α-(1,3)-Glucan-educated" DCs stimulated the activation of naive T cells and polarized a subset of these cells into CD4+CD25+FoxP3+ regulatory T cells (Tregs). Mechanistically, Treg stimulation by α-(1,3)-glucan was dependent on the PD-L1 pathway that negatively regulated interferon-gamma (IFN-γ) secretion. Short α-(1,3)-oligosaccharides lacked the capacity to induce maturation of DCs but significantly blocked α-(1,3)-glucan-induced Treg polarization. Conclusions: PD-L1 dictates the balance between Treg and IFN-γ responses induced by α-(1,3)-glucan. Our data provide a rationale for the exploitation of immunotherapeutic approaches that target PD-1-PD-L1 to enhance protective immune responses to A. fumigatus infections.


Asunto(s)
Aspergillus fumigatus/inmunología , Antígeno B7-H1/genética , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Expresión Génica , Glucanos/inmunología , Activación de Linfocitos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Biomarcadores , Citocinas/metabolismo , Humanos , Interferón gamma/metabolismo , Ratones , Ratones Noqueados , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/metabolismo
17.
J Neuroinflammation ; 14(1): 58, 2017 03 20.
Artículo en Inglés | MEDLINE | ID: mdl-28320438

RESUMEN

BACKGROUND: Intravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (Treg) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking. METHODS: Ten newly diagnosed Guillain-Barré syndrome (GBS) patients were treated with IVIG at the rate of 0.4 g/kg for three to five consecutive days. Clinical evaluation for muscular weakness was performed by Medical Research Council (MRC) and modified Rankin scoring (MRS) system. Heparinized blood samples were collected before and 1, 2, and 4-5 weeks post-IVIG therapy. Peripheral blood mononuclear cells were stained for surface CD4 and intracellular Foxp3, IFN-γ, and tumor necrosis factor alpha (TNF-α) and were analyzed by flow cytometry. IL-33 and prostaglandin E2 in the plasma were measured by ELISA. RESULTS: The fold changes in plasma IL-33 at week 1 showed no correlation with the MRC and MRS scores at weeks 1, 2, and ≥4 post-IVIG therapy. Clinical recovery following IVIG therapy appears to be associated with Treg cell response. Contrary to murine study, there was no association between the fold changes in IL-33 at week 1 and Treg cell frequency at weeks 1, 2, and ≥4 post-IVIG therapy. Treg cell-mediated clinical response to IVIG therapy in GBS patients was associated with reciprocal regulation of effector T cells-expressing TNF-α. CONCLUSION: Treg cell expansion by IVIG in patients with autoimmune diseases lack correlation with IL-33. Treg cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to IVIG therapy.


Asunto(s)
Síndrome de Guillain-Barré , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Interleucina-33/sangre , Linfocitos T Reguladores/patología , Anciano , Anciano de 80 o más Años , Dinoprostona/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Estudios de Seguimiento , Síndrome de Guillain-Barré/sangre , Síndrome de Guillain-Barré/tratamiento farmacológico , Síndrome de Guillain-Barré/patología , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas
18.
Molecules ; 21(7)2016 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-27428940

RESUMEN

Extracts of Viscum album (VA); a semi-parasitic plant, are frequently used in the complementary therapy of cancer and other immunological disorders. Various reports show that VA modulates immune system and exerts immune-adjuvant activities that might influence tumor regression. Currently, several therapeutic preparations of VA are available and hence an insight into the mechanisms of action of different VA preparations is necessary. In the present study, we performed a comparative study of five different preparations of VA on maturation and activation of human dendritic cells (DCs) and ensuing CD4⁺ T cell responses. Monocyte-derived human DCs were treated with VA Qu Spez, VA Qu Frf, VA M Spez, VA P and VA A. Among the five VA preparations tested VA Qu Spez, a fermented extract with a high level of lectins, significantly induced DC maturation markers CD83, CD40, HLA-DR and CD86, and secretion of pro-inflammatory cytokines such as IL-6, IL-8, IL-12 and TNF-α. Furthermore, analysis of T cell cytokines in DC-T cell co-culture revealed that VA Qu Spez significantly stimulated IFN-γ secretion without modulating regulatory T cells and other CD4⁺ T cytokines IL-4, IL-13 and IL-17A. Our study thus delineates differential effects of VA preparations on DC maturation; function and T cell responses.


Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Activación de Linfocitos/efectos de los fármacos , Extractos Vegetales/farmacología , Viscum album/química , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/biosíntesis , Células Dendríticas/citología , Células Dendríticas/metabolismo , Humanos , Subgrupos Linfocitarios/citología , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo
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