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1.
JCI Insight ; 7(4)2022 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-35191395

RESUMEN

The intensity and longevity of inflammatory responses to inhaled allergens is determined largely by the balance between effector and regulatory immune responses, but the mechanisms that determine the relative magnitudes of these opposing forces remain poorly understood. We have found that the type of adjuvant used during allergic sensitization has a profound effect on both the nature and longevity of the pulmonary inflammation triggered by subsequent reexposure to that same provoking allergen. TLR ligand adjuvants and house dust extracts primed immune responses characterized by a mixed neutrophilic and eosinophilic inflammation that was suppressed by multiple daily allergen challenges. During TLR ligand-mediated allergic sensitization, mice displayed transient airway neutrophilia, which triggered the release of TGF-ß into the airway. This neutrophil-dependent production of TGF-ß during sensitization had a delayed, suppressive effect on eosinophilic responses to subsequent allergen challenge. Neutrophil depletion during sensitization did not affect numbers of Foxp3+ Tregs but increased proportions of Gata3+CD4+ T cells, which, upon their transfer to recipient mice, triggered stronger eosinophilic inflammation. Thus, a neutrophil/TGF-ß axis acts during TLR-mediated allergic sensitization to fine-tune the phenotype of developing allergen-specific CD4+ T cells and limit their pathogenicity, suggesting a novel immunotherapeutic approach to control eosinophilia in asthma.


Asunto(s)
Alérgenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Neutrófilos/metabolismo , Hipersensibilidad Respiratoria/inmunología , Células Th2/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Linfocitos T CD4-Positivos/patología , Modelos Animales de Enfermedad , Recuento de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/patología , Hipersensibilidad Respiratoria/patología , Factor de Crecimiento Transformador beta/metabolismo
2.
Am J Respir Cell Mol Biol ; 64(6): 698-708, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33647226

RESUMEN

Asthma is a common respiratory disease currently affecting more than 300 million worldwide and is characterized by airway inflammation, hyperreactivity, and remodeling. It is a heterogeneous disease consisting of corticosteroid-sensitive T-helper cell type 2-driven eosinophilic and corticosteroid-resistant, T-helper cell type 17-driven neutrophilic phenotypes. One pathway recently described to regulate asthma pathogenesis is cholesterol trafficking. Scavenger receptors, in particular SR-BI (scavenger receptor class B type I), are known to direct cellular cholesterol uptake and efflux. We recently defined SR-BI functions in pulmonary host defense; however, the function of SR-BI in asthma pathogenesis is unknown. To elucidate the role of SR-BI in allergic asthma, SR-BI-sufficient (SR-BI+/+) and SR-BI-deficient (SR-BI-/-) mice were sensitized (Days 0 and 7) and then challenged (Days 14, 15, and 16) with a house dust mite (HDM) preparation administered through oropharyngeal aspiration. Airway inflammation and cytokine production were quantified on Day 17. When compared with SR-BI+/+ mice, the HDM-challenged SR-BI-/- mice had increased neutrophils and pulmonary IL-17A production in BAL fluid. This augmented IL-17A production in SR-BI-/- mice originated from a non-T-cell source that included neutrophils and alveolar macrophages. Given that SR-BI regulates adrenal steroid hormone production, we tested whether the changes in SR-BI-/- mice were glucocorticoid dependent. Indeed, SR-BI-/- mice were adrenally insufficient during the HDM challenge, and corticosterone replacement decreased pulmonary neutrophilia and IL-17A production in SR-BI-/- mice. Taken together, these data indicate that SR-BI dampens pulmonary neutrophilic inflammation and IL-17A production in allergic asthma at least in part by maintaining adrenal function.


Asunto(s)
Asma/metabolismo , Asma/patología , Antígenos CD36/metabolismo , Inflamación/patología , Interleucina-17/metabolismo , Neutrófilos/patología , Insuficiencia Suprarrenal/complicaciones , Insuficiencia Suprarrenal/inmunología , Animales , Asma/inmunología , Asma/parasitología , Antígenos CD36/deficiencia , Hipersensibilidad/complicaciones , Pulmón/parasitología , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Neutrófilos/inmunología , Ovalbúmina/inmunología , Pyroglyphidae/fisiología , Células Th17/inmunología
3.
JCI Insight ; 52019 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-31184998

RESUMEN

Airway neutrophilia occurs in approximately 50% of patients with asthma and is associated with particularly severe disease. Unfortunately, this form of asthma is usually refractory to corticosteroid treatment, and there is an unmet need for new therapies. Pulmonary neutrophilic inflammation is associated with Th17 cells, whose differentiation is controlled by the nuclear receptor, RORγt. Here, we tested whether VTP-938, a selective inverse agonist of this receptor, can reduce disease parameters in animal models of neutrophilic asthma. When administered prior to allergic sensitization through the airway, the RORγt inverse agonist blunted allergen-specific Th17 cell development in lung-draining lymph nodes and attenuated allergen-induced production of IL-17. VTP-938 also reduced pulmonary production of IL-17 and airway neutrophilia when given during the allergen challenge of the model. Finally, in an environmentally relevant model of allergic responses to house dust extracts, VTP-938 suppressed production of IL-17 and neutrophilic inflammation, and also markedly diminished airway hyperresponsiveness. Together, these findings suggest that orally available inverse agonists of RORγt might provide an effective therapy to treat glucocorticoid-resistant neutrophilic asthma.


Asunto(s)
Asma/tratamiento farmacológico , Hipersensibilidad/tratamiento farmacológico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/uso terapéutico , Hipersensibilidad Respiratoria/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Polvo , Hipersensibilidad/inmunología , Inflamación , Interleucina-17 , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Neumonía , Células Th17/inmunología
4.
Methods Mol Biol ; 1799: 237-246, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29956156

RESUMEN

Pulmonary dendritic cells (DCs) are potent antigen-presenting cells that can activate both naïve and memory/effector T cells. However, very little is known of how movements and localization of DCs contribute to these events. To study this, we have developed new procedures that combine precision-cut lung slices with cell staining using fluorescently tagged antibodies to detect individual cell types. In this chapter, we describe these methods in detail and show how they can be used to study the localization of not only DCs but also other leukocytes of interest, as well as structural cells within the lung.


Asunto(s)
Quimiotaxis de Leucocito/inmunología , Leucocitos/inmunología , Leucocitos/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Imagen Molecular , Animales , Ratones , Microscopía Confocal , Imagen Molecular/métodos
5.
J Allergy Clin Immunol ; 142(4): 1229-1242.e6, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29154958

RESUMEN

BACKGROUND: Mechanisms that elicit mucosal TH17 cell responses have been described, yet how these cells are sustained in chronically inflamed tissues remains unclear. OBJECTIVE: We sought to understand whether maintenance of lung TH17 inflammation requires environmental agents in addition to antigen and to identify the lung antigen-presenting cell (APC) types that sustain the self-renewal of TH17 cells. METHODS: Animals were exposed repeatedly to aspiration of ovalbumin alone or together with environmental adjuvants, including common house dust extract (HDE), to test their role in maintaining lung inflammation. Alternatively, antigen-specific effector/memory TH17 cells, generated in culture with CD4+ T cells from Il17a fate-mapping mice, were adoptively transferred to assess their persistence in genetically modified animals lacking distinct lung APC subsets or cell-specific Toll-like receptor (TLR) 4 signaling. TH17 cells were also cocultured with lung APC subsets to determine which of these could revive their expansion and activation. RESULTS: TH17 cells and the consequent neutrophilic inflammation were poorly sustained by inhaled antigen alone but were augmented by inhalation of antigen together with HDE. This was associated with weight loss and changes in lung physiology consistent with interstitial lung disease. The effect of HDE required TLR4 signaling predominantly in lung hematopoietic cells, including CD11c+ cells. CD103+ and CD11b+ conventional dendritic cells interacted directly with TH17 cells in situ and revived the clonal expansion of TH17 cells both ex vivo and in vivo, whereas lung macrophages and B cells could not. CONCLUSION: TH17-dependent inflammation in the lungs can be sustained by persistent TLR4-mediated activation of lung conventional dendritic cells.


Asunto(s)
Células Dendríticas/inmunología , Inflamación/inmunología , Pulmón/inmunología , Células Th17/inmunología , Receptor Toll-Like 4/inmunología , Alérgenos/inmunología , Animales , Aspergillus oryzae/inmunología , Polvo , Endotoxinas/inmunología , Ratones Endogámicos C57BL , Ratones Transgénicos , Ovalbúmina/inmunología , Receptor Toll-Like 4/genética
6.
Endocrinology ; 159(1): 103-118, 2018 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-28927243

RESUMEN

Endometriosis is a gynecological disease that negatively affects the health of 1 in 10 women. Although more information is known about late stage disease, the early initiation of endometriosis and lesion development is poorly understood. Herein, we use a uterine tissue transfer mouse model of endometriosis to examine early disease development and its dependence on estradiol (E2) and estrogen receptor (ER) α within 72 hours of disease initiation. Using wild-type and ERα knockout mice as hosts or donors, we find substantial infiltration of neutrophils and macrophages into the peritoneal cavity. Examining cell infiltration, lesion gene expression, and peritoneal fluid, we find that E2/ERα plays a minor role in early lesion development. Immune-mediated signaling predominates E2-mediated signaling, but 48 hours after the initiation of disease, a blunted interleukin (IL)-6-mediated response is found in developing lesions lacking ERα. Our data provide evidence that the early initiation of endometriosis is predominantly dependent on the immune system, whereas E2/ERα/IL-6-mediated cross-talk plays a partial role. These findings suggest there are two phases of endometriosis-an immune-dependent phase and a hormone-dependent phase, and that targeting the innate immune system could prevent lesion attachment in this susceptible population of women.


Asunto(s)
Endometriosis/metabolismo , Endometrio/metabolismo , Receptor alfa de Estrógeno/agonistas , Interleucina-6/metabolismo , Activación de Macrófagos , Infiltración Neutrófila , Transducción de Señal , Animales , Líquido Ascítico/inmunología , Líquido Ascítico/metabolismo , Líquido Ascítico/patología , Biomarcadores/metabolismo , Progresión de la Enfermedad , Endometriosis/inmunología , Endometriosis/patología , Endometriosis/fisiopatología , Endometrio/inmunología , Endometrio/patología , Endometrio/fisiopatología , Estradiol/administración & dosificación , Estradiol/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación de la Expresión Génica , Inmunidad Innata , Interleucina-6/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Ovariectomía , Distribución Aleatoria
7.
Nature ; 551(7678): 105-109, 2017 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-29072299

RESUMEN

T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor ß (TGFß) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFß enables TH17 cell differentiation remains elusive. Here we reveal that TGFß enables TH17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGFß signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGFß neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFß stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFß-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable TH17 cell differentiation. This study reveals a critical mechanism by which TGFß controls TH17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating TH17-related diseases.


Asunto(s)
Diferenciación Celular , Proteínas de Unión al ADN/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Proteína Smad4/metabolismo , Células Th17/citología , Células Th17/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Diferenciación Celular/genética , Femenino , Eliminación de Gen , Humanos , Interleucina-6/metabolismo , Masculino , Ratones , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/deficiencia , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal , Proteína Smad4/deficiencia , Proteína Smad4/genética
8.
Environ Health Perspect ; 125(9): 097024, 2017 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-28960179

RESUMEN

BACKGROUND: Arsenic exposure via drinking water impacts millions of people worldwide. Although arsenic has been associated epidemiologically with increased lung infections, the identity of the lung cell types targeted by peroral arsenic and the associated immune mechanisms remain poorly defined. OBJECTIVES: We aimed to determine the impact of peroral arsenic on pulmonary antibacterial host defense. METHODS: Female C57BL/6 mice were administered drinking water with 0, 250 ppb, or 25 ppm sodium arsenite for 5 wk and then challenged intratracheally with Klebsiella pneumoniae, Streptococcus pneumoniae, or lipopolysaccharide. Bacterial clearance and immune responses were profiled. RESULTS: Arsenic had no effect on bacterial clearance in the lung or on the intrapulmonary innate immune response to bacteria or lipopolysaccharide, as assessed by neutrophil recruitment to, and cytokine induction in, the airspace. Alveolar macrophage TNFα production was unaltered. By contrast, arsenic-exposed mice had significantly reduced plasma TNFα in response to systemic lipopolysaccharide challenge, together suggesting that the local airway innate immune response may be relatively preserved from arsenic intoxication. Despite intact intrapulmonary bacterial clearance during pneumonia, arsenic-exposed mice suffered dramatically increased bacterial dissemination to the bloodstream. Mechanistically, this was linked to increased respiratory epithelial permeability, as revealed by intratracheal FITC-dextran tracking, serum Club Cell protein 16 measurement, and other approaches. Consistent with barrier disruption at the alveolar level, arsenic-exposed mice had evidence for alveolar epithelial type 1 cell injury. CONCLUSIONS: Peroral arsenic has little effect on local airway immune responses to bacteria but compromises respiratory epithelial barrier integrity, increasing systemic translocation of inhaled pathogens and small molecules. https://doi.org/10.1289/EHP1878.


Asunto(s)
Intoxicación por Arsénico/microbiología , Arsénico/toxicidad , Sustancias Peligrosas/toxicidad , Pulmón/efectos de los fármacos , Administración Oral , Animales , Células Epiteliales , Femenino , Klebsiella pneumoniae , Pulmón/microbiología , Pulmón/fisiopatología , Ratones , Ratones Endogámicos C57BL , Permeabilidad
9.
J Clin Invest ; 127(9): 3313-3326, 2017 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-28758900

RESUMEN

Asthma is associated with exposure to a wide variety of allergens and adjuvants. The extent to which overlap exists between the cellular and molecular mechanisms triggered by these various agents is poorly understood, but it might explain the differential responsiveness of patients to specific therapies. In particular, it is unclear why some, but not all, patients benefit from blockade of TNF. Here, we characterized signaling pathways triggered by distinct types of adjuvants during allergic sensitization. Mice sensitized to an innocuous protein using TLR ligands or house dust extracts as adjuvants developed mixed eosinophilic and neutrophilic airway inflammation and airway hyperresponsiveness (AHR) following allergen challenge, whereas mice sensitized using proteases as adjuvants developed predominantly eosinophilic inflammation and AHR. TLR ligands, but not proteases, induced TNF during allergic sensitization. TNF signaled through airway epithelial cells to reprogram them and promote Th2, but not Th17, development in lymph nodes. TNF was also required during the allergen challenge phase for neutrophilic and eosinophilic inflammation. In contrast, TNF was dispensable for allergic airway disease in a protease-mediated model of asthma. These findings might help to explain why TNF blockade improves lung function in only some patients with asthma.


Asunto(s)
Hipersensibilidad/metabolismo , Inflamación/fisiopatología , Hipersensibilidad Respiratoria/metabolismo , Receptores Toll-Like/metabolismo , Factor de Necrosis Tumoral alfa/fisiología , Alérgenos , Animales , Asma/metabolismo , Asma/fisiopatología , Hiperreactividad Bronquial/fisiopatología , Diferenciación Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Eosinófilos/citología , Hipersensibilidad/fisiopatología , Interleucina-17/metabolismo , Ligandos , Pulmón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/citología , Ovalbúmina/metabolismo , Hipersensibilidad Respiratoria/fisiopatología , Transducción de Señal , Células Th17/citología , Células Th2/citología
10.
J Vis Exp ; (122)2017 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-28448013

RESUMEN

Inhalation of allergens and pathogens elicits multiple changes in a variety of immune cell types in the lung. Flow cytometry is a powerful technique for quantitative analysis of cell surface proteins on immune cells, but it provides no information on the localization and migration patterns of these cells within the lung. Similarly, chemotaxis assays can be performed to study the potential of cells to respond to chemotactic factors in vitro, but these assays do not reproduce the complex environment of the intact lung. In contrast to these aforementioned techniques, the location of individual cell types within the lung can be readily visualized by generating Precision-cut Lung Slices (PCLS), staining them with commercially available, fluorescently tagged antibodies, and visualizing the sections by confocal microscopy. PCLS can be used for both live and fixed lung tissue, and the slices can encompass areas as large as a cross section of an entire lobe. We have used this protocol to successfully visualize the location of a wide variety of cell types in the lung, including distinct types of dendritic cells, macrophages, neutrophils, T cells and B cells, as well as structural cells such as lymphatic, endothelial, and epithelial cells. The ability to visualize cellular interactions, such as those between dendritic cells and T cells, in live, three-dimensional lung tissue, can reveal how cells move within the lung and interact with one another at steady state and during inflammation. Thus, when used in combination with other procedures, such as flow cytometry and quantitative PCR, PCLS can contribute to a comprehensive understanding of cellular events that underlie allergic and inflammatory diseases of the lung.


Asunto(s)
Células Dendríticas/inmunología , Células Epiteliales/inmunología , Técnicas Histológicas/métodos , Pulmón/citología , Técnicas de Cultivo de Tejidos , Alérgenos , Animales , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Macrófagos/inmunología , Ratones , Manejo de Especímenes/métodos
11.
Am J Physiol Lung Cell Mol Physiol ; 309(10): L1208-18, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26386119

RESUMEN

The induction of allergen-specific T helper 2 (Th2) cells by lung dendritic cells (DCs) is a critical step in allergic asthma development. Airway delivery of purified allergens or microbial products can promote Th2 priming by lung DCs, but how environmentally relevant quantities and combinations of these factors affect lung DC function is unclear. Here, we investigated the ability of house dust extract (HDE), which contains a mixture of environmental adjuvants, to prime Th2 responses against an innocuous inhaled antigen. Inhalational exposure to HDE conditioned lung conventional DCs, but not monocyte-derived DCs, to induce antigen-specific Th2 differentiation. Conditioning of DCs by HDE was independent of Toll-like receptor 4 signaling, indicating that environmental endotoxin is dispensable for programming DCs to induce Th2 responses. DCs directly treated with HDE underwent maturation but were poor stimulators of Th2 differentiation. In contrast, DCs treated with bronchoalveolar lavage fluid (BALF) from HDE-exposed mice induced robust Th2 differentiation. DC conditioning by BALF was independent of the proallergic cytokines IL-25, IL-33, and thymic stromal lymphopoietin. BALF treatment of DCs resulted in upregulation of CD80 but low expression of CD40, CD86, and IL-12p40, which was associated with Th2 induction. These findings support a model whereby environmental adjuvants in house dust indirectly program DCs to prime Th2 responses by triggering the release of endogenous soluble factor(s) by airway cells. Identifying these factors could lead to novel therapeutic targets for allergic asthma.


Asunto(s)
Células Dendríticas/inmunología , Polvo/inmunología , Pulmón/patología , Células Th2/inmunología , Animales , Antígenos CD/metabolismo , Asma/inmunología , Asma/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Interleucinas/metabolismo , Pulmón/inmunología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados
12.
Environ Health Perspect ; 122(1): 34-42, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24168764

RESUMEN

BACKGROUND: Humans with asthma display considerable heterogeneity with regard to T helper (Th) 2-associated eosinophilic and Th17-associated neutrophilic inflammation, but the impact of the environment on these different forms of asthma is poorly understood. OBJECTIVE: We studied the nature and longevity of asthma-like responses triggered by inhalation of allergen together with environmentally relevant doses of inhaled lipopolysaccharide (LPS). METHODS: Ovalbumin (OVA) was instilled into the airways of mice together with a wide range of LPS doses. Following a single OVA challenge, or multiple challenges, animals were assessed for pulmonary cytokine production, airway inflammation, and airway hyperresponsiveness (AHR). RESULTS: Mice instilled with OVA together with very low doses (≤10⁻³ µg) of LPS displayed modest amounts of Th2 cytokines, with associated airway eosinophilia and AHR after a single challenge, and these responses were sustained after multiple OVA challenges. When the higher but still environmentally relevant dose of 10⁻¹ µg LPS was used, mice initially displayed similar Th2 responses, as well as Th17-associated neutrophilia. After multiple OVA challenges, however, the 10⁻¹ µg LPS animals also accumulated large numbers of allergen-specific T regulatory (Treg) cells with high levels of inducible co-stimulatory molecule (ICOS). As a result, asthma-like features in these mice were shorter-lived than in mice sensitized using lower doses of LPS. CONCLUSIONS: The nature and longevity of Th2, Th17, and Treg immune responses to inhaled allergen are dependent on the quantity of LPS inhaled at the time of allergic sensitization. These findings might account in part for the heterogeneity of inflammatory infiltrates seen in lungs of asthmatics.


Asunto(s)
Asma/inmunología , Lipopolisacáridos/inmunología , Animales , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ovalbúmina/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Células Th2/inmunología
13.
J Immunol ; 188(7): 3053-61, 2012 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-22393151

RESUMEN

α-Galactosylceramide represents a new class of vaccine adjuvants and immunomodulators that stimulate NKT cells to secrete Th1 and Th2 cytokines. Synthetic variants with short or unsaturated acyl chains exhibit a striking Th2 bias in vivo but no evidence of defect in TCR signaling or stimulation of NKT cells in vitro. Using cd1d1(fl/fl) mice, we demonstrated that distinct APC types explained the cytokine bias in vivo. Whereas NKT stimulation by α-Galactosylceramide required CD1d expression by dendritic cells (DCs), presentation of the Th2 variants was promiscuous and unaffected by DC-specific ablation of CD1d. This DC-independent stimulation failed to activate the feedback loop between DC IL-12 and NK cell IFN-γ, explaining the Th2 bias. Conversely, forced presentation of the Th2 variants by DC induced high IL-12. Thus, lipid structural variations that do not alter TCR recognition can activate distinct Th1 or Th2 cellular networks by changing APC targeting in vivo.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Galactosilceramidas/química , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Células T Asesinas Naturales/efectos de los fármacos , Animales , Presentación de Antígeno , Células Presentadoras de Antígenos/clasificación , Antígenos CD1d/biosíntesis , Antígenos CD1d/genética , Antígenos CD1d/inmunología , Linfocitos B/inmunología , Células Cultivadas/efectos de los fármacos , Células Cultivadas/inmunología , Células Cultivadas/metabolismo , Células Dendríticas/inmunología , Retroalimentación Fisiológica , Galactosilceramidas/inmunología , Galactosilceramidas/farmacología , Regulación de la Expresión Génica , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Organismos Libres de Patógenos Específicos , Relación Estructura-Actividad
14.
J Exp Med ; 208(10): 2113-24, 2011 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-21930768

RESUMEN

Airborne exposure to microbial cell wall lipids such as lipopolysaccharide triggers innate immune responses that regulate susceptibility to allergic airway inflammation. α-Glycosylceramides represent another widespread class of microbial lipids that directly stimulate innate-like, IL-4- and IL-13-producing, CD1d-restricted NKT cells. In this study, we demonstrate that NKT cells constitutively accumulate and reside in the microvasculature of the mouse lung. After a single airborne exposure to lipid antigen, they promptly extravasate to orchestrate the formation of peribronchiolar and interstitial lymphohistiocytic granulomas containing numerous eosinophils. Concomitant airborne exposure to ovalbumin (OVA) induces the priming of OVA-specific Th2 cells and IgE antibodies by the same dendritic cell coexpressing CD1d and MHC class II. Although NKT cell activation remains confined to the lipid-exposed lung and draining lymph nodes, Th2 cells recirculate and seed the lung of a parabiotic partner, conferring susceptibility to OVA challenge months after the initial exposure, in a manner independent of NKT cells and CD1d. Thus, transient recruitment and activation of lung-resident intravascular NKT cells can trigger long-term susceptibility to allergic airway inflammation.


Asunto(s)
Antígenos/inmunología , Hiperreactividad Bronquial/inmunología , Lípidos/inmunología , Células T Asesinas Naturales/inmunología , Neumonía/inmunología , Administración por Inhalación , Animales , Células Presentadoras de Antígenos/inmunología , Antígenos/administración & dosificación , Antígenos CD1d/inmunología , Líquido del Lavado Bronquioalveolar/citología , Quimiocinas/genética , Quimiocinas/inmunología , Células Dendríticas/inmunología , Genes MHC Clase II , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Ovalbúmina/inmunología
15.
J Exp Med ; 208(6): 1179-88, 2011 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-21624939

RESUMEN

Innate-like NKT cells conspicuously accumulate within the liver microvasculature of healthy mice, crawling on the luminal side of endothelial cells, but their general recirculation pattern and the mechanism of their intravascular behavior have not been elucidated. Using parabiotic mice, we demonstrated that, despite their intravascular location, most liver NKT cells failed to recirculate. Antibody blocking experiments established that they were retained locally through constitutive LFA-1-intercellular adhesion molecule (ICAM) 1 interactions. This unprecedented lifelong intravascular residence could be induced in conventional CD4 T cells by the sole expression of promyelocytic leukemia zinc finger (PLZF), a transcription factor specifically expressed in the NKT lineage. These findings reveal the unique genetic and biochemical pathway that underlies the innate intravascular surveillance program of NKT cells.


Asunto(s)
Regulación de la Expresión Génica , Molécula 1 de Adhesión Intercelular/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Hígado/irrigación sanguínea , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Células T Asesinas Naturales/metabolismo , Animales , Linfocitos T CD4-Positivos/citología , Adhesión Celular , Linaje de la Célula , Citometría de Flujo/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microcirculación , Microscopía Fluorescente/métodos , Proteína de la Leucemia Promielocítica con Dedos de Zinc
16.
J Allergy Clin Immunol ; 125(5): 980-4, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20304475

RESUMEN

Asthma is a multifactorial disease of the airways characterized by airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. Conventional MHC class II-restricted CD4(+) T cells are considered a key cell in asthma pathogenesis because they have a broad T-cell receptor repertoire, providing specificity and reactivity to diverse protein allergens. This notion was challenged when a study found that invariant Natural Killer (NK) T cells were the predominant T cells in the lung and bronchoalveolar lavage fluid of all asthmatic subjects studied. This finding was provocative because invariant NKT cells have a very limited T-cell receptor repertoire and are specific for a restricted set of lipid antigens that bind to CD1d, a nonpolymorphic MHC-like molecule. However, multiple subsequent studies failed to replicate the initial study and instead found that invariant NKT cells are present as a small fraction of the total T cells in the asthmatic lung. Thus, we believe that although CD1d-restricted NKT cells might play a role in modulating the asthmatic phenotype, they are not the critical drivers of the asthmatic response, a role we believe is still held by conventional MHC class II-restricted CD4(+) T cells.


Asunto(s)
Asma/etiología , Asma/inmunología , Células T Asesinas Naturales/citología , Células T Asesinas Naturales/inmunología , Animales , Antígenos CD1d/metabolismo , Hiperreactividad Bronquial/complicaciones , Hiperreactividad Bronquial/inmunología , Humanos , Ratones , Células Th2/inmunología
17.
J Immunol ; 182(1): 623-35, 2009 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19109196

RESUMEN

STAT6-mediated chemokine production in the lung is required for Th2 lymphocyte and eosinophil homing into the airways in allergic pulmonary inflammation, and thus is a potential therapeutic target in asthma. However, the critical cellular source of STAT6-mediated chemokine production has not been defined. In this study, we demonstrate that STAT6 in bone marrow-derived myeloid cells was sufficient for the production of CCL17, CCL22, CCL11, and CCL24 and for Th2 lymphocyte and eosinophil recruitment into the allergic airway. In contrast, STAT6 in airway-lining cells did not mediate chemokine production or support cellular recruitment. Selective depletion of CD11b(+) myeloid cells in the lung identified these cells as the critical cellular source for the chemokines CCL17 and CCL22. These data reveal that CD11b(+) myeloid cells in the lung help orchestrate the adaptive immune response in asthma, in part, through the production of STAT6-inducible chemokines and the recruitment of Th2 lymphocytes into the airway.


Asunto(s)
Antígeno CD11b/biosíntesis , Quimiotaxis de Leucocito/inmunología , Pulmón/inmunología , Células Mieloides/inmunología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/patología , Factor de Transcripción STAT6/fisiología , Células Th2/inmunología , Animales , Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/patología , Células Cultivadas , Quimiocina CCL17/biosíntesis , Quimiocina CCL22/biosíntesis , Quimiocina CCL24/biosíntesis , Modelos Animales de Enfermedad , Inmunidad Innata , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Células Mieloides/metabolismo , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Hipersensibilidad Respiratoria/metabolismo , Factor de Transcripción STAT6/deficiencia , Factor de Transcripción STAT6/genética , Células Th2/patología , Células Th2/trasplante
18.
Proc Natl Acad Sci U S A ; 105(12): 4814-9, 2008 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-18347328

RESUMEN

Cerebral malaria is a significant cause of global mortality, causing an estimated two million deaths per year, mainly in children. The pathogenesis of this disease remains incompletely understood. Chemokines have been implicated in the development of cerebral malaria, and the IFN-inducible CXCR3 chemokine ligand IP-10 (CXCL10) was recently found to be the only serum biomarker that predicted cerebral malaria mortality in Ghanaian children. We show that the CXCR3 chemokine ligands IP-10 and Mig (CXCL9) were highly induced in the brains of mice with murine cerebral malaria caused by Plasmodium berghei ANKA. Mice deficient in CXCR3 were markedly protected against cerebral malaria and had far fewer T cells in the brain compared with wild-type mice. In competitive transfer experiments, CXCR3-deficient CD8(+) T cells were 7-fold less efficient at migrating into the infected brains than wild-type CD8(+) T cells. Adoptive transfer of wild-type CD8(+) effector T cells restored susceptibility of CXCR3-deficient mice to cerebral malaria and also restored brain proinflammatory cytokine and chemokine production and recruitment of T cells, independent of CXCR3. Mice deficient in IP-10 or Mig were both partially protected against cerebral malaria mortality when infected with P. berghei ANKA. Brain immunohistochemistry revealed Mig staining of endothelial cells, whereas IP-10 staining was mainly found in neurons. These data demonstrate that CXCR3 on CD8(+) T cells is required for T cell recruitment into the brain and the development of murine cerebral malaria and suggest that the CXCR3 ligands Mig and IP-10 play distinct, nonredundant roles in the pathogenesis of this disease.


Asunto(s)
Quimiocina CXCL10/inmunología , Quimiocina CXCL9/inmunología , Malaria Cerebral/inmunología , Malaria Cerebral/patología , Receptores CXCR3/inmunología , Animales , Encéfalo/parasitología , Encéfalo/patología , Complejo CD3/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/parasitología , Movimiento Celular , Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Ligandos , Malaria Cerebral/parasitología , Malaria Cerebral/prevención & control , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plasmodium berghei/inmunología , Receptores de Citocinas/deficiencia , Bazo/metabolismo , Bazo/patología , Tasa de Supervivencia , Regulación hacia Arriba/genética
19.
Annu Rev Immunol ; 26: 205-32, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18304002

RESUMEN

T cells are critical mediators of the allergic airway inflammation seen in asthma. Pathogenic allergen-specific T cells are generated in regional lymph nodes and are then recruited into the airway by chemoattractants produced by the asthmatic lung. These recruited effector T cells and their products then mediate the cardinal features of asthma: airway eosinophilia, mucus hypersecretion, and airway hyperreactivity. There has been considerable progress in delineating the molecular mechanisms that control T cell trafficking into peripheral tissue, including the asthmatic lung. In this review, we summarize these advances and formulate them into a working model that proposes that T cell trafficking into and out of the allergic lung is controlled by several discrete regulatory pathways that involve the collaboration of innate and acquired immune cells.


Asunto(s)
Asma/inmunología , Quimiotaxis/inmunología , Linfocitos T/inmunología , Animales , Asma/patología , Quimiocinas/inmunología , Humanos , Pulmón/citología , Pulmón/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Modelos Inmunológicos , Linfocitos T/citología
20.
J Immunol ; 179(3): 1901-12, 2007 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-17641057

RESUMEN

Human allergic asthma is a chronic inflammatory disease of the airways thought to be driven by allergen-specific Th2 cells, which are recruited into the lung in response to inhaled allergen. To identify chemoattractant receptors that control this homing pattern, we used endobronchial segmental allergen challenge in human atopic asthmatics to define the pattern of chemoattractant receptor expression on recruited T cells as well as the numbers of recruited CD1d-restricted NKT cells and levels of chemokines in the bronchoalveolar (BAL) fluid. CD1d-restricted NKT cells comprised only a small minority of BAL T cells before or after Ag challenge. BAL T cells were enriched in their expression of specific chemoattractant receptors compared with peripheral blood T cells prechallenge, including CCR5, CCR6, CXCR3, CXCR4, and BLT1. Surprisingly, following segmental allergen challenge, no chemoattractant receptor was specifically increased. However, CCR6 and CXCR3, which were expressed on virtually all CD4(+) BAL T cells prechallenge, were markedly decreased on all recruited BAL T cells following Ag challenge, suggesting that these receptors were internalized following encounter with ligand in the airway. Our data therefore suggests a role for CCR6 and CXCR3, in conjunction with other chemoattractant receptors, in the recruitment of inflammatory T cells into the BAL during the allergic asthmatic response.


Asunto(s)
Asma/inmunología , Bronquios/inmunología , Movimiento Celular/inmunología , Epítopos de Linfocito T/fisiología , Receptores de Quimiocina/fisiología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto , Alérgenos/administración & dosificación , Animales , Asma/metabolismo , Asma/patología , Bronquios/metabolismo , Bronquios/patología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Interferón gamma/biosíntesis , Interleucina-4/biosíntesis , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Masculino , Persona de Mediana Edad , Receptores CCR6 , Receptores CXCR3 , Receptores de Quimiocina/biosíntesis , Receptores de Quimiocina/sangre , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Linfocitos T/patología
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