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1.
Nat Immunol ; 25(9): 1637-1649, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39060651

RESUMEN

Approximately 25% of cancers are preceded by chronic inflammation that occurs at the site of tumor development. However, whether this multifactorial oncogenic process, which commonly occurs in the intestines, can be initiated by a specific immune cell population is unclear. Here, we show that an intestinal T cell subset, derived from interleukin-17 (IL-17)-producing helper T (TH17) cells, induces the spontaneous transformation of the intestinal epithelium. This subset produces inflammatory cytokines, and its tumorigenic potential is not dependent on IL-17 production but on the transcription factors KLF6 and T-BET and interferon-γ. The development of this cell type is inhibited by transforming growth factor-ß1 (TGFß1) produced by intestinal epithelial cells. TGFß signaling acts on the pretumorigenic TH17 cell subset, preventing its progression to the tumorigenic stage by inhibiting KLF6-dependent T-BET expression. This study therefore identifies an intestinal T cell subset initiating cancer.


Asunto(s)
Mucosa Intestinal , Factor 6 Similar a Kruppel , Proteínas de Dominio T Box , Células Th17 , Animales , Células Th17/inmunología , Ratones , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Factor 6 Similar a Kruppel/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Transducción de Señal/inmunología , Ratones Endogámicos C57BL , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Ratones Noqueados , Interferón gamma/metabolismo , Interferón gamma/inmunología , Interleucina-17/metabolismo , Interleucina-17/inmunología , Ratones Transgénicos , Proteínas Proto-Oncogénicas/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Neoplasias Intestinales/inmunología , Neoplasias Intestinales/patología , Neoplasias Intestinales/metabolismo , Humanos
2.
Cell ; 176(5): 998-1013.e16, 2019 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-30712876

RESUMEN

Lung cancer is closely associated with chronic inflammation, but the causes of inflammation and the specific immune mediators have not been fully elucidated. The lung is a mucosal tissue colonized by a diverse bacterial community, and pulmonary infections commonly present in lung cancer patients are linked to clinical outcomes. Here, we provide evidence that local microbiota provoke inflammation associated with lung adenocarcinoma by activating lung-resident γδ T cells. Germ-free or antibiotic-treated mice were significantly protected from lung cancer development induced by Kras mutation and p53 loss. Mechanistically, commensal bacteria stimulated Myd88-dependent IL-1ß and IL-23 production from myeloid cells, inducing proliferation and activation of Vγ6+Vδ1+ γδ T cells that produced IL-17 and other effector molecules to promote inflammation and tumor cell proliferation. Our findings clearly link local microbiota-immune crosstalk to lung tumor development and thereby define key cellular and molecular mediators that may serve as effective targets in lung cancer intervention.


Asunto(s)
Interacciones Microbiota-Huesped/inmunología , Linfocitos Intraepiteliales/inmunología , Neoplasias Pulmonares/inmunología , Animales , Proliferación Celular , Femenino , Interleucina-17/inmunología , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Linfocitos Intraepiteliales/metabolismo , Linfocitos Intraepiteliales/fisiología , Pulmón/inmunología , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota/inmunología , Factor 88 de Diferenciación Mieloide/metabolismo , Neutrófilos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta , Simbiosis/inmunología , Linfocitos T/inmunología
3.
Immunity ; 57(7): 1665-1680.e7, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38772365

RESUMEN

Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.


Asunto(s)
Glucólisis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Interleucina-17 , Animales , Humanos , Interleucina-17/metabolismo , Interleucina-17/inmunología , Ratones , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Piel/inmunología , Piel/patología , Piel/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Transportador de Glucosa de Tipo 1/genética , Psoriasis/inmunología , Psoriasis/metabolismo , Epitelio/inmunología , Epitelio/metabolismo , Ratones Noqueados , Transducción de Señal/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Modelos Animales de Enfermedad , Ácido Láctico/metabolismo , Enfermedad Crónica , Inflamación/inmunología , Ratones Endogámicos C57BL
4.
Immunity ; 56(1): 43-57.e10, 2023 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-36630917

RESUMEN

There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that regional epithelial expression of the transcription factor GATA4 controls bacterial colonization and inflammatory tissue immunity in the proximal small intestine by regulating retinol metabolism and luminal IgA. Furthermore, in mice without jejunal GATA4 expression, the commensal segmented filamentous bacteria promoted pathogenic inflammatory immune responses that disrupted barrier function and increased mortality upon Citrobacter rodentium infection. In celiac disease patients, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. Taken together, these results reveal broad impacts of GATA4-regulated intestinal regionalization on bacterial colonization and tissue immunity, highlighting an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease.


Asunto(s)
Infecciones por Enterobacteriaceae , Factor de Transcripción GATA4 , Microbioma Gastrointestinal , Mucosa Intestinal , Animales , Humanos , Ratones , Actinobacillus , Microbioma Gastrointestinal/inmunología , Factor de Transcripción GATA4/metabolismo , Inmunidad Mucosa , Interleucina-17/inmunología , Interleucina-17/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Intestino Delgado , Simbiosis
5.
Nat Immunol ; 20(8): 992-1003, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31263279

RESUMEN

Here we identify a group 2 innate lymphoid cell (ILC2) subpopulation that can convert into interleukin-17 (IL-17)-producing NKp44- ILC3-like cells. c-Kit and CCR6 define this ILC2 subpopulation that exhibits ILC3 features, including RORγt, enabling the conversion into IL-17-producing cells in response to IL-1ß and IL-23. We also report a role for transforming growth factor-ß in promoting the conversion of c-Kit- ILC2s into RORγt-expressing cells by inducing the upregulation of IL23R, CCR6 and KIT messenger RNA in these cells. This switch was dependent on RORγt and the downregulation of GATA-3. IL-4 was able to reverse this event, supporting a role for this cytokine in maintaining ILC2 identity. Notably, this plasticity has physiological relevance because a subset of RORγt+ ILC2s express the skin-homing receptor CCR10, and the frequencies of IL-17-producing ILC3s are increased at the expense of ILC2s within the lesional skin of patients with psoriasis.


Asunto(s)
Interleucina-17/inmunología , Linfocitos/inmunología , Psoriasis/patología , Piel/patología , Células Cultivadas , Humanos , Interleucina-1beta/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Interleucina-4/inmunología , Linfocitos/citología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Psoriasis/inmunología , Receptores CCR10/metabolismo , Piel/inmunología , Factor de Crecimiento Transformador beta/metabolismo
6.
Nat Immunol ; 20(5): 534-545, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30962593

RESUMEN

Lymph-node (LN) stromal cell populations expand during the inflammation that accompanies T cell activation. Interleukin-17 (IL-17)-producing helper T cells (TH17 cells) promote inflammation through the induction of cytokines and chemokines in peripheral tissues. We demonstrate a critical requirement for IL-17 in the proliferation of LN and splenic stromal cells, particularly fibroblastic reticular cells (FRCs), during experimental autoimmune encephalomyelitis and colitis. Without signaling via the IL-17 receptor, activated FRCs underwent cell cycle arrest and apoptosis, accompanied by signs of nutrient stress in vivo. IL-17 signaling in FRCs was not required for the development of TH17 cells, but failed FRC proliferation impaired germinal center formation and antigen-specific antibody production. Induction of the transcriptional co-activator IκBζ via IL-17 signaling mediated increased glucose uptake and expression of the gene Cpt1a, encoding CPT1A, a rate-limiting enzyme of mitochondrial fatty acid oxidation. Hence, IL-17 produced by locally differentiating TH17 cells is an important driver of the activation of inflamed LN stromal cells, through metabolic reprogramming required to support proliferation and survival.


Asunto(s)
Proliferación Celular , Fibroblastos/inmunología , Interleucina-17/inmunología , Ganglios Linfáticos/inmunología , Células del Estroma/inmunología , Animales , Formación de Anticuerpos/genética , Formación de Anticuerpos/inmunología , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Células Cultivadas , Colitis/genética , Colitis/inmunología , Colitis/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Fibroblastos/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Ganglios Linfáticos/citología , Ganglios Linfáticos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/inmunología , Receptores de Interleucina-17/metabolismo , Células del Estroma/metabolismo , Células Th17/inmunología , Células Th17/metabolismo
7.
Cell ; 165(3): 679-89, 2016 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-27040495

RESUMEN

Increasing antibiotic resistance among bacterial pathogens has rendered some infections untreatable with available antibiotics. Klebsiella pneumoniae, a bacterial pathogen that has acquired high-level antibiotic resistance, is a common cause of pulmonary infections. Optimal clearance of K. pneumoniae from the host lung requires TNF and IL-17A. Herein, we demonstrate that inflammatory monocytes are rapidly recruited to the lungs of K. pneumoniae-infected mice and produce TNF, which markedly increases the frequency of IL-17-producing innate lymphoid cells. While pulmonary clearance of K. pneumoniae is preserved in neutrophil-depleted mice, monocyte depletion or TNF deficiency impairs IL-17A-dependent resolution of pneumonia. Monocyte-mediated bacterial uptake and killing is enhanced by ILC production of IL-17A, indicating that innate lymphocytes engage in a positive-feedback loop with monocytes that promotes clearance of pneumonia. Innate immune defense against a highly antibiotic-resistant bacterial pathogen depends on crosstalk between inflammatory monocytes and innate lymphocytes that is mediated by TNF and IL-17A.


Asunto(s)
Infecciones por Klebsiella/inmunología , Klebsiella pneumoniae/fisiología , Animales , Inflamación/inmunología , Interleucina-17/inmunología , Infecciones por Klebsiella/microbiología , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Linfocitos/inmunología , Ratones , Monocitos/inmunología , Factor de Necrosis Tumoral alfa/inmunología
8.
Nat Immunol ; 19(4): 354-365, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-29563620

RESUMEN

Mechanisms that degrade inflammatory mRNAs are well known; however, stabilizing mechanisms are poorly understood. Here, we show that Act1, an interleukin-17 (IL-17)-receptor-complex adaptor, binds and stabilizes mRNAs encoding key inflammatory proteins. The Act1 SEFIR domain binds a stem-loop structure, the SEFIR-binding element (SBE), in the 3' untranslated region (UTR) of Cxcl1 mRNA, encoding an inflammatory chemokine. mRNA-bound Act1 directs formation of three compartmentally distinct RNA-protein complexes (RNPs) that regulate three disparate events in inflammatory-mRNA metabolism: preventing mRNA decay in the nucleus, inhibiting mRNA decapping in P bodies and promoting translation. SBE RNA aptamers decreased IL-17-mediated mRNA stabilization in vitro, IL-17-induced skin inflammation and airway inflammation in a mouse asthma model, thus providing a therapeutic strategy for autoimmune diseases. These results reveal a network in which Act1 assembles RNPs on the 3' UTRs of select mRNAs and consequently controls receptor-mediated mRNA stabilization and translation during inflammation.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Inflamación/inmunología , Interleucina-17/metabolismo , Estabilidad del ARN/fisiología , Transducción de Señal/inmunología , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Regulación de la Expresión Génica/inmunología , Inflamación/metabolismo , Interleucina-17/inmunología , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Receptores de Interleucina-17/metabolismo
9.
Nat Immunol ; 18(6): 604-611, 2017 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-28518154

RESUMEN

Shortly after the discovery of interleukin 17 (IL-17)-producing CD4+ helper T cells (TH17 cells), it was found that γδ T cells can also secrete large amounts of this pro-inflammatory cytokine. A decade later, it is now known that IL-17+ γδ T cells (γδ17 T cells) are often the main providers of IL-17A in various models of inflammatory diseases, while they also contribute to protective immune responses to infectious organisms. Due to an intricate thymic program of differentiation, γδ17 T cells are able to respond faster than TH17 cells do and thus predominate in the early stages of inflammatory responses. Here we review the current knowledge of the development, activation and pathophysiological functions of γδ17 T cells, aiming to increase the awareness in the community of the therapeutic potential of this 'other side' of IL-17-mediated immune responses.


Asunto(s)
Inflamación/inmunología , Interleucina-17/inmunología , Subgrupos de Linfocitos T/inmunología , Células Th17/inmunología , Animales , Diferenciación Celular/inmunología , Humanos , Inmunidad Innata/inmunología , Ratones , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Timo , Recombinación V(D)J
10.
Nat Immunol ; 18(6): 612-621, 2017 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-28518156

RESUMEN

Increased understanding of the biology of interleukin 17 (IL-17) has revealed that this cytokine is a central player in immunity at the sites most exposed to microorganisms. Although it has been strongly associated with immunopathology, IL-17 also has an important role in host defense. The regulation of IL-17 secretion seems to be shared among various cell types, each of which can concomitantly secrete additional products. IL-17 has only modest activity on its own; its impact in immunity arises from its synergistic action with other factors, its self-sustaining feedback loop and, in some cases, its role as a counterpart of interferon-γ (IFN-γ). Together these attributes provide a robust response against microorganisms, but they can equally contribute to immune pathology. Here we focus on a discussion of the role of IL-17 during infection.


Asunto(s)
Inmunidad Adaptativa/inmunología , Artritis Reumatoide/inmunología , Inmunidad Innata/inmunología , Infecciones/inmunología , Interleucina-17/inmunología , Neoplasias/inmunología , Psoriasis/inmunología , Animales , Retroalimentación , Humanos , Interferón gamma/inmunología , Ratones
11.
Immunity ; 52(3): 499-512.e5, 2020 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-32187518

RESUMEN

Interleukin-17A (IL-17A), IL-17F, and IL-17A/F heterodimers are key cytokines of the innate and adaptive immune response. Dysregulation of the IL-17 pathway contributes to immune pathology, and it is therefore important to elucidate the molecular mechanisms that govern IL-17 recognition and signaling. The receptor IL-17RC is thought to act in concert with IL-17RA to transduce IL-17A-, IL-17F-, and IL-17A/F-mediated signals. We report the crystal structure of the extracellular domain of human IL-17RC in complex with IL-17F. In contrast to the expected model, we found that IL-17RC formed a symmetrical 2:1 complex with IL-17F, thus competing with IL-17RA for cytokine binding. Using biophysical techniques, we showed that IL-17A and IL-17A/F also form 2:1 complexes with IL-17RC, suggesting the possibility of IL-17RA-independent IL-17 signaling pathways. The crystal structure of the IL-17RC:IL-17F complex provides a structural basis for IL-17F signaling through IL-17RC, with potential therapeutic applications for respiratory allergy and inflammatory bowel diseases.


Asunto(s)
Interleucina-17/inmunología , Multimerización de Proteína/inmunología , Receptores de Interleucina-17/inmunología , Transducción de Señal/inmunología , Unión Competitiva , Cristalografía por Rayos X , Células HEK293 , Humanos , Interleucina-17/química , Interleucina-17/metabolismo , Modelos Moleculares , Unión Proteica , Conformación Proteica , Receptores de Interleucina-17/química , Receptores de Interleucina-17/metabolismo
12.
Immunity ; 52(3): 528-541.e7, 2020 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-32160525

RESUMEN

Helminths, allergens, and certain protists induce type 2 immune responses, but the underlying mechanisms of immune activation remain poorly understood. In the small intestine, chemosensing by epithelial tuft cells results in the activation of group 2 innate lymphoid cells (ILC2s), which subsequently drive increased tuft cell frequency. This feedforward circuit is essential for intestinal remodeling and helminth clearance. ILC2 activation requires tuft-cell-derived interleukin-25 (IL-25), but whether additional signals regulate the circuit is unclear. Here, we show that tuft cells secrete cysteinyl leukotrienes (cysLTs) to rapidly activate type 2 immunity following chemosensing of helminth infection. CysLTs cooperate with IL-25 to activate ILC2s, and tuft-cell-specific ablation of leukotriene synthesis attenuates type 2 immunity and delays helminth clearance. Conversely, cysLTs are dispensable for the tuft cell response induced by intestinal protists. Our findings identify an additional tuft cell effector function and suggest context-specific regulation of tuft-ILC2 circuits within the small intestine.


Asunto(s)
Cisteína/inmunología , Mucosa Intestinal/inmunología , Intestino Delgado/inmunología , Leucotrienos/inmunología , Nippostrongylus/inmunología , Infecciones por Strongylida/inmunología , Animales , Araquidonato 5-Lipooxigenasa/genética , Araquidonato 5-Lipooxigenasa/inmunología , Araquidonato 5-Lipooxigenasa/metabolismo , Cisteína/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/parasitología , Inmunidad Innata/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-17/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitología , Intestino Delgado/citología , Intestino Delgado/metabolismo , Leucotrienos/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Linfocitos/parasitología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Nippostrongylus/fisiología , Infecciones por Strongylida/parasitología
13.
Immunity ; 52(2): 342-356.e6, 2020 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-32023490

RESUMEN

Interleukin-17A (IL-17A) is a major mediator of tissue inflammation in many autoimmune diseases. Anti-IL-17A is an effective treatment for psoriasis and is showing promise in clinical trials in multiple sclerosis. In this study, we find that IL-17A-defective mice or mice treated with anti-IL-17A at induction of experimental autoimmune encephalomyelitis (EAE) are resistant to disease and have defective priming of IL-17-secreting γδ T (γδT17) cells and Th17 cells. However, T cells from Il17a-/- mice induce EAE in wild-type mice following in vitro culture with autoantigen, IL-1ß, and IL-23. Furthermore, treatment with IL-1ß or IL-17A at induction of EAE restores disease in Il17a-/- mice. Importantly, mobilization of IL-1ß-producing neutrophils and inflammatory monocytes and activation of γδT17 cells is reduced in Il17a-/- mice. Our findings demonstrate that a key function of IL-17A in central nervous system (CNS) autoimmunity is to recruit IL-1ß-secreting myeloid cells that prime pathogenic γδT17 and Th17 cells.


Asunto(s)
Autoinmunidad/inmunología , Interleucina-17/inmunología , Interleucina-1beta/metabolismo , Linfocitos Intraepiteliales/inmunología , Células Mieloides/inmunología , Células Th17/inmunología , Animales , Autoantígenos/inmunología , Autoinmunidad/genética , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Interleucina-17/antagonistas & inhibidores , Interleucina-17/deficiencia , Interleucina-17/metabolismo , Interleucina-1beta/inmunología , Interleucina-23/inmunología , Interleucina-23/metabolismo , Linfocitos Intraepiteliales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Monocitos/metabolismo , Células Mieloides/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Células Th17/metabolismo
14.
Nat Immunol ; 17(4): 422-32, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26950239

RESUMEN

T cell responses are guided by cytokines that induce transcriptional regulators, which ultimately control differentiation of effector and memory T cells. However, it is unknown how the activities of these molecular regulators are coordinated and integrated during the differentiation process. Using genetic approaches and transcriptional profiling of antigen-specific CD8(+) T cells, we reveal a common program of effector differentiation that is regulated by IL-2 and IL-12 signaling and the combined activities of the transcriptional regulators Blimp-1 and T-bet. The loss of both T-bet and Blimp-1 leads to abrogated cytotoxic function and ectopic IL-17 production in CD8(+) T cells. Overall, our data reveal two major overlapping pathways of effector differentiation governed by the availability of Blimp-1 and T-bet and suggest a model for cytokine-induced transcriptional changes that combine, quantitatively and qualitatively, to promote robust effector CD8(+) T cell differentiation.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Interleucina-12/inmunología , Interleucina-2/inmunología , Proteínas de Dominio T Box/inmunología , Factores de Transcripción/inmunología , Animales , Infecciones por Arenaviridae/inmunología , Inmunoprecipitación de Cromatina , Citocinas/inmunología , Citometría de Flujo , Perfilación de la Expresión Génica , Subtipo H1N1 del Virus de la Influenza A , Interleucina-17/inmunología , Virus de la Coriomeningitis Linfocítica , Ratones , Infecciones por Orthomyxoviridae/inmunología , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Transcripción STAT4/inmunología , Factor de Transcripción STAT5/inmunología , Análisis de Secuencia de ARN , Transducción de Señal
15.
Nat Immunol ; 17(8): 997-1004, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27322655

RESUMEN

Dysregulated expression of interleukin 17 (IL-17) in the colonic mucosa is associated with colonic inflammation and cancer. However, the cell-intrinsic molecular mechanisms by which IL-17 expression is regulated remain unclear. We found that deficiency in the ubiquitin ligase Itch led to spontaneous colitis and increased susceptibility to colon cancer. Itch deficiency in the TH17 subset of helper T cells, innate lymphoid cells and γδ T cells resulted in the production of elevated amounts of IL-17 in the colonic mucosa. Mechanistically, Itch bound to the transcription factor ROR-γt and targeted ROR-γt for ubiquitination. Inhibition or genetic inactivation of ROR-γt attenuated IL-17 expression and reduced spontaneous colonic inflammation in Itch(-/-) mice. Thus, we have identified a previously unknown role for Itch in regulating IL-17-mediated colonic inflammation and carcinogenesis.


Asunto(s)
Colitis/inmunología , Colon/patología , Neoplasias Colorrectales/inmunología , Mucosa Intestinal/inmunología , Linfocitos/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Células Th17/fisiología , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Células Cultivadas , Sulfato de Dextran , Humanos , Interleucina-17/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación
16.
Nat Immunol ; 17(5): 583-92, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26998763

RESUMEN

Interleukin 1ß (IL-1ß) is critical for the in vivo survival, expansion and effector function of IL-17-producing helper T (T(H)17) cells during autoimmune responses, including experimental autoimmune encephalomyelitis (EAE). However, the spatiotemporal role and cellular source of IL-1ß during EAE pathogenesis are poorly defined. In the present study, we uncovered a T cell-intrinsic inflammasome that drives IL-1ß production during T(H)17-mediated EAE pathogenesis. Activation of T cell antigen receptors induced expression of pro-IL-1ß, whereas ATP stimulation triggered T cell production of IL-1ß via ASC-NLRP3-dependent caspase-8 activation. IL-1R was detected on T(H)17 cells but not on type 1 helper T (T(H)1) cells, and ATP-treated T(H)17 cells showed enhanced survival compared with ATP-treated T(H)1 cells, suggesting autocrine action of T(H)17-derived IL-1ß. Together these data reveal a critical role for IL-1ß produced by a T(H)17 cell-intrinsic ASC-NLRP3-caspase-8 inflammasome during inflammation of the central nervous system.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Linfocitos T/inmunología , Células Th17/inmunología , Adenosina Trifosfato/farmacología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Adaptadoras de Señalización CARD , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Proteínas Portadoras/metabolismo , Caspasa 8/genética , Caspasa 8/inmunología , Caspasa 8/metabolismo , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Células Cultivadas , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Citometría de Flujo , Expresión Génica/inmunología , Immunoblotting , Inflamasomas/genética , Inflamasomas/inmunología , Inflamasomas/metabolismo , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-17/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteína con Dominio Pirina 3 de la Familia NLR , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Células Th17/efectos de los fármacos , Células Th17/metabolismo
17.
Immunity ; 50(4): 892-906, 2019 04 16.
Artículo en Inglés | MEDLINE | ID: mdl-30995505

RESUMEN

The interleukin 17 (IL-17) family of cytokines contains 6 structurally related cytokines, IL-17A through IL-17F. IL-17A, the prototypical member of this family, just passed the 25th anniversary of its discovery. Although less is known about IL-17B-F, IL-17A (commonly known as IL-17) has received much attention for its pro-inflammatory role in autoimmune disease. Over the past decade, however, it has become clear that the functions of IL-17 are far more nuanced than simply turning on inflammation. Accumulating evidence indicates that IL-17 has important context- and tissue-dependent roles in maintaining health during response to injury, physiological stress, and infection. Here, we discuss the functions of the IL-17 family, with a focus on the balance between the pathogenic and protective roles of IL-17 in cancer and autoimmune disease, including results of therapeutic blockade and novel aspects of IL-17 signal transduction regulation.


Asunto(s)
Citocinas/inmunología , Interleucina-17/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Encéfalo/inmunología , Regulación de la Expresión Génica , Humanos , Infecciones/inmunología , Inflamación/inmunología , Interleucina-17/antagonistas & inhibidores , Ratones , Terapia Molecular Dirigida , Neoplasias/inmunología , Proteínas de Unión al ARN/inmunología , Receptores de Interleucina-17/antagonistas & inhibidores , Receptores de Interleucina-17/inmunología , Transducción de Señal , Estrés Fisiológico/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Heridas y Lesiones/inmunología
18.
Immunity ; 50(2): 446-461.e9, 2019 02 19.
Artículo en Inglés | MEDLINE | ID: mdl-30709742

RESUMEN

Production of interleukin-17 (IL-17) and IL-22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk-kinase-coupled signaling pathway in dendritic cells (DCs) was critical for commensal-dependent production of IL-17 and IL-22 by CD4+ T cells. The Syk-coupled C-type lectin receptor Mincle detected mucosal-resident commensals in the Peyer's patches (PPs), triggered IL-6 and IL-23p19 expression, and thereby regulated function of intestinal Th17- and IL-17-secreting ILCs. Mice deficient in Mincle or with selective depletion of Syk in CD11c+ cells had impaired production of intestinal RegIIIγ and IgA and increased systemic translocation of gut microbiota. Consequently, Mincle deficiency led to liver inflammation and deregulated lipid metabolism. Thus, sensing of commensals by Mincle and Syk signaling in CD11c+ cells reinforces intestinal immune barrier and promotes host-microbiota mutualism, preventing systemic inflammation.


Asunto(s)
Células Dendríticas/inmunología , Microbioma Gastrointestinal/inmunología , Interleucina-17/inmunología , Interleucinas/inmunología , Lectinas Tipo C/inmunología , Proteínas de la Membrana/inmunología , Quinasa Syk/inmunología , Animales , Células Dendríticas/metabolismo , Microbioma Gastrointestinal/fisiología , Humanos , Interleucina-17/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/metabolismo , Ganglios Linfáticos Agregados/microbiología , Transducción de Señal/inmunología , Quinasa Syk/genética , Quinasa Syk/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Interleucina-22
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