Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
1.
Annu Rev Immunol ; 31: 475-527, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23516984

RESUMEN

There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. CD4(+) T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.


Asunto(s)
Tuberculosis Pulmonar/inmunología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Mycobacterium tuberculosis/inmunología , Resultado del Tratamiento , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiología
2.
J Immunol ; 197(12): 4714-4726, 2016 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-27849167

RESUMEN

Tuberculosis causes ∼1.5 million deaths every year, thus remaining a leading cause of death from infectious diseases in the world. A growing body of evidence demonstrates that type I IFN plays a detrimental role in tuberculosis pathogenesis, likely by interfering with IFN-γ-dependent immunity. In this article, we reveal a novel mechanism by which type I IFN may confer protection against Mycobacterium tuberculosis infection in the absence of IFN-γ signaling. We show that production of type I IFN by M. tuberculosis-infected macrophages induced NO synthase 2 and inhibited arginase 1 gene expression. In vivo, absence of both type I and type II IFN receptors led to strikingly increased levels of arginase 1 gene expression and protein activity in infected lungs, characteristic of alternatively activated macrophages. This correlated with increased lung bacterial burden and pathology and decreased survival compared with mice deficient in either receptor. Increased expression of other genes associated with alternatively activated macrophages, as well as increased expression of Th2-associated cytokines and decreased TNF expression, were also observed. Thus, in the absence of IFN-γ signaling, type I IFN suppressed the switching of macrophages from a more protective classically activated phenotype to a more permissive alternatively activated phenotype. Together, our data support a model in which suppression of alternative macrophage activation by type I IFN during M. tuberculosis infection, in the absence of IFN-γ signaling, contributes to host protection.


Asunto(s)
Interferón Tipo I/metabolismo , Pulmón/inmunología , Macrófagos/inmunología , Mycobacterium tuberculosis/inmunología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Tuberculosis Pulmonar/inmunología , Animales , Arginasa/genética , Arginasa/metabolismo , Carga Bacteriana , Citocinas/metabolismo , Regulación de la Expresión Génica , Humanos , Interferón gamma/metabolismo , Pulmón/microbiología , Activación de Macrófagos , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/genética , Receptores de Interferón/genética , Transducción de Señal , Células Th2/inmunología
3.
J Immunol ; 193(7): 3600-12, 2014 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-25187652

RESUMEN

Tuberculosis, caused by the intracellular bacterium Mycobacterium tuberculosis, currently causes ∼1.4 million deaths per year, and it therefore remains a leading global health problem. The immune response during tuberculosis remains incompletely understood, particularly regarding immune factors that are harmful rather than protective to the host. Overproduction of the type I IFN family of cytokines is associated with exacerbated tuberculosis in both mouse models and in humans, although the mechanisms by which type I IFN promotes disease are not well understood. We have investigated the effect of type I IFN on M. tuberculosis-infected macrophages and found that production of host-protective cytokines such as TNF-α, IL-12, and IL-1ß is inhibited by exogenous type I IFN, whereas production of immunosuppressive IL-10 is promoted in an IL-27-independent manner. Furthermore, much of the ability of type I IFN to inhibit cytokine production was mediated by IL-10. Additionally, type I IFN compromised macrophage activation by the lymphoid immune response through severely disrupting responsiveness to IFN-γ, including M. tuberculosis killing. These findings describe important mechanisms by which type I IFN inhibits the immune response during tuberculosis.


Asunto(s)
Interferón Tipo I/inmunología , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-12/inmunología , Interleucinas/inmunología , Macrófagos/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Animales , Interferón Tipo I/genética , Interferón gamma/genética , Interleucina-10/genética , Interleucina-12/genética , Interleucina-1beta/inmunología , Interleucinas/genética , Activación de Macrófagos/inmunología , Macrófagos/microbiología , Macrófagos/patología , Ratones , Ratones Noqueados , Tuberculosis/genética , Tuberculosis/patología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
4.
Nature ; 466(7309): 973-7, 2010 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-20725040

RESUMEN

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. Efforts to control it are hampered by difficulties with diagnosis, prevention and treatment. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease. Current tests, however, cannot identify which individuals will develop disease. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines. Here we identify a whole-blood 393 transcript signature for active TB in intermediate and high-burden settings, correlating with radiological extent of disease and reverting to that of healthy controls after treatment. A subset of patients with latent TB had signatures similar to those in patients with active TB. We also identify a specific 86-transcript signature that discriminates active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-gamma and type I IFN-alphabeta signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis suggest that this TB signature reflects changes in cellular composition and altered gene expression. Although an IFN-inducible signature was also observed in whole blood of patients with systemic lupus erythematosus (SLE), their complete modular signature differed from TB, with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto underappreciated role of type I IFN-alphabeta signalling in the pathogenesis of TB, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.


Asunto(s)
Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Interferón Tipo I/inmunología , Neutrófilos/inmunología , Transcripción Genética/genética , Tuberculosis/sangre , Tuberculosis/genética , Sangre/metabolismo , Estudios de Casos y Controles , Humanos , Tuberculosis Latente/sangre , Tuberculosis Latente/diagnóstico , Tuberculosis Latente/genética , Tuberculosis Latente/inmunología , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/genética , Mycobacterium tuberculosis/inmunología , Transducción de Señal , Tuberculosis/diagnóstico , Tuberculosis/inmunología , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/inmunología
5.
J Immunol ; 191(4): 1732-43, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23842752

RESUMEN

Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading cause of mortality and morbidity worldwide, causing ≈ 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL-12, IL-1, and TNF-α, as well as IFN-γ and CD4(+) Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I IFN have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL-10 is known to inhibit the immune response to M. tuberculosis in murine models through the negative regulation of key proinflammatory cytokines and the subsequent Th1 response. We show in this study, using a combination of transcriptomic analysis, genetics, and pharmacological inhibitors, that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I IFN production. The TPL-2-ERK1/2 signaling pathway regulated production by macrophages of several cytokines important in the immune response to M. tuberculosis as well as regulating induction of a large number of additional genes, many in a type I IFN-dependent manner. In the absence of TPL-2 in vivo, excess type I IFN promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I IFN may promote susceptibility to this important disease.


Asunto(s)
Regulación de la Expresión Génica/inmunología , Interferón Tipo I/biosíntesis , Quinasas Quinasa Quinasa PAM/inmunología , Sistema de Señalización de MAP Quinasas , Proteínas Proto-Oncogénicas/inmunología , Tuberculosis/inmunología , Animales , Carga Bacteriana , Citocinas/biosíntesis , Citocinas/genética , Resistencia a la Enfermedad , Regulación hacia Abajo/inmunología , Femenino , Perfilación de la Expresión Génica , Interferón Tipo I/genética , Interleucina-10/inmunología , Listeria monocytogenes/inmunología , Listeria monocytogenes/aislamiento & purificación , Listeriosis/inmunología , Quinasas Quinasa Quinasa PAM/deficiencia , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/aislamiento & purificación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/deficiencia , Transcripción Genética
6.
J Infect Dis ; 209(2): 270-4, 2014 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23935205

RESUMEN

Influenza followed by severe acute bacterial pneumonia is a major cause of mortality worldwide. Several mechanisms account for this enhanced susceptibility, including increased production of type I interferon (IFN). In individuals infected with Mycobacterium tuberculosis, the influence of acute viral infections on tuberculosis progression is unclear. We show that prior exposure of mice to influenza A virus, followed by M. tuberculosis infection, leads to enhanced mycobacterial growth and decreased survival. Following M. tuberculosis/influenza virus coinfection, mycobacterial growth is enhanced by a type I IFN signaling pathway. Our findings highlight the detrimental influence influenza virus infection can have before or during M. tuberculosis infection.


Asunto(s)
Coinfección/inmunología , Virus de la Influenza A/inmunología , Mycobacterium tuberculosis/inmunología , Infecciones por Orthomyxoviridae/inmunología , Receptor de Interferón alfa y beta/inmunología , Tuberculosis/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/complicaciones , Transducción de Señal , Análisis de Supervivencia , Tuberculosis/complicaciones
7.
PLoS Pathog ; 8(1): e1002480, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22291590

RESUMEN

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that persists lifelong in the host. In ∼4% of infected people, HTLV-1 causes a chronic disabling neuroinflammatory disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is unknown and treatment remains ineffective. We used gene expression microarrays followed by flow cytometric and functional assays to investigate global changes in blood transcriptional profiles of HTLV-1-infected and seronegative individuals. We found that perturbations of the p53 signaling pathway were a hallmark of HTLV-1 infection. In contrast, a subset of interferon (IFN)-stimulated genes was over-expressed in patients with HAM/TSP but not in asymptomatic HTLV-1 carriers or patients with the clinically similar disease multiple sclerosis. The IFN-inducible signature was present in all circulating leukocytes and its intensity correlated with the clinical severity of HAM/TSP. Leukocytes from patients with HAM/TSP were primed to respond strongly to stimulation with exogenous IFN. However, while type I IFN suppressed expression of the HTLV-1 structural protein Gag it failed to suppress the highly immunogenic viral transcriptional transactivator Tax. We conclude that over-expression of a subset of IFN-stimulated genes in chronic HTLV-1 infection does not constitute an efficient host response but instead contributes to the development of HAM/TSP.


Asunto(s)
Regulación de la Expresión Génica , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Interferón Tipo I/metabolismo , Leucocitos/metabolismo , Paraparesia Espástica Tropical/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Productos del Gen gag/metabolismo , Productos del Gen tax/metabolismo , Humanos , Leucocitos/virología , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Biología de Sistemas/métodos
8.
Eur J Immunol ; 41(7): 1941-7, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21509782

RESUMEN

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains one of the world's largest infectious disease problems. Despite decades of intensive study, the immune response to Mtb is incompletely characterised, reflecting the extremely complex interaction between pathogen and host. Pathways that may alter the balance between host protection and pathogenesis are therefore of great interest. One pathway shown to play a role in the pathogenesis of chronic infections, including TB, is the programmed death-1 (PD-1) pathway. We show here that the expression of the programmed death ligand 1 (PD-L1), which interacts with PD-1, is increased in whole blood from active TB patients compared with whole blood from healthy controls or Mtb-exposed individuals, and that expression by neutrophils is largely responsible for this increase.


Asunto(s)
Antígenos CD/sangre , Mycobacterium tuberculosis/inmunología , Neutrófilos/inmunología , Tuberculosis/inmunología , Adulto , Antígenos CD/genética , Antígenos CD/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Antígeno B7-H1 , Citometría de Flujo , Humanos , Análisis por Micromatrices , Receptor de Muerte Celular Programada 1 , Tuberculosis/sangre
9.
J Med Chem ; 65(1): 633-664, 2022 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-34928601

RESUMEN

The Janus family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) play an essential role in the receptor signaling of cytokines that have been implicated in the pathogenesis of severe asthma, and there is emerging interest in the development of small-molecule-inhaled JAK inhibitors as treatments. Here, we describe the optimization of a quinazoline series of JAK inhibitors and the results of mouse lung pharmacokinetic (PK) studies where only low concentrations of parent compound were observed. Subsequent investigations revealed that the low exposure was due to metabolism by aldehyde oxidase (AO), so we sought to identify quinazolines that were not metabolized by AO. We found that specific substituents at the quinazoline 2-position prevented AO metabolism and this was rationalized through computational docking studies in the AO binding site, but they compromised kinome selectivity. Results presented here highlight that AO metabolism is a potential issue in the lung.


Asunto(s)
Aldehído Oxidasa/metabolismo , Inhibidores de las Cinasas Janus/farmacocinética , Pulmón/metabolismo , Administración Intranasal , Administración Intravenosa , Animales , Sitios de Unión , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Inhibidores de las Cinasas Janus/administración & dosificación , Inhibidores de las Cinasas Janus/síntesis química , Hígado/metabolismo , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Simulación del Acoplamiento Molecular , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Relación Estructura-Actividad
10.
Proc Natl Acad Sci U S A ; 105(32): 11287-92, 2008 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-18685112

RESUMEN

NKT cell subsets can be divided based on CD4 and NK1.1 expression and tissue of origin, but the developmental and functional relationships between the different subsets still are poorly understood. A comprehensive study of 19 cytokines across different NKT cell subsets revealed that no two NKT subpopulations exhibited the same cytokine profile, and, remarkably, the amounts of each cytokine produced varied by up to 100-fold or more among subsets. This study also revealed the existence of a population of CD4(-)NK1.1(-) NKT cells that produce high levels of the proinflammatory cytokine IL-17 within 2-3 h of activation. On intrathymic transfer these cells develop into mature CD4(-)NK1.1(+) but not into CD4(+)NK1.1(+) NKT cells, indicating that CD4(-)NK1.1(-) NKT cells include an IL-17-producing subpopulation, and also mark the elusive branch point for CD4(+) and CD4(-) NKT cell sublineages.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Interleucina-17/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Linfocitos T CD4-Positivos/citología , Mediadores de Inflamación/inmunología , Células Asesinas Naturales/citología , Ratones , Especificidad de Órganos/inmunología , Subgrupos de Linfocitos T/citología , Factores de Tiempo
11.
Int Immunol ; 20(2): 267-76, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18192669

RESUMEN

The contribution of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway to intrathymic negative selection is a controversial subject with two studies suggesting a key role for TRAIL, while others demonstrated normal negative selection, in TRAIL- and TRAIL receptor-deficient mice. The basis of these discrepancies is unclear and may in part reflect differences in the negative selection models under investigation. Considering the importance of the negative selection process in the establishment of a competent immune system, it is essential that these discrepancies be fully resolved. In this study, we failed to identify a role for TRAIL in an acute model of peptide antigen-specific negative selection using a TCR transgenic system as well as antibody-mediated TCR/CD3 ligation in vitro and in vivo. Moreover, thymic dendritic cells, the main cellular mediators of negative selection in the thymus, did not constitutively express TRAIL, and TRAIL receptor (DR5) expression was negative or extremely low on thymocytes. Furthermore, in vitro thymocyte deletion was normal in C57BL/6 TRAIL(-/-) gld mice, suggesting that TRAIL and FasL do not function cooperatively to induce negative selection. These results, combined with the fact that aged C57BL/6 TRAIL(-/-) mice showed no signs of spontaneous autoimmunity, strongly indicate that intrathymic negative selection occurs normally in the absence of TRAIL signaling.


Asunto(s)
Selección Genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Timo/inmunología , Timo/metabolismo , Animales , Apoptosis , Enfermedades Autoinmunes , Complejo CD3 , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/deficiencia , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Timo/citología
12.
PLoS One ; 11(2): e0150251, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26918359

RESUMEN

Analysis of the mouse transcriptional response to Listeria monocytogenes infection reveals that a large set of genes are perturbed in both blood and tissue and that these transcriptional responses are enriched for pathways of the immune response. Further we identified enrichment for both type I and type II interferon (IFN) signaling molecules in the blood and tissues upon infection. Since type I IFN signaling has been reported widely to impair bacterial clearance we examined gene expression from blood and tissues of wild type (WT) and type I IFNαß receptor-deficient (Ifnar1-/-) mice at the basal level and upon infection with L. monocytogenes. Measurement of the fold change response upon infection in the absence of type I IFN signaling demonstrated an upregulation of specific genes at day 1 post infection. A less marked reduction of the global gene expression signature in blood or tissues from infected Ifnar1-/- as compared to WT mice was observed at days 2 and 3 after infection, with marked reduction in key genes such as Oasg1 and Stat2. Moreover, on in depth analysis, changes in gene expression in uninfected mice of key IFN regulatory genes including Irf9, Irf7, Stat1 and others were identified, and although induced by an equivalent degree upon infection this resulted in significantly lower final gene expression levels upon infection of Ifnar1-/- mice. These data highlight how dysregulation of this network in the steady state and temporally upon infection may determine the outcome of this bacterial infection and how basal levels of type I IFN-inducible genes may perturb an optimal host immune response to control intracellular bacterial infections such as L. monocytogenes.


Asunto(s)
Interferón Tipo I/fisiología , Listeriosis/inmunología , Transcripción Genética/inmunología , Transcriptoma , Animales , Células Sanguíneas/metabolismo , Resistencia a la Enfermedad , Regulación de la Expresión Génica/inmunología , Interferón gamma/fisiología , Listeriosis/genética , Listeriosis/metabolismo , Recuento de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Interferón alfa y beta/deficiencia , Transducción de Señal , Bazo/metabolismo , Subgrupos de Linfocitos T/inmunología
13.
Curr Opin Immunol ; 23(1): 46-56, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21131187

RESUMEN

The tripartite motif containing (TRIM) proteins are a family of proteins that have been implicated in many biological processes including cell differentiation, apoptosis, transcriptional regulation and signaling pathways. Many TRIM proteins are upregulated by the immunologically important Type I and Type II interferons and several, including TRIM5α and TRIM19/PML, restrict viral replication. There is growing evidence that TRIMs also play an important role in the broader immune response through regulating signaling pathways such as the RIG-I pathway. In this review we discuss recent research elucidating TRIM regulation of a number of pathways important in immunity and review the latest findings relating to viral restriction by TRIMs.


Asunto(s)
Inmunidad Innata , Proteínas/inmunología , Secuencias de Aminoácidos , Animales , Humanos , Proteínas/química , Proteínas/metabolismo , Transducción de Señal , Virosis/inmunología
14.
J Immunol ; 179(10): 6630-7, 2007 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-17982053

RESUMEN

One interesting aspect of NKT cell development is that although they are thymus dependent, the pivotal transition from NK1.1(-) to NK1.1(+) can often take place after immature NK1.1(-) NKT cells are exported to the periphery. NK1.1(-) NKT cells in general are regarded as immature precursors of NK1.1(+) NKT cells, meaning that peripheral NK1.1(-) NKT cells are regarded as a transient, semimature population of recent thymic emigrant NKT cells. In this study, we report the unexpected finding that most NK1.1(-) NKT cells in the periphery of naive mice are actually part of a stable, mature and functionally distinct NKT cell population. Using adult thymectomy, we show that the size of the peripheral NK1.1(-) NKT cell pool is maintained independently of thymic export and is not the result of NK1.1 down-regulation by mature cells. We also demonstrate that most peripheral NK1.1(-) NKT cells are functionally distinct from their immature thymic counterparts, and from NK1.1(+) NKT cells in the periphery. We conclude that the vast majority of peripheral NK1.1(-) NKT cells are part of a previously unrecognized, mature NKT cell subset.


Asunto(s)
Antígenos de Superficie/inmunología , Regulación hacia Abajo/inmunología , Células Asesinas Naturales/inmunología , Lectinas Tipo C/inmunología , Linfocitos T/inmunología , Timo/inmunología , Animales , Antígenos Ly , Antígenos de Superficie/biosíntesis , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Lectinas Tipo C/biosíntesis , Ratones , Subfamilia B de Receptores Similares a Lectina de Células NK , Especificidad de Órganos/inmunología , Linfocitos T/citología , Linfocitos T/metabolismo , Timo/citología , Timo/crecimiento & desarrollo , Timo/metabolismo
15.
J Immunol ; 176(7): 4059-65, 2006 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-16547241

RESUMEN

The NKT cell pool in the thymus contains immature (NK1.1(-)) and mature (NK1.1(+)) subsets that represent distinct linear stages of a linear developmental pathway. An unexplained paradox is why immature NK1.1(-) NKT cells are mainly exported to the periphery instead of the more mature and more abundant NK1.1(+) NKT cells. In this study we have determined that mature NK1.1(+) NKT cells are retained by the thymus to form an extremely long-lived resident population capable of rapid and prolonged production of IFN-gamma and IL-4. The retention of mature NKT cells provides an explanation for why the periphery is mainly seeded by immature NK1.1(-) cells despite mature NK1.1(+) NKT cells being more abundant in the thymus. This is the first study to identify a mature T cell subset retained within the thymus and is additional evidence of the distinct developmental pathways of mainstream T cells and NKT cells.


Asunto(s)
Diferenciación Celular , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Timo/citología , Timo/inmunología , Envejecimiento/inmunología , Animales , Citocinas/biosíntesis , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/metabolismo , Timo/trasplante , Factores de Tiempo
16.
J Immunol ; 175(6): 3762-8, 2005 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-16148122

RESUMEN

After being positively selected on CD1d-expressing thymocytes, NKT cells undergo a series of developmental changes that can take place inside or outside the thymus. We asked whether CD1d continues to play a role in late-stage NKT cell development and, in particular, during the functionally significant acquisition of NK1.1 that is indicative of NKT cell maturity. We report that CD1d is indeed crucial for this step, because immature NK1.1(-) NKT cells fail to fully mature when transferred to a CD1d-deficient environment. Surprisingly, however, the lack of CD1d did not greatly affect the long-term survival of NKT cells, and they continued to express CD69 and slowly proliferate. This directly contradicts the currently held view that these phenomena are caused by autoreactivity directed against CD1d/TCR-restricted self-Ags. Our findings demonstrate an ongoing role for TCR-mediated signaling throughout NKT cell development, but the characteristic semiactivated basal state of NKT cells is controlled by CD1d-independent factors or is intrinsic to the cells themselves.


Asunto(s)
Antígenos CD1/fisiología , Homeostasis , Células Asesinas Naturales/fisiología , Animales , Antígenos CD , Antígenos CD1/genética , Antígenos CD1d , Antígenos de Diferenciación de Linfocitos T , Diferenciación Celular , Proliferación Celular , Supervivencia Celular , Células Asesinas Naturales/citología , Lectinas Tipo C , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T , Transducción de Señal , Linfocitos T
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA