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1.
Neurogastroenterol Motil ; 31(1): e13467, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30240048

RESUMO

BACKGROUND: Neuroimmune interactions are essential to maintain gut homeostasis and prevent intestinal disorders but so far, the impact of enteric glial cells (EGC) on immune cells remains a relatively unexplored area of research. As a dysregulation of critical cytokines such as interleukine-7 (IL-7) was suggested to exacerbate gut chronic inflammation, we investigated whether EGC could be a source of IL-7 in the gastrointestinal tract. METHODS: Expression of IL-7 in the rat enteric nervous system was analyzed by immunochemistry and Q-PCR. IL-7 variants were cloned and specific antibodies against rat IL-7 isoforms were raised to characterize their expression in the submucosal plexus. IL-7 isoforms were produced in vitro to analyze their impact on T-cell survival. KEY RESULTS: Neurons and glial cells of the rat enteric nervous system expressed IL-7 at both mRNA and protein levels. Novel rat IL-7 isoforms with distinct C-terminal parts were detected. Three of these isoforms were found in EGC or in both enteric neurons and EGC. Exposure of EGC to pro-inflammatory cytokines (IL-1ß and/or TNFα) induced an upregulation of all IL-7 isoforms. Interestingly, time-course and intensity of the upregulation varied according to the presence or absence of exon 5a in IL-7 variants. Functional analysis on T lymphocytes revealed that only canonical IL-7 protects T cells from cell death. CONCLUSIONS AND INFERENCES: IL-7 and its variants are expressed by neurons and glial cells in the enteric nervous system. Their distinct expression and upregulation in inflammatory conditions suggest a role in gut homeostasis which could be critical in case of chronic inflammatory diseases.


Assuntos
Inflamação/imunologia , Interleucina-7/imunologia , Neuroglia/imunologia , Neuroimunomodulação/imunologia , Plexo Submucoso/imunologia , Animais , Feminino , Interleucina-7/biossíntese , Intestino Delgado/imunologia , Intestino Delgado/inervação , Neurônios/imunologia , Isoformas de Proteínas , Ratos , Ratos Sprague-Dawley , Linfócitos T/imunologia
2.
Cardiovasc Ther ; 36(6): e12479, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30451388

RESUMO

AIMS: Mesenchymal stem cells (MSCs) hold significant promise as potential therapeutic candidates following cardiac injury. However, to ensure survival of transplanted cells in ischemic environment, it is beneficial to precondition them with growth factors that play important role in cell survival and proliferation. Aim of this study is to use interleukin-7 (IL-7), a cell survival growth factor, to enhance the potential of rat bone marrow MSCs in terms of cell fusion in vitro and cardiac function in vivo. METHODS: Mesenchymal stem cells were transfected with IL-7 gene through retroviral vector. Normal and transfected MSCs were co-cultured with neonatal cardiomyocytes (CMs) and cell fusion was analyzed by flow cytometry and fluorescence microscopy. These MSCs were also transplanted in rat model of myocardial infarction (MI) and changes at tissue level and cardiac function were assessed by histological analysis and echocardiography, respectively. RESULTS: Co-culture of IL-7 transfected MSCs and CMs showed significantly higher (P < 0.01) number of fused cells as compared to normal MSCs. Histological analysis of hearts transplanted with IL-7 transfected MSCs showed significant reduction (P < 0.001) in infarct size and better preservation (P < 0.001) of left ventricular wall thickness as compared to normal MSCs. Presence of cardiac-specific proteins, α-actinin, and troponin-T showed that the transplanted MSCs were differentiated into cardiomyocytes. Echocardiographic recordings of the experimental group transplanted with transfected MSCs showed significant increase in the ejection fraction and fractional shortening (P < 0.01), and decrease in diastolic and systolic left ventricular internal diameters (P < 0.001) and end systolic and diastolic volumes (P < 0.01 and P < 0.001, respectively). CONCLUSION: Interleukin-7 is able to enhance the fusogenic properties of MSCs and improve cardiac function. This improvement may be attributed to the supportive action of IL-7 on cell proliferation and cell survival contributing to the regeneration of damaged myocardium.


Assuntos
Fusão Celular , Interleucina-7/biossíntese , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/cirurgia , Miócitos Cardíacos/metabolismo , Animais , Animais Recém-Nascidos , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Interleucina-7/genética , Masculino , Contração Miocárdica , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Regeneração , Volume Sistólico , Transfecção , Função Ventricular Esquerda , Remodelação Ventricular
3.
Rev Peru Med Exp Salud Publica ; 34(3): 436-444, 2017.
Artigo em Espanhol | MEDLINE | ID: mdl-29267767

RESUMO

OBJECTIVES: To evaluate the effect of ZnO, TiO2 and SiO2 nanoparticles on cell viability and expression of the interleukin 7, interleukin 3, and granulocyte-macrophage colony stimulating factor (GM-CSF) genes in Mus musculus. MATERIAL AND METHODS: Red bone marrow was extracted from five Balb/c mice for the analysis of cell viability using the MTT test. The mice were divided into two groups of five each: one group was inoculated intraperitoneally with 0.5, 1.0, 2.5, 5.0, and 10 mg/kg of ZnO and SiO2 nanoparticles, respectively, and the other group was inoculated with 5.0, 10.0, 15.0, 20.0, and 25 mg/kg of TiO2 nanoparticles, respectively. Thirty hours later, RNA was extracted from the red bone marrow of the mice in both groups for gene expression analysis using quantitative PCR and RT-PCR. RESULTS: ZnO and SiO2 nanoparticles reduced cell viability in a dose-dependent manner by 37% and 26%, respectively, starting at a dose of 1 mg/kg. TiO2 nanoparticles at 5 mg/kg and 10 mg/kg reduced the gene expression of interleukins 7 and 3 by 55.3% and 70.2%, respectively, and SiO2 nanoparticles caused the greatest decrease (91%) in the expression of GM-CSF. ZnO nanoparticles reduced the expression of GM-CSF starting at doses of 20 mg/kg and 25 mg/kg. CONCLUSIONS: ZnO, SiO2 and TiO2 nanoparticles affect cell viability and gene expression in the mouse bone marrow.


Assuntos
Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Interleucina-3/biossíntese , Interleucina-7/biossíntese , Nanopartículas , Dióxido de Silício/farmacologia , Titânio/farmacologia , Óxido de Zinco/farmacologia , Animais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Interleucina-3/genética , Interleucina-7/genética , Camundongos , Camundongos Endogâmicos BALB C
4.
Nat Commun ; 8: 15068, 2017 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-28485401

RESUMO

Foxp3+ regulatory T cells (Treg cells) modulate the immune system and maintain self-tolerance, but whether they affect haematopoiesis or haematopoietic stem cell (HSC)-mediated reconstitution after transplantation is unclear. Here we show that B-cell lymphopoiesis is impaired in Treg-depleted mice, yet this reduced B-cell lymphopoiesis is rescued by adoptive transfer of affected HSCs or bone marrow cells into Treg-competent recipients. B-cell reconstitution is abrogated in both syngeneic and allogeneic transplantation using Treg-depleted mice as recipients. Treg cells can control physiological IL-7 production that is indispensable for normal B-cell lymphopoiesis and is mainly sustained by a subpopulation of ICAM1+ perivascular stromal cells. Our study demonstrates that Treg cells are important for B-cell differentiation from HSCs by maintaining immunological homoeostasis in the bone marrow microenvironment, both in physiological conditions and after bone marrow transplantation.


Assuntos
Linfócitos B/imunologia , Medula Óssea/imunologia , Microambiente Celular , Fatores de Transcrição Forkhead/metabolismo , Linfopoese/imunologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-7/biossíntese , Depleção Linfocítica , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Biológicos , Células Estromais/metabolismo , Transplante Homólogo
5.
J Virol ; 91(7)2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28100620

RESUMO

Rabies continues to present a public health threat in most countries of the world. The most efficient way to prevent and control rabies is to implement vaccination programs for domestic animals. However, traditional inactivated vaccines used in animals are costly and have relatively low efficiency, which impedes their extensive use in developing countries. There is, therefore, an urgent need to develop single-dose and long-lasting rabies vaccines. However, little information is available regarding the mechanisms underlying immunological memory, which can broaden humoral responses following rabies vaccination. In this study, a recombinant rabies virus (RABV) that expressed murine interleukin-7 (IL-7), referred to here as rLBNSE-IL-7, was constructed, and its effectiveness was evaluated in a mouse model. rLBNSE-IL-7 induced higher rates of T follicular helper (Tfh) cells and germinal center (GC) B cells from draining lymph nodes (LNs) than the parent virus rLBNSE. Interestingly, rLBNSE-IL-7 improved the percentages of long-lived memory B cells (Bmem) in the draining LNs and plasma cells (PCs) in the bone marrow (BM) for up to 360 days postimmunization (dpi). As a result of the presence of the long-lived PCs, it also generated prolonged virus-neutralizing antibodies (VNAs), resulting in better protection against a lethal challenge than that seen with rLBNSE. Moreover, consistent with the increased numbers of Bmem and PCs after a boost with rLBNSE, rLBNSE-IL-7-immunized mice promptly produced a more potent secondary anti-RABV neutralizing antibody response than rLBNSE-immunized mice. Overall, our data suggest that overexpressing IL-7 improved the induction of long-lasting primary and secondary antibody responses post-RABV immunization.IMPORTANCE Extending humoral immune responses using adjuvants is an important method to develop long-lasting and efficient vaccines against rabies. However, little information is currently available regarding prolonged immunological memory post-RABV vaccination. In this study, a novel rabies vaccine that expressed murine IL-7 was developed. This vaccine enhanced the numbers of Tfh cells and the GC responses, resulting in upregulated quantities of Bmem and PCs. Moreover, we found that the long-lived PCs that were elicited by the IL-7-expressing recombinant virus (rLBNSE-IL-7) were able to sustain VNA levels much longer than those elicited by the parent rLBNSE virus. Upon reexposure to the pathogen, the longevous Bmem, which maintained higher numbers for up to 360 dpi with rLBNSE-IL-7 compared to rLBNSE, could differentiate into antibody-secreting cells, resulting in rapid and potent secondary production of VNAs. These results suggest that the expression of IL-7 is beneficial for induction of potent and long-lasting humoral immune responses.


Assuntos
Imunidade Humoral , Interleucina-7/biossíntese , Vacinas Antirrábicas/imunologia , Vírus da Raiva/imunologia , Raiva/prevenção & controle , Animais , Anticorpos Antivirais/sangue , Linhagem Celular , Cricetinae , Feminino , Expressão Gênica , Interleucina-7/genética , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Raiva/imunologia , Vacinação
6.
Biomedica ; 37(4): 571-576, 2017 Dec 01.
Artigo em Espanhol | MEDLINE | ID: mdl-29373776

RESUMO

Introducción. El caseinato de sodio, una sal de la caseína utilizada como agente proinflamatorio en ratones, es capaz de inducir granulopoyesis en vivo e incrementar la producción de citocinas esenciales en dicho evento.Objetivo. Evaluar si el caseinato de sodio es capaz de inducir un efecto biológico en células de origen linfoide y la producción de citocinas involucradas con este linaje.Materiales y métodos: Se utilizaron ratones hembra BALB/c de 8 a 12 semanas de edad. Los animales se inyectaron cuatro veces, con intervalos de 48 horas, por vía intraperitoneal con 1 ml de caseinato de sodio (10 % de SFB p/v). La población de linfocitos B y la incorporación de bromodesoxiuridina (BrdU) se analizaron mediante citometría de flujo. La detección de la interleucina 7 se evaluó mediante la técnica de ELISA.Resultados. Tras la inyección por vía intraperitoneal, el número de linfocitos B 220+ provenientes del bazo de ratones tratados con caseinato de sodio aumentó comparados con los que solo recibieron el vehículo como tratamiento (89,01±1,03 Vs. 75,66±2,08), así como la incorporación de BrdU en células B220+ (38,59±4,48 Vs. 11,82±1,04). Se evidenció, asimismo, el incremento en la concentración de la interleucina 7 (IL-7) en el suero de los ratones tratados con caseinato de sodio, comparados con los que solo recibieron el vehículo (62,1±17,5 Vs. 26,9±4,4 pg/ml).Conclusión. El caseinato de sodio fue capaz de aumentar el número de linfocitos B en bazo de ratones, así como inducir la producción de IL-7, citocina clave para la linfopoyesis B.


Assuntos
Linfócitos B/efeitos dos fármacos , Caseínas/farmacologia , Linfopoese/efeitos dos fármacos , Animais , Medula Óssea/efeitos dos fármacos , Caseínas/administração & dosagem , Caseínas/toxicidade , Divisão Celular , Feminino , Injeções Intraperitoneais , Interleucina-7/biossíntese , Interleucina-7/sangue , Interleucina-7/genética , Contagem de Linfócitos , Linfocinas/biossíntese , Linfocinas/genética , Camundongos , Camundongos Endogâmicos BALB C , Baço/citologia , Baço/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
7.
Invest Ophthalmol Vis Sci ; 56(13): 7831-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26658504

RESUMO

PURPOSE: Innate immune signaling elicited by polyinosinic-polycytidylic acid (poly I:C) induces IL-7 production and early inflammatory responses in the salivary gland and accelerates the development of Sjögren's syndrome (SS)-like sialadenitis. Whether poly I:C can induce similar responses in the lacrimal gland (LAC) has not been characterized. In this study, we examined the early responses and pathologic changes of the LAC tissue in response to poly I:C treatment. METHODS: Poly I:C or recombinant human IL-7 was injected intraperitoneally into C57BL/6 mice, and the LAC was harvested at different time points. Expression of chemokines and cytokines in the LAC was measured by RT-PCR, immunofluorescence staining, and immunohistochemistry. Leukocytic infiltration and caspase-3 activation were analyzed by hematoxylin and eosin staining and immunohistochemistry. Serum antinuclear antibody levels were also determined. Tear secretion was measured by phenol red cotton threads. RESULTS: Administration of poly I:C induced IL-7 gene expression and protein production in the LAC. Poly I:C also induced the expression of CXCR3 ligands, monocyte chemoattractant protein-1, IL-23p19, and TNF-α in the LAC in an IL-7-dependent fashion. Similarly to poly I:C, administration of exogenous IL-7 also up-regulated these proinflammatory mediators. Furthermore, repeated administration of poly I:C to C57BL/6 mice over an 8-day period caused leukocytic infiltration and caspase-3 activation in the LAC, antinuclear antibody production, and impaired tear secretion. CONCLUSIONS: Poly I:C induces IL-7 production, early inflammatory responses, and characteristic pathologies of SS-like dacryoadenitis in non-autoimmune-prone C57BL/6 mice. These findings provide new evidence that viral infection-elicited innate immune signaling may be one of the early triggers of SS-like dacryoadenitis.


Assuntos
DNA/genética , Dacriocistite/metabolismo , Regulação da Expressão Gênica , Imunidade Inata , Interleucina-7/genética , Aparelho Lacrimal/metabolismo , Síndrome de Sjogren/metabolismo , Animais , Dacriocistite/genética , Dacriocistite/imunologia , Modelos Animais de Doenças , Feminino , Imuno-Histoquímica , Interleucina-7/biossíntese , Aparelho Lacrimal/patologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Síndrome de Sjogren/genética , Síndrome de Sjogren/imunologia , Lágrimas/metabolismo , Fatores de Tempo
8.
Leuk Res ; 39(12): 1437-42, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26467815

RESUMO

In acute lymphoblastic leukemia (ALL) the bone marrow microenvironment provides growth and survival signals that may confer resistance to chemotherapy. Granulocyte colony-stimulating factor (G-CSF) potently inhibits lymphopoiesis by targeting stromal cells that comprise the lymphoid niche in the bone marrow. To determine whether lymphoid niche disruption by G-CSF sensitizes ALL cells to chemotherapy, we conducted a pilot study of G-CSF in combination with chemotherapy in patients with relapsed or refractory ALL. Thirteen patients were treated on study; three patients achieved a complete remission (CR/CRi) for an overall response rate of 23%. In the healthy volunteers, G-CSF treatment disrupted the lymphoid niche, as evidenced by reduced expression of CXCL12, interleukin-7, and osteocalcin. However, in most patients with relapsed/refractory ALL expression of these genes was markedly suppressed at baseline. Thus, although G-CSF treatment was associated with ALL cell mobilization into the blood, and increased apoptosis of bone marrow resident ALL cells, alterations in the bone marrow microenvironment were modest and highly variable. These data suggest that disruption of lymphoid niches by G-CSF to sensitize ALL cells to chemotherapy may be best accomplished in the consolidation where the bone marrow microenvironment is more likely to be normal.


Assuntos
Medula Óssea/patologia , Células-Tronco Neoplásicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Nicho de Células-Tronco , Microambiente Tumoral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Ativador de Células B/biossíntese , Fator Ativador de Células B/genética , Quimiocina CXCL12/biossíntese , Quimiocina CXCL12/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Etoposídeo/administração & dosagem , Feminino , Filgrastim/administração & dosagem , Filgrastim/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Ifosfamida/administração & dosagem , Interleucina-7/biossíntese , Interleucina-7/genética , Masculino , Mesna/administração & dosagem , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Osteocalcina/biossíntese , Osteocalcina/genética , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Indução de Remissão , Terapia de Salvação , Nicho de Células-Tronco/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Adulto Jovem
9.
Cancer Immunol Res ; 3(12): 1364-74, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26297711

RESUMO

Adoptive cellular therapy, in which activated tumor-reactive T cells are transferred into lymphodepleted recipients, is a promising cancer treatment option. Activation of T cells decreases IL7 responsiveness; therefore, IL15 is generally considered the main driver of effector T-cell responses in this setting. However, we found in lymphodepleted mice that CD8(+) T cells activated with IL12 showed enhanced engraftment that was initially dependent on host IL7, but not IL15. Mechanistically, enhanced IL7 responsiveness was conferred by elevated IL7Rα expression, which was critical for antitumor immunity. Elevated IL7Rα expression was achievable without IL12, as polyclonal CD8(+) T cells activated with high T-cell receptor (TCR) stimulation depended on T-cell IL7Rα expression and host IL7 for maximal engraftment. Finally, IL12 conditioning during the activation of human CD8(+) T cells, including TCR-modified T cells generated using a clinically relevant protocol, led to enhanced IL7Rα expression. Our results demonstrate the importance of the donor IL7Rα/host IL7 axis for effector CD8(+) T-cell engraftment and suggest novel strategies to improve adoptive cellular therapy as a cancer treatment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Subunidade p35 da Interleucina-12/imunologia , Interleucina-7/imunologia , Receptores de Interleucina-7/biossíntese , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/transplante , Linhagem Celular Tumoral , Humanos , Subunidade p35 da Interleucina-12/biossíntese , Interleucina-15/biossíntese , Interleucina-15/imunologia , Interleucina-7/biossíntese , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-7/imunologia
10.
Immunology ; 146(1): 89-99, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25988531

RESUMO

Natural killer T cells (NKT cells) are comprised of several subsets. However, the possible differences in their developmental mechanisms have not been fully investigated. To evaluate the dependence of some NKT subpopulations on nuclear factor-κB-inducing kinase (NIK) for their generation, we analysed the differentiation of NKT cells, dividing them into subsets in various tissues of alymphoplasia (aly/aly), a mutant mouse strain that lacks functional NIK. The results indicated that the efficient differentiation of both invariant NKT (iNKT) and non-iNKT cells relied on NIK expression in non-haematopoietic cells; however, the dependence of non-iNKT cells was lower than that of iNKT cells. Especially, the differentiation of CD8(+) non-iNKT cells was markedly resistant to the aly mutation. The proportion of two other NKT cell subsets, NK1.1(+) γδ T cells and NK1.1(-) iNKT cells, was also significantly reduced in aly/aly mice, and this defect in their development was reversed in wild-type host mice given aly/aly bone marrow cells. In exerting effector functions, NIK in NKT-αß cells appeared dispensable, as NIK-deficient NKT-αß cells could secrete interleukin-4 or interferon-γ and exhibit cytolytic activity at a level comparable to that of aly/+ NKT-αß cells. Collectively, these results imply that the NIK in thymic stroma may be critically involved in the differentiation of most NKT cell subsets (although the level of NIK dependence may vary among the subsets), and also that NIK in NKT-αß cells may be dispensable for their effector function.


Assuntos
Linfócitos T CD8-Positivos/citologia , Células T Matadoras Naturais/citologia , Proteínas Serina-Treonina Quinases/genética , Subpopulações de Linfócitos T/citologia , Animais , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Interferon gama/metabolismo , Interleucina-15/biossíntese , Interleucina-4/metabolismo , Interleucina-7/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia
11.
J Virol ; 89(4): 2112-20, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25473049

RESUMO

UNLABELLED: Regulatory T (Treg) cells are important in the maintenance of self-tolerance, and the depletion of Treg cells correlates with autoimmune development. It has been shown that type I interferon (IFN) responses induced early in the infection of mice can drive memory (CD44hi) CD8 and CD4 T cells into apoptosis, and we questioned here whether the apoptosis of CD44-expressing Treg cells might be involved in the infection-associated autoimmune development. Instead, we found that Treg cells were much more resistant to apoptosis than CD44hi CD8 and CD4 T cells at days 2 to 3 after lymphocytic choriomeningitis virus infection, when type I IFN levels are high. The infection caused a downregulation of the interleukin-7 (IL-7) receptor, needed for survival of conventional T cells, while increasing on Treg cells the expression of the high-affinity IL-2 receptor, needed for STAT5-dependent survival of Treg cells. The stably maintained Treg cells early during infection may explain the relatively low incidence of autoimmune manifestations among infected patients. IMPORTANCE: Autoimmune diseases are controlled in part by regulatory T cells (Treg) and are thought to sometimes be initiated by viral infections. We tested the hypothesis that Treg may die off at early stages of infection, when virus-induced factors kill other lymphocyte types. Instead, we found that Treg resisted this cell death, perhaps reducing the tendency of viral infections to cause immune dysfunction and induce autoimmunity.


Assuntos
Apoptose , Infecções por Arenaviridae/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/virologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Sobrevivência Celular , Regulação da Expressão Gênica , Interferon Tipo I/imunologia , Interleucina-7/biossíntese , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/fisiologia
12.
J Immunol ; 194(1): 243-51, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-25429074

RESUMO

Notch signaling is an important regulator for the development and function of both αß and γδ T cells, whereas roles of Notch signaling in T cell maintenance remain unclear. We reported previously that the Notch-Hes1 pathway was involved in the intrathymic development of naturally occurring IL-17-producing (IL-17(+)) γδ T cells. To gain insight into additional roles for the Notch axis in the homeostasis of γδ T cells, we performed a genome-wide analysis of Notch target genes and identified the novel promoter site of IL-7Rα driven by the Notch-RBP-Jκ pathway. Constitutive Notch signaling had the potential to induce IL-7Rα expression on γδ T cells in vivo, as well as in vitro, whereas conditional deletion of RBP-Jκ abrogated IL-7Rα expression, but not Hes1 expression, by γδ T cells and selectively reduced the pool size of IL-7Rα(high) IL-17(+) γδ T cells in the periphery. In the absence of IL-7Rα-mediated signaling, IL-17(+) γδ T cells were barely maintained in adult mice. Addition of exogenous IL-7 in vitro selectively expanded IL-17(+) γδ T cells. Thus, our results revealed a novel role for the Notch-RBP-Jκ-IL-7Rα axis that is independent of Hes1 for homeostasis of IL-17(+) γδ T cells.


Assuntos
Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/imunologia , Interleucina-17/biossíntese , Receptor Notch1/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Interleucina-7/imunologia , Animais , Anticorpos/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Proliferação de Células/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/biossíntese , Homeostase , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Interferon gama/biossíntese , Interleucina-7/biossíntese , Interleucina-7/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Interleucina-7/biossíntese , Transdução de Sinais , Linfócitos T/imunologia , Fatores de Transcrição HES-1
13.
Immunity ; 41(3): 451-464, 2014 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-25220211

RESUMO

Innate immune responses are critical for mucosal immunity. Here we describe an innate lymphocyte population, iCD8α cells, characterized by expression of CD8α homodimers. iCD8α cells exhibit innate functional characteristics such as the capacity to engulf and kill bacteria. Development of iCD8α cells depends on expression of interleukin-2 receptor γ chain (IL-2Rγc), IL-15, and the major histocompatibility complex (MHC) class Ib protein H2-T3, also known as the thymus leukemia antigen or TL. While lineage tracking experiments indicated that iCD8α cells have a lymphoid origin, their development was independent of the transcriptional suppressor Id2, suggesting that these cells do not belong to the family of innate lymphoid cells. Finally, we identified cells with a similar phenotype in humans, which were profoundly depleted in newborns with necrotizing enterocolitis. These findings suggest a critical role of iCD8α cells in immune responses associated with the intestinal epithelium.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos CD8/biossíntese , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/citologia , Linfócitos/imunologia , Animais , Citrobacter rodentium/imunologia , Citocalasina D/farmacologia , Enterocolite Necrosante , Helicobacter pylori/imunologia , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Proteína 2 Inibidora de Diferenciação/genética , Subunidade gama Comum de Receptores de Interleucina/biossíntese , Interleucina-15/biossíntese , Interleucina-2/biossíntese , Interleucina-7/biossíntese , Mucosa Intestinal/imunologia , Ativação Linfocitária/imunologia , Linfócitos/classificação , Linfócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia
14.
Cytokine Growth Factor Rev ; 25(4): 391-401, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25130296

RESUMO

Interleukin-7 is a non-redundant growth, differentiation and survival factor for human T lymphocytes. Most circulating, mature T cells express the receptor for IL-7, but not all. Importantly, CD4 Tregs express greatly reduced levels of IL-7R compared to conventional CD4 T cells, presenting an opportunity to selectively target the latter cells with either more IL-7 to boost responses, or to block IL-7 signalling to limit responses. This article reviews what is known about regulation of IL-7R expression, and recent progress in therapeutic approaches related to IL-7 and its receptor.


Assuntos
Subunidade alfa de Receptor de Interleucina-7/imunologia , Interleucina-7/imunologia , Interleucina-7/uso terapêutico , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/imunologia , Humanos , Memória Imunológica/imunologia , Interleucina-7/biossíntese , Subunidade alfa de Receptor de Interleucina-7/biossíntese , Linfopenia/imunologia , Neoplasias/terapia , Transdução de Sinais/imunologia
15.
J Immunol ; 193(6): 2831-42, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25114101

RESUMO

The leukocyte-specific tyrosine phosphatase, CD45, severely impacts T cell development and activation by modulating TCR signaling. CD45-deficient (CD45KO) mice have reduced peripheral T cell numbers where CD8 T cells are underrepresented. In this article, we show that CD45KO mice are unable to support efficient homeostatic proliferation, affecting CD8 T cells more than CD4 T cells. Using CD45-RAG1 double-deficient (45RAGKO) mice, we show that lymphopenia-induced proliferation (LIP) of CD45-sufficient T cells is defective in a host environment lacking CD45 on innate immune cells. We identify two deficiencies in the 45RAGKO mice that affect LIP. One involves CD11c(+) cells and the second the production of IL-7 by lymphoid stromal cells. CD45KO dendritic cells were not defective in foreign Ag-induced T cell proliferation, yet CD45KO CD11c(+) cells were unable to rescue the spontaneous LIP in the 45RAGKO mice. This was in contrast with the CD45-sufficient CD11c(+) cells that partially rescued this spontaneous proliferation and did so without affecting IL-7 levels. The absence of CD45 also led to reduced IL-7 production by lymphoid stromal cells, suggesting an indirect effect of CD45 on innate immune cells in influencing IL-7 production by lymphoid stromal cells. These findings demonstrate a novel role for CD45 on innate immune cells in promoting lymphopenia-induced T cell proliferation and suggest that innate immune cells may communicate with stromal cells to regulate IL-7 production.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígenos Comuns de Leucócito/imunologia , Ativação Linfocitária/imunologia , Linfopenia/imunologia , Animais , Antígeno CD11c/biossíntese , Relação CD4-CD8 , Diferenciação Celular/imunologia , Proliferação de Células , Células Dendríticas/imunologia , Imunidade Inata , Interleucina-7/biossíntese , Antígenos Comuns de Leucócito/biossíntese , Antígenos Comuns de Leucócito/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Células Estromais/imunologia
16.
PLoS One ; 9(2): e88201, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24586307

RESUMO

Age-related macular degeneration (AMD) is a major disease affecting central vision, but the pathogenic mechanisms are not fully understood. Using a mouse model, we examined the relationship of two factors implicated in AMD development: oxidative stress and the immune system. Carboxyethylpyrrole (CEP) is a lipid peroxidation product associated with AMD in humans and AMD-like pathology in mice. Previously, we demonstrated that CEP immunization leads to retinal infiltration of pro-inflammatory M1 macrophages before overt retinal degeneration. Here, we provide direct and indirect mechanisms for the effect of CEP on macrophages, and show for the first time that antigen-specific T cells play a leading role in AMD pathogenesis. In vitro, CEP directly induced M1 macrophage polarization and production of M1-related factors by retinal pigment epithelial (RPE) cells. In vivo, CEP eye injections in mice induced acute pro-inflammatory gene expression in the retina and human AMD eyes showed distinctively diffuse CEP immunolabeling within RPE cells. Importantly, interferon-gamma (IFN-γ) and interleukin-17 (IL-17)-producing CEP-specific T cells were identified ex vivo after CEP immunization and promoted M1 polarization in co-culture experiments. Finally, T cell immunosuppressive therapy inhibited CEP-mediated pathology. These data indicate that T cells and M1 macrophages activated by oxidative damage cooperate in AMD pathogenesis.


Assuntos
Macrófagos/citologia , Macrófagos/imunologia , Degeneração Macular/etiologia , Degeneração Macular/imunologia , Estresse Oxidativo/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Transporte Biológico/efeitos dos fármacos , Ciclosporina/farmacologia , Modelos Animais de Doenças , Feminino , Humanos , Imunização , Interferon gama/biossíntese , Interleucina-7/biossíntese , Degeneração Macular/metabolismo , Masculino , Camundongos , Pirróis/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Epitélio Pigmentado da Retina/imunologia , Epitélio Pigmentado da Retina/metabolismo , Sirolimo/farmacologia
17.
Gut ; 63(4): 665-73, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23787026

RESUMO

BACKGROUND: IL-7 and IL-15 are produced by hepatocytes and are critical for the expansion and function of CD8 T cells. IL-15 needs to be presented by IL-15Rα for efficient stimulation of CD8 T cells. METHODS: We analysed the hepatic levels of IL-7, IL-15, IL-15Rα and interferon regulatory factors (IRF) in patients with chronic hepatitis C (CHC) (78% genotype 1) and the role of IRF1 and IRF2 on IL-7 and IL-15Rα expression in Huh7 cells with or without hepatitis C virus (HCV) replicon. RESULTS: Hepatic expression of both IL-7 and IL-15Rα, but not of IL-15, was reduced in CHC. These patients exhibited decreased hepatic IRF2 messenger RNA levels and diminished IRF2 staining in hepatocyte nuclei. We found that IRF2 controls basal expression of both IL-7 and IL-15Rα in Huh7 cells. IRF2, but not IRF1, is downregulated in cells with HCV genotype 1b replicon and this was accompanied by decreased expression of IL-7 and IL-15Rα, a defect reversed by overexpressing IRF2. Treating Huh7 cells with IFNα plus oncostatin M increased IL-7 and IL-15Rα mRNA more intensely than either cytokine alone. This effect was mediated by strong upregulation of IRF1 triggered by the combined treatment. Induction of IRF1, IL-7 and IL-15Rα by IFNα plus oncostatin M was dampened in replicon cells but the combination was more effective than either cytokine alone. CONCLUSIONS: HCV genotype 1 infection downregulates IRF2 in hepatocytes attenuating hepatocellular expression of IL-7 and IL-15Rα. Our data reveal a new mechanism by which HCV abrogates specific T-cell responses and point to a novel therapeutic approach to stimulate anti-HCV immunity.


Assuntos
Hepacivirus/fisiologia , Hepatite C Crônica/fisiopatologia , Hepatócitos/fisiologia , Fatores Reguladores de Interferon/fisiologia , Western Blotting , Linfócitos T CD8-Positivos/fisiologia , Regulação Viral da Expressão Gênica/genética , Regulação Viral da Expressão Gênica/fisiologia , Genótipo , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatite C Crônica/metabolismo , Hepatite C Crônica/virologia , Hepatócitos/metabolismo , Hepatócitos/virologia , Humanos , Fator Regulador 1 de Interferon/biossíntese , Fator Regulador 1 de Interferon/fisiologia , Fator Regulador 2 de Interferon/biossíntese , Fator Regulador 2 de Interferon/fisiologia , Interleucina-15/biossíntese , Interleucina-15/fisiologia , Subunidade alfa de Receptor de Interleucina-15/biossíntese , Subunidade alfa de Receptor de Interleucina-15/fisiologia , Interleucina-7/biossíntese , Interleucina-7/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Replicação Viral/fisiologia
18.
PLoS One ; 8(11): e78966, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24236077

RESUMO

Bacillus Calmette-Guérin (BCG), the only approved tuberculosis vaccine, provides only limited protection. Previously, we generated a recombinant derivative (BCG ΔureC::hly), which secretes the pore-forming toxin listeriolysin O (LLO) of Listeria monocytogenes. This vaccine shows superior protection against tuberculosis in preclinical models and is safe in humans. Here we describe two new vaccine strains which express human interleukin-7 (hIL)-7 or hIL-18 in the genetic background of BCG ΔureC::hly to modulate specific T cell immunity. Both strains exhibited an uncompromised in vitro growth pattern, while inducing a proinflammatory cytokine profile in human dendritic cells (DCs). Human DCs harbouring either strain efficiently promoted secretion of IL-2 by autologous T cells in a coculture system, suggesting superior immunogenicity. BALB/c mice vaccinated with BCG ΔureC::hly, BCG ΔureC::hly_hIL7 or BCG ΔureC::hly_hIL18 developed a more robust Th1 response than after vaccination with parental BCG. Both strains provided significantly better protection than BCG in a murine Mycobacterium tuberculosis challenge model but efficacy remained comparable to that afforded by BCG ΔureC::hly. We conclude that expression of hIL-7 or hIL-18 enhanced specific T cell responses but failed to improve protection over BCG ΔureC::hly in mice.


Assuntos
Vacina BCG/imunologia , Interleucina-18/biossíntese , Interleucina-7/biossíntese , Mycobacterium tuberculosis/imunologia , Células Th1/imunologia , Tuberculose/prevenção & controle , Vacinação , Animais , Antígenos de Bactérias/imunologia , Vacina BCG/genética , Ligante de CD40/metabolismo , Células Cultivadas , Feminino , Expressão Gênica , Humanos , Interleucina-18/genética , Interleucina-7/genética , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Baço/imunologia , Baço/patologia , Células Th1/metabolismo
19.
PLoS One ; 8(10): e77605, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24147035

RESUMO

Elevated IL-7 in the target tissues is closely associated with multiple autoimmune disorders, including Sjögren's syndrome (SS). We recently found that IL-7 plays an essential role in the development and onset of primary SS (pSS) in C57BL/6.NOD-Aec1Aec2 mice, a well-defined mouse model of primary SS. However, environmental signals that cause excessive IL-7 production are not well-characterized. Innate immune signaling plays a critical role in shaping the adaptive immune responses including autoimmune responses. We and others have previously shown that innate immune signaling can induce IL-7 expression in lungs and intestines of C57BL/6 mice. In this study, we characterized the effects of poly I:C, a double-stranded RNA analog and toll-like receptor 3 agonist, on the induction of IL-7 expression in salivary glands and on pSS development. We showed that poly I:C administration to C57BL/6 mice rapidly induced IL-7 expression in the salivary glands in a type 1 IFN- and IFN-γ-dependent manner. Moreover, poly I:C-induced IL-7 contributed to the optimal up-regulation of CXCL9 in the salivary glands, which may subsequently promote recruitment of more IFN-γ-producing T cells. Repeated administration of poly I:C to C57BL/6.NOD-Aec1Aec2 mice accelerated the development of SS-like exocrinopathy, and this effect was abolished by the blockade of IL-7 receptor signaling with a neutralizing antibody. Finally, poly I:C or a combination of IFN-α and IFN-γ induced IL-7 gene expression and protein production in a human salivary gland epithelial cell line. Hence, we demonstrate that IL-7 expression in the salivary gland cells can be induced by poly I:C and delineate a crucial mechanism by which innate immune signals facilitate the development of pSS, which is through induction of IL-7 in the target tissues.


Assuntos
Imunidade Inata , Interleucina-7/biossíntese , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Transdução de Sinais , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Animais , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interferon Tipo I/metabolismo , Interferon gama/metabolismo , Interleucina-7/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ligantes , Camundongos , Camundongos Knockout , Poli I-C/farmacologia , Receptores CXCR3/metabolismo , Glândulas Salivares/efeitos dos fármacos , Síndrome de Sjogren/genética , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo
20.
J Immunol ; 191(3): 1200-9, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23794633

RESUMO

Thymic epithelial cells (TECs) help orchestrate thymopoiesis, and TEC differentiation relies on bidirectional interactions with thymocytes. Although the molecular mediators that stimulate medullary thymic epithelial cell (mTEC) maturation are partially elucidated, the signals that regulate cortical thymic epithelial cell (cTEC) homeostasis remain elusive. Using IL-7 reporter mice, we show that TECs coexpressing high levels of IL-7 (Il7(YFP+) TECs) reside within a subset of CD205(+)Ly51(+)CD40(low) cTECs that coexpresses Dll4, Ccl25, Ccrl1, Ctsl, Psmb11, and Prss16 and segregates from CD80(+)CD40(high) mTECs expressing Tnfrsf11a, Ctss, and Aire. As the frequency of Il7(YFP+) TECs gradually declines as mTEC development unfolds, we explored the relationship between Il7(YFP+) TECs and mTECs. In thymic organotypic cultures, the thymocyte-induced reduction in Il7(YFP+) TECs dissociates from the receptor activator of NF-κB-mediated differentiation of CD80(+) mTECs. Still, Il7(YFP+) TECs can generate some CD80(+) mTECs in a stepwise differentiation process via YFP(-)Ly51(low)CD80(low) intermediates. Il7(YFP+) TECs are sustained in Rag2(-/-) mice, even following in vivo anti-CD3ε treatment that mimics the process of pre-TCR ß-selection of thymocytes to the double positive (DP) stage. Using Marilyn-Rag2(-/-) TCR transgenic, we find that positive selection into the CD4 lineage moderately reduces the frequency of Il7(YFP+) TECs, whereas negative selection provokes a striking loss of Il7(YFP+) TECs. These results imply that the strength of MHC/peptide-TCR interactions between TECs and thymocytes during selection constitutes a novel rheostat that controls the maintenance of IL-7-expressing cTECs.


Assuntos
Células Epiteliais/imunologia , Interleucina-7/biossíntese , Timo/imunologia , Animais , Antígenos CD/metabolismo , Antígeno B7-1/metabolismo , Complexo CD3/imunologia , Antígenos CD40/metabolismo , Proteínas de Ligação ao Cálcio , Catepsina L/biossíntese , Catepsinas/biossíntese , Diferenciação Celular/imunologia , Movimento Celular , Células Cultivadas , Quimiocinas CC/biossíntese , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Células Epiteliais/metabolismo , Homeostase , Interleucina-7/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Lectinas Tipo C/metabolismo , Ativação Linfocitária , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor , Técnicas de Cultura de Órgãos , Receptor Ativador de Fator Nuclear kappa-B/biossíntese , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Receptores CCR/biossíntese , Receptores de Superfície Celular/metabolismo , Serina Endopeptidases/biossíntese , Timócitos/metabolismo , Timo/metabolismo , Fatores de Transcrição/biossíntese
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