Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 570
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
J Exp Med ; 217(4)2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-31985756

RESUMO

In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)-induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell-independent (TI) antibody responses. The causative mutation was in Pdia6, an essential gene encoding protein disulfide isomerase A6 (PDIA6), an oxidoreductase that functions in nascent protein folding in the endoplasmic reticulum. The immune deficiency caused by the Pdia6 mutation was, with the exception of a residual T cell developmental defect, completely rescued in irradiated wild-type recipients of PDIA6-deficient bone marrow cells, both in the absence or presence of competition. The viable hypomorphic allele uncovered in these studies reveals an essential role for PDIA6 in hematopoiesis, but one extrinsic to cells of the hematopoietic lineage. We show evidence that this role is in the proper folding of Wnt3a, BAFF, IL-7, and perhaps other factors produced by the extra-hematopoietic compartment that contribute to the development and lineage commitment of hematopoietic cells.


Assuntos
Linfócitos/imunologia , Células Mieloides/imunologia , Isomerases de Dissulfetos de Proteínas/imunologia , Animais , Fator Ativador de Células B/imunologia , Linhagem Celular , Feminino , Células HEK293 , Hematopoese/imunologia , Humanos , Interleucina-7/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Proteína Wnt3A/imunologia
2.
Nat Immunol ; 20(12): 1584-1593, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31745336

RESUMO

The cytokine IL-7 and its receptor, IL-7R, are critical for T cell and, in the mouse, B cell development, as well as differentiation and survival of naive T cells, and generation and maintenance of memory T cells. They are also required for innate lymphoid cell (ILC) development and maintenance, and consequently for generation of lymphoid structures and barrier defense. Here we discuss the central role of IL-7 and IL-7R in the lymphoid system and highlight the impact of their deregulation, placing a particular emphasis on their 'dark side' as promoters of cancer development. We also explore therapeutic implications and opportunities associated with either positive or negative modulation of the IL-7-IL-7R signaling axis.


Assuntos
Imunoterapia/tendências , Interleucina-7/metabolismo , Neoplasias/imunologia , Receptores de Interleucina-7/metabolismo , Linfócitos T/fisiologia , Animais , Diferenciação Celular , Sobrevivência Celular , Homeostase , Humanos , Interleucina-7/imunologia , Receptores de Interleucina-7/imunologia
3.
PLoS Biol ; 17(10): e3000383, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31661488

RESUMO

Thymic involution and proliferation of naive T cells both contribute to shaping the naive T-cell repertoire as humans age, but a clear understanding of the roles of each throughout a human life span has been difficult to determine. By measuring nuclear bomb test-derived 14C in genomic DNA, we determined the turnover rates of CD4+ and CD8+ naive T-cell populations and defined their dynamics in healthy individuals ranging from 20 to 65 years of age. We demonstrate that naive T-cell generation decreases with age because of a combination of declining peripheral division and thymic production during adulthood. Concomitant decline in T-cell loss compensates for decreased generation rates. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of CD4+ naive T-cell turnover, using mass cytometry to profile candidate signaling pathways involved in T-cell activation and proliferation relative to CD31 expression, a marker of thymic proximity for the CD4+ naive T-cell population. We show that basal nuclear factor κB (NF-κB) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-κB signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-κB phosphorylation in CD4+CD31- naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naive T-cell turnover as a putative regulator of naive T-cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T-cell clones that accumulate with age.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem da Célula/imunologia , Homeostase/imunologia , Timo/imunologia , Adulto , Idoso , Envelhecimento/genética , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Linhagem da Célula/genética , Proliferação de Células , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Homeostase/genética , Humanos , Imunofenotipagem , Interleucina-7/genética , Interleucina-7/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/imunologia , Fosforilação , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Transdução de Sinais , Timo/citologia , Timo/crescimento & desenvolvimento
4.
Nat Commun ; 10(1): 4575, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594933

RESUMO

IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide. In monocytes, both surface IL7R and sIL7R expression strongly associate with allelic carriage of rs6897932, a disease-associated IL7R polymorphism. Monocytes produce more sIL7R than CD4 + T cells, and the amount is additionally correlated with the expression of DDX39A, encoding a splicing factor. Synovial fluid-derived monocytes from patients with spondyloarthritis are enriched for IL7R+ cells with a unique transcriptional profile that overlaps with IL-7-induced gene sets. Our data thus suggest a previously unappreciated function for monocytes in IL-7 biology and IL7R-associated diseases.


Assuntos
Autoimunidade/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Interleucina-7/imunologia , Monócitos/imunologia , Espondilite Anquilosante/genética , Alelos , RNA Helicases DEAD-box/imunologia , RNA Helicases DEAD-box/metabolismo , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Voluntários Saudáveis , Humanos , Interleucina-7/metabolismo , Subunidade alfa de Receptor de Interleucina-7/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Lipopolissacarídeos/imunologia , Monócitos/metabolismo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de RNA , Análise de Célula Única , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Líquido Sinovial/citologia , Líquido Sinovial/imunologia , Regulação para Cima/imunologia
5.
Int Immunopharmacol ; 75: 105773, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349155

RESUMO

Enterovirus 71 (EV71) always induces severe hand, foot, and mouth disease with neurological complications, such as encephalitis. Interleukin (IL)-7 augments CD8+ T cells activity in chronic viral infection and cancers. However, few studies have focused on common γ-chain (γc) cytokine expression and regulatory function of IL-7 to CD8+ T cells in EV71 associated encephalitis. In this study, twenty-one patients with EV71 associated encephalitis, twenty-seven patients with febrile convulsion (FC), and twenty healthy individuals were enrolled. γc cytokine (IL-2, IL-4, IL-7 and IL-15) concentration was measured by ELISA. IL-7 receptor α chain (membrane/soluble CD127) expression was also investigated. Purified CD8+ T cells were stimulated with recombinant human IL-7 in vitro. The regulatory activity of IL-7 to CD8+ T cells from peripheral blood and cerebrospinal fluids (CSF) was investigated in direct and indirect contact co-culture with U-87MG cells. IL-7 in the serum and CSF, but not IL-2, IL-4, or IL-15, was significant increased in EV71 associated encephalitis. Both total CD127 mRNA relative level and membrane/soluble CD127 expression was comparable among three groups. IL-7 stimulation promoted CD8+ T cells proliferation, up-regulated perforin/granzyme B level, but reduced programmed death-1 expression in CD8+ T cells from EV71 associated encephalitis patients. Cytotoxicity and interferon-γ production of CD8+ T cells from peripheral blood and CSF was also augmented in response to IL-7 stimulation in both direct and indirect co-culture systems in EV71 associated encephalitis. The present data indicated that IL-7 induced cytolytic and non-cytolytic functions of CD8+ T cells in EV71 associated encephalitis. IL-7 might be considered as one of the immunomodulatory therapeutic candidates for EV71 infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Encefalite/imunologia , Enterovirus Humano A , Infecções por Enterovirus/imunologia , Interleucina-7/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Encefalite/etiologia , Infecções por Enterovirus/complicações , Feminino , Humanos , Lactente , Interleucina-7/farmacologia , Masculino , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia
6.
Cancer Immunol Immunother ; 68(7): 1195-1209, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31177329

RESUMO

The anti-tumor efficacy of TCR-engineered T cells in vivo depends largely on less-differentiated subsets such as T cells with naïve-like T cell (TN) phenotypes with greater expansion and long-term persistence. To increase these subsets, we compared the generation of New York esophageal squamous cell carcinoma-1 (NY-ESO-1)-specific T cells under supplementation with either IL-2 or IL-7/IL-15. PBMCs were transduced with MS3II-NY-ESO-1-siTCR retroviral vector. T cell generation was adapted from a CD19-specific CART cell production protocol. Comparable results in viability, expansion and transduction efficiency of T cells under stimulation with either IL-2 or IL-7/IL-15 were observed. IL-7/IL-15 led to an increase of CD4+ T cells and a decrease of CD8+ T cells, enriched the amount of TN among CD4+ T cells but not among CD8+ T cells. In a 51Cr release assay, similar specific lysis of NY-ESO-1-positive SW982 sarcoma cells was achieved. However, intracellular cytokine staining revealed a significantly increased production of IFN-γ and TNF-α in T cells generated by IL-2 stimulation. To validate these unexpected findings, NY-ESO-1-specific T cell production was evaluated in another protocol originally established for TCR-engineered T cells. IL-7/IL-15 increased the proportion of TN. However, the absolute number of TN did not increase due to a significantly slower expansion of T cells with IL-7/IL-15. In conclusion, IL-7/IL-15 does not seem to be superior to IL-2 for the generation of NY-ESO-1-specific T cells. This is in sharp contrast to the observations in CD19-specific CART cells. Changes of cytokine cocktails should be carefully evaluated for individual vector systems.


Assuntos
Antígenos de Neoplasias/metabolismo , Engenharia Celular/métodos , Imunoterapia Adotiva/métodos , Proteínas de Membrana/metabolismo , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Antígenos CD19/metabolismo , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Técnicas de Cultura de Células/métodos , Linhagem Celular Tumoral , Meios de Cultura , Humanos , Interleucina-15/imunologia , Interleucina-2/imunologia , Interleucina-7/imunologia , Proteínas de Membrana/imunologia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/genética
7.
J Gen Virol ; 100(4): 602-615, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30875282

RESUMO

Canine distemper (CD) causes gastrointestinal and respiratory and/or neurological signs and results in high morbidity and mortality, remaining a threat to carnivores around the world. Live-attenuated vaccines have been widely used to reduce the number of CD outbreaks, but efforts are still needed to improve immune efficiency. Interleukin-7 (IL-7) has been reported to boost host immunity by recruiting follicle helper T (TFH) or germinal center (GC) B cells. Here, we constructed a recombinant canine distemper virus (rCDV) by reverse genetics and evaluated the properties of six intergenic sites for insertion of a foreign gene. We found that the P/M intergenic region was the optimal site to insert a foreign gene into the CDV genome. The effect of overexpressing IL-7 on rCDV immunogenicity was then evaluated in a mouse model. We found that mice immunized with rCDV-IL7 could not significantly enhance the maturation of dendritic cells (DCs) but significantly facilitated the generation of TFH cells, GC B cells and plasma cells (PCs), as well as the formation of GCs, consequently enhancing the production of CDV-specific neutralizing antibodies and total IgG. Together, these results suggested that the overexpression of IL-7 by rCDV could enhance humoral responses by activating the TFH-GC B-PC axis, which will help to improve vaccines for CD.


Assuntos
Vírus da Cinomose Canina/imunologia , Cinomose/imunologia , Imunidade Humoral/imunologia , Interleucina-7/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Cães , Feminino , Centro Germinativo/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Linfócitos T Auxiliares-Indutores/imunologia , Vacinação/métodos , Vacinas Atenuadas/imunologia , Células Vero , Vacinas Virais/imunologia
8.
PLoS One ; 14(2): e0211716, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30730978

RESUMO

Massive apoptosis of lymphocytes is a hallmark of sepsis. The resulting immunosuppression is associated with secondary infections, which are often lethal. Moreover, sepsis-survivors are burdened with increased morbidity and mortality for several years after the sepsis episode. The duration and clinical consequences of sepsis induced-immunosuppression are currently unknown. We have used the mouse model of peritoneal contamination and infection (PCI) to investigate the quantitative and qualitative recovery of T lymphocytes for 3.5 months after sepsis with or without IL-7 treatment. Thymic output and the numbers of naive and effector/memory CD4+ and CD8+ lymphocytes quickly recovered after sepsis. IL-7 treatment resulted in an accelerated recovery of CD8+ lymphocytes. Next generation sequencing revealed no significant narrowing of the T cell receptor repertoire 3.5 months after sepsis. In contrast, detailed functional analyses of T helper (Th)-cell responses towards a fungal antigen revealed a significant loss of Th cells. Whereas cytokine production was not impaired at the single cell level, the absolute number of Th cells specific for the fungal antigen was reduced. Our data indicate a clinically relevant loss of pathogen-specific T cell clones after sepsis. Given the small number of naive T lymphocytes specific for a given antigen, this decrement of T cell clones remains undetected even by sensitive methods such as deep sequencing. Taken together, our data are compatible with long lasting impairments in CD4+ T-cell responses after sepsis despite rapid recovery of T lymphocyte populations.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Sepse/imunologia , Animais , Antígenos de Fungos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Memória Imunológica/imunologia , Interleucina-7/imunologia , Contagem de Linfócitos/métodos , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/imunologia
9.
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
10.
Anticancer Res ; 39(1): 107-112, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30591446

RESUMO

BACKGROUND/AIM: The human natural killer cell line NK-92 is increasingly being used in adoptive cell immunotherapies, either in vitro or in animal models transduced with different chimeric antigen receptor (CAR) constructs. Herein, NK-92 cells were analyzed with respect to their proliferation and cytotoxicity, in the presence of interleukin-2 (IL-2) and interleukin-15 (IL-15). MATERIALS AND METHODS: A time-resolved fluorometric assay (TDA-labeled K562 target cells) was used for measuring the cytotoxic activity of NK-92 cells treated with IL-2, IL-4, IL-7 and/or IL-15. Their proliferation, in the presence of these common cytokine receptor γ chain (γc)-dependent cytokines, was measured by traditional tritiated thymidine ([3H]-TdR) incorporation. RESULTS: IL-2 and IL-15, but not IL-4 or IL-7, were able to induce a dose-dependent proliferation of NK-92 cells. IL-15 was, depending on the dose and culture time, up to 10 times more potent compared to corresponding concentrations of IL-2, whereas their combination could potentiate the NK-activity almost equally well. No synergistic effects could be noticed with respect to the cytotoxicity and the proliferation of these cells. CONCLUSION: Data presented here indicate that of the common gamma chain receptor-dependent cytokines tested here, IL-15 alone is able to cultivate and trigger NK-92 cells to such an extent so that they can be used for immune-based cancer therapies. Implications with respect to CAR-transduced NK-92 cells are also discussed.


Assuntos
Proliferação de Células/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Ensaios Clínicos como Assunto , Relação Dose-Resposta Imunológica , Humanos , Interleucina-15/imunologia , Interleucina-15/farmacologia , Interleucina-2/imunologia , Interleucina-2/farmacologia , Interleucina-4/imunologia , Interleucina-4/farmacologia , Interleucina-7/imunologia , Interleucina-7/farmacologia , Células K562 , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia
11.
Front Immunol ; 9: 2258, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364182

RESUMO

Interleukin-7 (IL-7) and Flt3-ligand (FL) are two cytokines important for the generation of B cells, as manifested by the impaired B cell development in mice deficient for either cytokine or their respective receptors and by the complete block in B cell differentiation in the absence of both cytokines. IL-7 is an important survival and proliferation factor for B cell progenitors, whereas FL acts on several early developmental stages, prior to B cell commitment. We have generated mice constitutively over-expressing both IL-7 and FL. These double transgenic mice develop splenomegaly and lymphadenopathy characterized by tremendously enlarged lymph nodes even in young animals. Lymphoid, myeloid and dendritic cell numbers are increased compared to mice over-expressing either of the two cytokines alone and the effect on their expansion is synergistic, rather than additive. B cell progenitors, early progenitors with myeloid and lymphoid potential (EPLM), common lymphoid progenitors (CLP) and lineage-, Sca1+, kit+ (LSK) cells are all increased not only in the bone marrow but also in peripheral blood, spleen and even lymph nodes. When transplanted into irradiated wild-type mice, lymph node cells show long-term multilineage reconstitution, further confirming the presence of functional hematopoietic progenitors therein. Our double transgenic mouse model shows that sustained and combined over-expression of IL-7 and FL leads to a massive expansion of most bone marrow hematopoietic progenitors and to their associated presence in peripheral lymphoid organs where they reside and potentially differentiate further, thus leading to the synergistic increase in mature lymphoid and myeloid cell numbers. The present study provides further in vivo evidence for the concerted action of IL-7 and FL on lymphopoiesis and suggests that extramedullary niches, including those in lymph nodes, can support the survival and maintenance of hematopoietic progenitors that under physiological conditions develop exclusively in the bone marrow.


Assuntos
Células-Tronco Hematopoéticas/imunologia , Interleucina-7/imunologia , Células Progenitoras Linfoides/imunologia , Proteínas de Membrana/imunologia , Células-Tronco Multipotentes/imunologia , Animais , Proliferação de Células/genética , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Expressão Gênica/imunologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Interleucina-7/genética , Interleucina-7/metabolismo , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/metabolismo
12.
PLoS One ; 13(8): e0202525, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30157233

RESUMO

BACKGROUND: A quarter of the world's population is estimated to be infected with Myobacterium tuberculosis (Mtb). Infection is detected by immune response to M. tuberculosis antigens using either tuberculin skin test (TST) and interferon gamma release (IGRA's), tests which have low sensitivity in immunocompromised. IL-7 is an important cytokine for T-cell function with potential to augment cytokine release in in-vitro assays. This study aimed to determine whether the addition of IL-7 in interferon-gamma release assays (IGRAs) improves its diagnostic performance of Mtb infection. METHODS: 44 cases with confirmed TB and 45 household contacts without TB were recruited and 1ml of blood was stimulated in two separate IGRA's tube set: one set of standard Quantiferon TB gold tubes mitogen, TB antigen and TB Nil; one set of customized Quantiferon TB gold tubes with added IL-7. Following IFN-γ and IP-10 release was determined using ELISA. RESULTS: We found that the addition of IL-7 led to significantly higher release of IFN-γ in individuals with active TB from 4.2IU/ml (IQR 1.4-6.9IU/ml) to 5.1IU/ml (IQR 1.5-8.1IU/ml, p = 0.0057), and we found an indication of a lower release of both IFN-γ and IP-10 in participants with negative tests. CONCLUSIONS: In TB cases addition of IL-7 in IGRA tubes augments IFN-γ but not IP-10 release, and seems to lower the response in controls. Whether IL-7 boosted IGRA holds potential over standard IGRA needs to be confirmed in larger studies in high and low TB incidence countries.


Assuntos
Interferon gama/imunologia , Interleucina-7/farmacologia , Tuberculose/diagnóstico , Adulto , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/isolamento & purificação , Quimiocina CXCL10/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Testes de Liberação de Interferon-gama , Interleucina-7/imunologia , Masculino , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Linfócitos T/imunologia , Linfócitos T/microbiologia , Teste Tuberculínico , Tuberculose/imunologia , Tuberculose/microbiologia
13.
J Exp Med ; 215(10): 2586-2599, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30158115

RESUMO

B cell progenitors require paracrine signals such as interleukin-7 (IL-7) provided by bone marrow stromal cells for proliferation and survival. Yet, how B cells regulate access to these signals in vivo remains unclear. Here we show that proB and IL-7+ cells form a cell circuit wired by IL-7R signaling, which controls CXCR4 and focal adhesion kinase (FAK) expression and restricts proB cell movement due to increased adhesion to IL-7+CXCL12Hi cells. PreBCR signaling breaks this circuit by switching the preB cell behavior into a fast-moving and lower-adhesion state via increased CXCR4 and reduced FAK/α4ß1 expression. This behavioral change reduces preB cell exposure to IL-7, thereby attenuating IL-7R signaling in vivo. Remarkably, IL-7 production is downregulated by signals provided by preB cells with unrepaired double-stranded DNA breaks and by preB acute lymphoblastic leukemic cells. Combined, these studies revealed that distinct cell circuits control the quality and homeostasis of B cell progenitors.


Assuntos
Interleucina-7/imunologia , Células-Tronco Mesenquimais/imunologia , Células Precursoras de Linfócitos B/imunologia , Receptores de Interleucina-7/imunologia , Transdução de Sinais/imunologia , Animais , Quimiocina CXCL12/genética , Interleucina-7/genética , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Knockout , Células Precursoras de Linfócitos B/citologia , Receptores de Interleucina-7/genética , Transdução de Sinais/genética
14.
J Immunol ; 201(4): 1229-1240, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30006375

RESUMO

Polysaccharide vaccines such as the Vi polysaccharide (ViPS) of Salmonella enterica serovar Typhi induce efficient Ab responses in adults but not in young children. The reasons for this difference are not understood. IL-7 dependency in B cell development increases progressively with age. IL-7Rα-mediated signals are required for the expression of many VH gene segments that are distal to DH-JH in the IgH locus and for the complete diversification of the BCR repertoire. Therefore, we hypothesized that B cells generated in the absence of IL-7 do not recognize a wide range of Ags because of a restricted BCR repertoire. Compared with adult wildtype mice, young wildtype mice and IL-7-deficient adult mice generated a significantly reduced Ab response to ViPS. Additionally, ViPS-binding B cells in adult wildtype mice predominantly used distal VH gene segments. Transgenic expression of either IL-7 or a BCR encoded by a distal VH gene segment permitted young mice to respond efficiently to bacterial polysaccharides. These results indicate that restricted VH gene usage early in life results in a paucity of Ag-specific B cell precursors, thus limiting antipolysaccharide responses.


Assuntos
Diversidade de Anticorpos/imunologia , Formação de Anticorpos/imunologia , Genes de Cadeia Pesada de Imunoglobulina/imunologia , Interleucina-7/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Diversidade de Anticorpos/genética , Formação de Anticorpos/genética , Linfócitos B/imunologia , Genes de Cadeia Pesada de Imunoglobulina/genética , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polissacarídeos Bacterianos/imunologia , Receptores de Antígenos de Linfócitos B/genética
15.
Mucosal Immunol ; 11(5): 1352-1362, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29907867

RESUMO

Asthmatics sensitized to fungi are reported to have more severe asthma, yet the immunopathogenic pathways contributing to this severity have not been identified. In a pilot assessment of human asthmatics, those subjects sensitized to fungi demonstrated elevated levels of the common γ-chain cytokine IL-7 in lung lavage fluid, which negatively correlated with the lung function measurement PC20. Subsequently, we show that IL-7 administration during experimental fungal asthma worsened lung function and increased the levels of type 2 cytokines (IL-4, IL-5, IL-13), proallergic chemokines (CCL17, CCL22) and proinflammatory cytokines (IL-1α, IL-1ß). Intriguingly, IL-7 administration also increased IL-22, which we have previously reported to drive immunopathogenic responses in experimental fungal asthma. Employing IL22CreR26ReYFP reporter mice, we identified γδ T cells, iNKT cells, CD4 T cells and ILC3s as sources of IL-22 during fungal asthma; however, only iNKT cells were significantly increased after IL-7 administration. IL-7-induced immunopathogenesis required both type 2 and IL-22 responses. Blockade of IL-7Rα in vivo resulted in attenuated IL-22 production, lower CCL22 levels, decreased iNKT cell, CD4 T-cell and eosinophil recruitment, yet paradoxically increased dynamic lung resistance. Collectively, these results suggest a complex role for IL-7 signaling in allergic fungal asthma.


Assuntos
Asma/imunologia , Asma/microbiologia , Fungos/imunologia , Interleucina-7/imunologia , Micoses/imunologia , Adulto , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Quimiocinas/imunologia , Citocinas/imunologia , Feminino , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Masculino , Projetos Piloto
16.
Cell Immunol ; 331: 1-8, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29903664

RESUMO

Adoptive cell therapy (ACT) of autologous tumor-infiltrating lymphocytes (TILs) has shown an effect on mediating tumor regression in some patients with highly advanced, refractory metastatic malignancy. Here, the in vitro generation of TILs isolated from malignant pleural effusion and ascites was compared with which using engineered cells for costimulatory enhancement (ECCE) and 3 common γ-chain cytokines, interleukin (IL)-2, IL-7, and IL-15, alone or in combination. We showed the robust clinical-scale production of TILs with a less differentiated 'young' phenotype by expansion in the presence of ECCE combined with IL-2/7/15. Furthermore, a major fraction of the TILs generated in this fashion was shown to produce much more IFN-γ and TNF-α, and displayed cytolytic activity against target cells expressing the relevant antigens. To our knowledge, this is the first time that the combination of ECCE and IL-2/7/15 has been applied for the generation of TILs isolated from malignant pleural effusion and ascites.


Assuntos
Ascite/imunologia , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Derrame Pleural Maligno/imunologia , Ligante 4-1BB/genética , Ligante 4-1BB/imunologia , Ligante 4-1BB/metabolismo , Adulto , Idoso , Ascite/patologia , Divisão Celular/imunologia , Células Cultivadas , Feminino , Humanos , Imunoterapia Adotiva/métodos , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-2/metabolismo , Interleucina-7/genética , Interleucina-7/imunologia , Interleucina-7/metabolismo , Células K562 , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Derrame Pleural Maligno/patologia
17.
Sci Rep ; 8(1): 9126, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29904108

RESUMO

Interleukin-7 is critical for T-cell development and displays antimicrobial and antitumor properties. It is referred to as a "critical enhancer of protective immunity". However, there is no information on interleukin-7 dynamics following colorectal surgery. Moreover, although robot-assisted surgery is gaining popularity, data on the immune response to it is almost non-existent. In this prospective non-randomized case-control study we found interleukin-7 dynamics to differ following robot-assisted and open approach and to affect postoperative immunity. Linear increases were seen in the robotic group while a cubic pattern with a maximum at 8 h in the open one. Low preoperative interleukin-7 was associated with developing surgical site infection. In turn, higher preoperative interleukin-7 was associated with preserved immune function: less pronounced drop in lymphocyte count and higher Δlymphocyte/Δneutrophil ratio in patients undergoing robotic surgery. The changes in other cytokines, namely, interleukin-12(p70), TNFα, interferon-γ, and interleukin-10 were independently associated with interleukin-7 dynamics. In turn, relative changes in interleukin-7 were independent predictors of changes in interferon-γ, key cytokine of favourable Th1 immune response. Taken together, we demonstrated different perioperative dynamics of interleukin-7, which may contribute to favourable outcomes following robotic colorectal surgery including lower incidence of surgical site infections, milder surgery-induced lymphopenia, and beneficial interferon-γ dynamics.


Assuntos
Cirurgia Colorretal , Interleucina-7/sangue , Procedimentos Cirúrgicos Robóticos , Infecção da Ferida Cirúrgica/sangue , Idoso , Feminino , Humanos , Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Período Perioperatório , Estudos Prospectivos , Infecção da Ferida Cirúrgica/imunologia
18.
J Immunol ; 200(12): 3970-3980, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29720424

RESUMO

Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In this article, we studied the development and homing characteristics of human peripheral blood Treg cell subsets and potential mechanisms inducing homing molecule expression in healthy children. We found contrasting patterns of circulating Treg cell gut and skin tropism, with abundant ß7 integrin+ Treg cells at birth and increasing cutaneous lymphocyte Ag (CLA+) Treg cells later in life. ß7 integrin+ Treg cells were predominantly naive, suggesting acquisition of Treg cell gut tropism early in development. In vitro, IL-7 enhanced gut homing but reduced skin homing molecule expression in conventional T cells, whereas IL-2 induced a similar effect only in Treg cells. This effect was more pronounced in cord compared with adult blood. Our results suggest that early in life, naive Treg cells may be driven for gut tropism by their increased sensitivity to IL-2-induced ß7 integrin upregulation, implicating a potential role of IL-2 in gut immune tolerance during this critical period of development.


Assuntos
Trato Gastrointestinal/imunologia , Interleucina-2/imunologia , Receptores de Retorno de Linfócitos/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Antígenos/imunologia , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Tolerância Imunológica/imunologia , Lactente , Recém-Nascido , Cadeias beta de Integrinas/imunologia , Interleucina-7/imunologia , Masculino , Pele/imunologia , Tropismo/imunologia , Regulação para Cima/imunologia
19.
J Immunol ; 201(1): 278-295, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29752311

RESUMO

Myeloid-derived suppressor cells (MDSCs) are known suppressors of antitumor immunity, affecting amino acid metabolism and T cell function in the tumor microenvironment. However, it is unknown whether MDSCs regulate B cell responses during tumor progression. Using a syngeneic mouse model of lung cancer, we show reduction in percentages and absolute numbers of B cell subsets including pro-, pre-, and mature B cells in the bone marrow (BM) of tumor-bearing mice. The kinetics of this impaired B cell response correlated with the progressive infiltration of MDSCs. We identified that IL-7 and downstream STAT5 signaling that play a critical role in B cell development and differentiation were also impaired during tumor progression. Global impairment of B cell function was indicated by reduced serum IgG levels. Importantly, we show that anti-Gr-1 Ab-mediated depletion of MDSCs not only rescued serum IgG and IL-7 levels but also reduced TGF-ß1, a known regulator of stromal IL-7, suggesting MDSC-mediated regulation of B cell responses. Furthermore, blockade of IL-7 resulted in reduced phosphorylation of downstream STAT5 and B cell differentiation in tumor-bearing mice and administration of TGF-ß-blocking Ab rescued these IL-7-dependent B cell responses. Adoptive transfer of BM-derived MDSCs from tumor-bearing mice into congenic recipients resulted in significant reductions of B cell subsets in the BM and in circulation. MDSCs also suppressed B cell proliferation in vitro in an arginase-dependent manner that required cell-to-cell contact. Our results indicate that tumor-infiltrating MDSCs may suppress humoral immune responses and promote tumor escape from immune surveillance.


Assuntos
Linfócitos B/imunologia , Interleucina-7/imunologia , Neoplasias Pulmonares/imunologia , Células Supressoras Mieloides/imunologia , Fator de Transcrição STAT5/imunologia , Evasão Tumoral/imunologia , Transferência Adotiva , Animais , Linfócitos B/citologia , Células da Medula Óssea/imunologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Feminino , Imunoglobulina G/sangue , Interleucina-7/sangue , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/transplante , Fosforilação , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta/sangue , Microambiente Tumoral/imunologia
20.
Viral Immunol ; 31(6): 417-425, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29672235

RESUMO

Signaling through interleukin (IL)-7 is essential and required for development, differentiation, proliferation, and homeostasis of T cells. However, the role of IL-7 in regulation of CD4+ T cells in chronic viral infections was not fully elucidated. Thus, the aim of the current study was to investigate the immunomodulatory activity of IL-7 to T follicular helper (Tfh) cells and its contribution to pathogenesis of chronic HCV, hepatitis C virus (HCV) infection. A total of 47 patients with chronic hepatitis C and 19 normal controls were enrolled. Serum IL-7 and proportion of Tfh cells was measured. The regulatory function of IL-7 to Tfh cells was also investigated in CD4+ T cells and CD4+ T/HCVcc-infected Huh7.5 cell cocultured system. Serum IL-7 concentration was significantly downregulated in patients with chronic hepatitis C, and was negatively correlated with HCV RNA level. Tfh frequency and Tfh-associated cytokines (IL-21 and IL-6) were also reduced in chronic HCV-infected patients. Moreover, recombinant IL-7 stimulation elevated proportion of Tfh cells and IL-21/IL-6 secretion in both HCV-specific and nonspecific manners. Furthermore, IL-7-treated CD4+ T cells exhibited elevated antiviral activities without killing infected hepatocytes, which presented as inhibition of HCV RNA, induction of antiviral proteins, and promotion of cytokine production (especially IL-21) in cocultured system. This process might be dependent on IL-6 secretion. The current data revealed that IL-7 regulated HCV-specific and nonspecific activated Tfh cells, which might contribute to viral clearance. IL-7 could be a potential therapeutic agent for the treatment of chronic hepatitis C.


Assuntos
Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Interleucina-7/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Regulação para Baixo , Feminino , Hepacivirus/isolamento & purificação , Hepatite C Crônica/sangue , Hepatite C Crônica/virologia , Hepatócitos , Humanos , Interleucina-7/sangue , Interleucina-7/metabolismo , Masculino , Cultura Primária de Células , Linfócitos T Auxiliares-Indutores/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA