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1.
Nat Immunol ; 20(7): 879-889, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182807

RESUMO

CD8+ T cells and natural killer (NK) cells are central cellular components of immune responses against pathogens and cancer, which rely on interleukin (IL)-15 for homeostasis. Here we show that IL-15 also mediates homeostatic priming of CD8+ T cells for antigen-stimulated activation, which is controlled by a deubiquitinase, Otub1. IL-15 mediates membrane recruitment of Otub1, which inhibits ubiquitin-dependent activation of AKT, a kinase that is pivotal for T cell activation and metabolism. Otub1 deficiency in mice causes aberrant responses of CD8+ T cells to IL-15, rendering naive CD8+ T cells hypersensitive to antigen stimulation characterized by enhanced metabolic reprograming and effector functions. Otub1 also controls the maturation and activation of NK cells. Deletion of Otub1 profoundly enhances anticancer immunity by unleashing the activity of CD8+ T cells and NK cells. These findings suggest that Otub1 controls the activation of CD8+ T cells and NK cells by functioning as a checkpoint of IL-15-mediated priming.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Cisteína Endopeptidases/metabolismo , Interleucina-15/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Cisteína Endopeptidases/deficiência , Enzimas Desubiquitinantes/metabolismo , Modelos Animais de Doenças , Metabolismo Energético , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-15/genética , Melanoma Experimental , Camundongos , Camundongos Transgênicos , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Interleucina-15/metabolismo , Tolerância a Antígenos Próprios/genética , Tolerância a Antígenos Próprios/imunologia , Transdução de Sinais , Especificidade do Receptor de Antígeno de Linfócitos T , Ubiquitinação
2.
J Immunol Res ; 2019: 1801560, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183385

RESUMO

Due to the existence of viral reservoirs, the rebound of human immunodeficiency virus type 1 (HIV-1) viremia can occur within weeks after discontinuing combined antiretroviral therapy. Immunotherapy could potentially be applied to eradicate reactivated HIV-1 in latently infected CD4+ T lymphocytes. Although the existence of HIV-1-specific CD8+ T memory stem cells (TSCMs) is well established, there are currently no reports regarding methods using CD8+ TSCMs to treat HIV-1 infection. In this study, we quantified peripheral blood antigen-specific CD8+ TSCMs and then expanded HIV-1-specific TSCMs that targeted optimal antigen epitopes (SL9, IL9, and TL9) in the presence of interleukin- (IL-) 21 or IL-15. The suppressive capacity of the expanded CD8+ TSCMs on HIV-1 production was measured by assessing cell-associated viral RNA and performing viral outgrowth assays. We found that the number of unmutated TL9-specific CD8+ TSCMs positively correlated with the abundance of CD4+ T cells and that the expression of IFN-γ was higher in TL9-specific CD8+ TSCMs than that in non-TL9-specific CD8+ TSCMs. Moreover, the antiviral capacities of IL-21-stimulated CD8+ TSCMs exceeded those of conventional CD8+ memory T cells and IL-15-stimulated CD8+ TSCMs. Thus, we demonstrated that IL-21 could efficiently expand HIV-1-specific CD8+ TSCMs to suppress HIV-1 replication. Our study provides new insight into the function of IL-21 in the in vitro suppression of HIV-1 replication.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Interleucinas/metabolismo , Células Cultivadas , Estudos de Coortes , Epitopos/imunologia , Antígenos HIV/imunologia , Humanos , Memória Imunológica , Interferon gama/metabolismo , Interleucina-15/metabolismo , Ativação Linfocitária , Replicação Viral
3.
Mediators Inflamm ; 2019: 4236562, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049024

RESUMO

Natural killer cells and NKT-like cells are the first line immune defense against tumor and virus infection. Deficient NK and NKT-like cell effector function may contribute to increased susceptibility to infection in SLE patients. We sought to examine the perforin and granzyme B expression, interferon-gamma (IFN-γ), and tumor-necrosis factor-alpha (TNF-α) production and CD107a degranulation of NK and NKT-like cells from SLE patients and their regulation by IL-15. We established that (1) perforin expression on SLE NK cells was decreased but unrelated to disease activity; (2) the MFI of granzyme B was increased in NK cells from SLE patients with active disease, associated with increased percentages of granzyme B+ CD56bright NK cells; (3) NK cells from active SLE patients, both CD56dim and CD56bright NK subsets, produced higher IFN-γ compared to controls; (4) CD56dim, but not CD56bright NK cells from active SLE patients, produced lower TNF-α, compared to inactive SLE patients and controls; (5) CD107a degranulation of SLE NK cells was comparable to controls; (6) IL-15 enhanced perforin/granzyme B expression, IFN-γ/TNF-α production, and CD107a degranulation of NK cells from SLE patients; and (7) similar observations were found for CD56+CD3+ NKT-like cells. Taken together, we demonstrated the differential expression of the heightened granzyme B and decreased TNF-α in NK and NKT-like cells in SLE patients. Higher granzyme B expression of NK and NKT-like cells in active SLE patients, further enhanced by circulating IL-15, may contribute to the maintenance of inflammation in SLE.


Assuntos
Citocinas/metabolismo , Interleucina-15/metabolismo , Células Matadoras Naturais/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Adulto , Idoso , Células Cultivadas , Feminino , Granzimas/metabolismo , Humanos , Interferon gama/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Perforina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Mediators Inflamm ; 2019: 3231696, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30733641

RESUMO

The bone marrow (BM) is not only a reservoir of hematopoietic stem cells but a repository of immunological memory cells. Further characterizing BM-resident memory T cells would be helpful to reveal the complicated relationship between the BM and immunological memory. In this study, we identified CD122high stem cell antigen-1 (Sca-1) high B cell lymphoma 2 (Bcl-2) high CD4+ stem cell-like memory T cells (TSCMs) as a distinct memory T cell subset, which preferentially reside in the BM, where they respond vigorously to blood-borne antigens. Interestingly, the natural CD4+ TSCMs homing to the BM colocalized with VCAM-1+ IL-15+ IL-7+ CXCL-12+ stromal cells. Furthermore, compared to spleen-resident CD4+ TSCMs, BM-resident TSCMs induced the production of high-affinity antibodies against influenza by B lymphocytes more efficiently. Taken together, these observations indicate that the BM provides an appropriate microenvironment for the survival of CD4+ TSCMs, which broadens our knowledge regarding the memory maintenance of antigen-specific CD4+ T lymphocytes.


Assuntos
Anticorpos Antivirais/imunologia , Células da Medula Óssea/citologia , Linfócitos T CD4-Positivos/citologia , Memória Imunológica , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/terapia , Animais , Ataxina-1/metabolismo , Linfócitos T CD8-Positivos/citologia , Quimiocina CXCL12/metabolismo , Células-Tronco Hematopoéticas/citologia , Interleucina-15/metabolismo , Subunidade beta de Receptor de Interleucina-2/metabolismo , Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células Estromais , Molécula 1 de Adesão de Célula Vascular/metabolismo
5.
Biomed Pharmacother ; 112: 108677, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30798123

RESUMO

Recombinant human interleukin-15 (IL-15) is a potent cancer immunotherapeutic candidate due to its excellent immune stimulating effects. Previous work demonstrated that IL-15 appeared with short half-life in circulation system, while the complex with its receptor can prolong the half-life as well as benefit its activities in vivo. Therefore, IL-15 complex was more favorably considered for clinical development. Herein we developed IL-15·sIL-15Rα/Fc, a complex comprising of IL-15 and the extracellular region of its receptor alpha subunit which fused to Immunoglobulin G (IgG1) Fc to further prolong the half-life in plasma. Through transient gene expression in HEK293 cells, we expressed the superagonist by co-transfection of plasmids encoding IL-15 and sIL-15Rα/Fc respectively, yielding 36 mg/L of product after purification. Pharmacokinetic study demonstrated that the combination profoundly prolonged the half-life of IL-15 to 13.1 h in mice, about 18 folds longer than that of IL-15 monomer which is around 0.7 h. The bioactivity of the superagonist was characterized by CTLL-2 cells proliferation assay in vitro, showing its capability of stimulating the expansion of memory CD8+ T cells (cluster of differentiation) in mouse spleen. Using a HT-29 xenograft NOD-SCID mouse model, we observed tumor growth inhibition in all groups that received the superagonist, indicating its anti-tumor efficacy via stimulating infused human immune cells. In addition, combo cancer treatment by IL-15·sIL-15Rα/Fc and programmed death-1 (PD-1) antibody have shown stronger inhibitory effects as compared with treatment with either single molecule. Therefore, we developed IL-15·sIL-15Rα/Fc to be a long half-life potential cancer immunotherapy candidate that can be applied alone or in synergy with PD-1/PD-L1 blockade.


Assuntos
Antineoplásicos Imunológicos/imunologia , Desenvolvimento de Medicamentos/métodos , Fragmentos Fc das Imunoglobulinas/imunologia , Subunidade alfa de Receptor de Interleucina-15/imunologia , Interleucina-15/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/metabolismo , Feminino , Células HEK293 , Células HT29 , Meia-Vida , Humanos , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/metabolismo , Imunoglobulina G/administração & dosagem , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Interleucina-15/administração & dosagem , Interleucina-15/metabolismo , Subunidade alfa de Receptor de Interleucina-15/administração & dosagem , Subunidade alfa de Receptor de Interleucina-15/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
Int J Biol Sci ; 15(2): 464-480, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30745835

RESUMO

Recently, interest in IL-15-differentiated cells has increased; however, the phenotypic definition of IL-15-differentiated bone marrow-derived cells (IL-15-DBMCs) is still under debate, particularly the generation of IFN-γ-producing innate cells such as premature NK (pre-mNK) cells, natural killer dendritic cells (NKDCs), interferon-producing killer dendritic cells (IKDCs), and type 1 innate lymphoid cells (ILC1s), all of which are IL-15-dependent. Here, we revisited the immunophenotypic characteristics of IFN-γ-producing IL-15-DBMCs and their functional role in the control of intracellular Mycobacterium tuberculosis (Mtb) infection. When comparing the cytokine levels between bone marrow-derived dendritic cells (BMDCs) and IL-15-DBMCs upon stimulation with various TLR agonists, only the CD11cint population of IL-15-DBMCs produced significant levels of IFN-γ, decreased levels of MHC-II, and increased levels of B220. Neither BMDCs nor IL-15-DBMCs were found to express DX5 or NK1.1, which are representative markers for the NK cell lineage and IKDCs. When the CD11cintB220+ population of IL-15-DBMCs was enriched, the Thy1.2+Sca-1+ population showed a marked increase in IFN-γ production. In addition, while depletion of the B220+ and Thy1.2+ populations of IL-15-DBMCs, but not the CD19+ population, inhibited IFN-γ production, enrichment of these cell populations increased IFN-γ. Ultimately, co-culture of sorted IFN-γ-producing B220+Thy1.2+ IL-15-DBMCs with Mtb-infected macrophages resulted in control of the intracellular growth of Mtb via the IFN-γ-nitric oxide axis in a donor cell number-dependent manner. Taken together, the results indicate that IFN-γ-producing IL-15-DBMCs could be redefined as CD11cintB220+Thy1.2+Sca-1+ cells, which phenotypically resemble both IKDCs and ILC1s, and may have therapeutic potential for controlling infectious intracellular bacteria such as Mtb.


Assuntos
Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Interferon gama/metabolismo , Interleucina-15/metabolismo , Animais , Antígeno CD11c/metabolismo , Diferenciação Celular/fisiologia , Feminino , Citometria de Fluxo , Antígenos Comuns de Leucócito/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis
7.
Cancer Immunol Immunother ; 68(5): 773-785, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30747243

RESUMO

Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate. Secondary endpoints were safety and assessment of immune correlates following TIL infusion. Twelve metastatic melanoma patients were treated with non-myeloablative lymphodepleting chemotherapy, TIL, and low-dose subcutaneous IL-2 (125,000 IU/kg/day, maximum 9-10 doses over 2 weeks). All but one patient had previously progressed after treatment with immune checkpoint inhibitors. No unexpected adverse events were observed, and patients received an average of 6.8 doses of IL-2. By RECIST v1.1, two patients experienced a partial response, one patient had an unconfirmed partial response, and six had stable disease. Biomarker assessment confirmed an increase in IL-15 levels following lymphodepleting chemotherapy as expected and a lack of peripheral regulatory T-cell expansion following protocol treatment. Interrogation of the TIL infusion product and monitoring of the peripheral blood following infusion suggested engraftment of TIL. In one responding patient, a population of T cells expressing a T-cell receptor Vß chain that was dominant in the infusion product was present at a high percentage in peripheral blood more than 2 years after TIL infusion. This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.).


Assuntos
Imunoterapia Adotiva/métodos , Interleucina-2/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Melanoma/terapia , Neoplasias Cutâneas/terapia , Adulto , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Interleucina-15/metabolismo , Linfócitos do Interstício Tumoral/transplante , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Cutâneas/imunologia , Resultado do Tratamento
8.
Biochem Biophys Res Commun ; 509(4): 994-1000, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30654941

RESUMO

Skeletal muscle performs 80% of the glucose metabolism in the body. Improvement of insulin resistance and prevention of diabetes by habitual exercise is considered beneficial due to the improved glucose uptake in skeletal muscles. Investigation of the mechanism by which skeletal muscles regulate glucose uptake can contribute to the prevention and treatment of diabetes. Myokines are a kind of cytokine secreted from skeletal muscle, which are expected to regulate muscle metabolism. Interleukin-15 (IL-15) is one such myokine that has been reported to improve glucose metabolism in vitro, although the mechanism remains unclear. In this study, we examined the glucose metabolism of skeletal muscle-specific IL-15 transgenic mice (IL-15TG), and investigated how IL-15 affects glucose metabolism in skeletal muscles. Although High Fat Diet-fed IL-15TG did not exhibit obvious difference in intraperitoneal insulin tolerance test, they had less impaired glucose tolerance compared to wild-type C57BL/6. Phosphorylation of AMP-activated protein kinase (AMPK), Akt substrate of 160 kDa (AS160), tre-2/USP6, BUB2, and cdc16 domain family member 1 (TBC1D1), and translocation of Glucose transporter type 4 (GLUT4) were accelerated in the skeletal muscle of IL-15TG. Our study demonstrated that overexpression of IL-15 in skeletal muscle improves glucose metabolism in skeletal muscle via AMPK pathway. We report the first in-vivo study that describes the signaling pathway of IL-15 in muscle glucose metabolism, and thereby contributes to the elucidation of the regulatory mechanism of muscle glucose metabolism by myokines.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Intolerância à Glucose/tratamento farmacológico , Transportador de Glucose Tipo 4/metabolismo , Interleucina-15/metabolismo , Músculo Esquelético/metabolismo , Animais , Transporte Biológico , Glucose/metabolismo , Glucose/farmacocinética , Resistência à Insulina , Interleucina-15/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Transdução de Sinais
9.
PLoS Pathog ; 15(1): e1007456, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30608984

RESUMO

Innate CD8+ T cells express a memory-like phenotype and demonstrate a strong cytotoxic capacity that is critical during the early phase of the host response to certain bacterial and viral infections. These cells arise in the thymus and depend on IL-4 and IL-15 for their development. Even though innate CD8+ T cells exist in the thymus of WT mice in low numbers, they are highly enriched in KO mice that lack certain kinases, leading to an increase in IL-4 production by thymic NKT cells. Our work describes that in C57BL/6 WT mice undergoing a Th1 biased infectious disease, the thymus experiences an enrichment of single positive CD8 (SP8) thymocytes that share all the established phenotypical and functional characteristics of innate CD8+ T cells. Moreover, through in vivo experiments, we demonstrate a significant increase in survival and a lower parasitemia in mice adoptively transferred with SP8 thymocytes from OT I-T. cruzi-infected mice, demonstrating that innate CD8+ thymocytes are able to protect against a lethal T. cruzi infection in an Ag-independent manner. Interestingly, we obtained similar results when using thymocytes from systemic IL-12 + IL-18-treated mice. This data indicates that cytokines triggered during the acute stage of a Th1 infectious process induce thymic production of IL-4 along with IL-15 expression resulting in an adequate niche for development of innate CD8+ T cells as early as the double positive (DP) stage. Our data demonstrate that the thymus can sense systemic inflammatory situations and alter its conventional CD8 developmental pathway when a rapid innate immune response is required to control different types of pathogens.


Assuntos
Interleucina-15/metabolismo , Interleucina-4/metabolismo , Timo/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/imunologia , Citocinas/metabolismo , Feminino , Imunidade Inata/genética , Interleucina-12/metabolismo , Interleucina-15/genética , Interleucina-18/metabolismo , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/imunologia , Transdução de Sinais , Células Th1/imunologia , Timócitos/metabolismo , Timo/metabolismo , Timo/patologia
10.
Trends Mol Med ; 25(1): 1-3, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30473188

RESUMO

Immunometabolism is important to T cell dysfunction in chronic infections. A recent publication in The Journal of Clinical Investigation (2018;128:5083-5094) [1] shows reduced mitochondrial fitness in regulatory CD4+ T cells (Tregs) of patients with HIV and failed immune restoration on antiretroviral therapy (ART). This defect can be reversed by IL-15, revealing a new immunotherapy target for regulatory T cell restoration.


Assuntos
Mitocôndrias/metabolismo , Linfócitos T Reguladores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Humanos , Interleucina-15/metabolismo
11.
Int J Sports Med ; 40(1): 16-22, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30497093

RESUMO

Interleukin (IL)-15 stimulates mitochondrial biogenesis, fat oxidation, glucose uptake and myogenesis in skeletal muscle. However, the mechanisms by which exercise triggers IL-15 expression remain to be elucidated in humans. This study aimed at determining whether high-intensity exercise and exercise-induced RONS stimulate IL-15/IL-15Rα expression and its signaling pathway (STAT3) in human skeletal muscle. Nine volunteers performed a 30-s Wingate test in normoxia and hypoxia (PIO2=75 mmHg), 2 h after placebo or antioxidant administration (α-lipoic acid, vitamin C and E) in a randomized double-blind design. Blood samples and muscle biopsies (vastus lateralis) were obtained before, immediately after, and 30 and 120 min post-exercise. Sprint exercise upregulated skeletal muscle IL-15 protein expression (ANOVA, P=0.05), an effect accentuated by antioxidant administration in hypoxia (ANOVA, P=0.022). In antioxidant conditions, the increased IL-15 expression at 120 min post-exercise (33%; P=0.017) was associated with the oxygen deficit caused by the sprint (r=-0.54; P=0.020); while, IL-15 and Tyr705-STAT3 AUCs were also related (r=0.50; P=0.036). Antioxidant administration promotes IL-15 protein expression in human skeletal muscle after sprint exercise, particularly in severe acute hypoxia. Therefore, during intense muscle contraction, a reduced PO2 and glycolytic rate, and possibly, an attenuated RONS generation may facilitate IL-15 production, accompanied by STAT3 activation, in a process that does not require AMPK phosphorylation.


Assuntos
Antioxidantes/farmacologia , Exercício/fisiologia , Interleucina-15/metabolismo , Músculo Esquelético/fisiologia , Transdução de Sinais , Adulto , Ácido Ascórbico/farmacologia , Método Duplo-Cego , Teste de Esforço , Humanos , Hipóxia , Masculino , Carbonilação Proteica , Receptores de Interleucina-15/metabolismo , Fator de Transcrição STAT3/metabolismo , Ácido Tióctico/farmacologia , Vitamina E/farmacologia , Adulto Jovem
12.
Nat Immunol ; 20(1): 10-17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30538328

RESUMO

Interleukin 15 (IL-15) is one of the most important cytokines that regulate the biology of natural killer (NK) cells1. Here we identified a signaling pathway-involving the serine-threonine kinase AKT and the transcription factor XBP1s, which regulates unfolded protein response genes2,3-that was activated in response to IL-15 in human NK cells. IL-15 induced the phosphorylation of AKT, which led to the deubiquitination, increased stability and nuclear accumulation of XBP1s protein. XBP1s bound to and recruited the transcription factor T-BET to the gene encoding granzyme B, leading to increased transcription. XBP1s positively regulated the cytolytic activity of NK cells against leukemia cells and was also required for IL-15-mediated NK cell survival through an anti-apoptotic mechanism. Thus, the newly identified IL-15-AKT-XBP1s signaling pathway contributes to enhanced effector functions and survival of human NK cells.


Assuntos
Interleucina-15/metabolismo , Células Matadoras Naturais/imunologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas com Domínio T/metabolismo , Proteína 1 de Ligação a X-Box/metabolismo , Sobrevivência Celular , Células Cultivadas , Citotoxicidade Imunológica , Regulação da Expressão Gênica , Granzimas/genética , Granzimas/metabolismo , Humanos , Fosforilação , Ligação Proteica , Estabilidade Proteica , Transdução de Sinais , Ubiquitinação , Resposta a Proteínas não Dobradas
13.
J Pediatr Hematol Oncol ; 41(4): 328-333, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29939941

RESUMO

X-linked severe combined immunodeficiency disease (SCID) is caused by mutations in the interleukin (IL)-2 receptor γ (IL2RG) gene and patients usually present with a TBNK SCID phenotype. Nevertheless, a minority of these patients present with a TBNK phenotype, similar to the IL-7R-deficient patients. We report a patient with a novel missense p.Glu297Gly mutation in the IL2RG gene presenting with a leaky TBNK SCID with delayed onset, moderate susceptibility to infections, and nodular regenerative hyperplasia. He presents with preserved STAT5 tyrosine phosphorylation in response to IL-15 stimulation but not in response to IL-2 and IL-7, resulting in the NK phenotype.


Assuntos
Subunidade gama Comum de Receptores de Interleucina/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/patologia , Linfócitos B/imunologia , Pré-Escolar , Humanos , Hiperplasia/patologia , Interleucina-15/metabolismo , Células Matadoras Naturais/imunologia , Masculino , Mutação de Sentido Incorreto , Fenótipo , Fosforilação , Fator de Transcrição STAT5/metabolismo , Linfócitos T/imunologia
14.
Vet Dermatol ; 30(1): 17-e6, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30417482

RESUMO

BACKGROUND: Oclacitinib is a Janus kinase inhibitor used to control pruritus and skin lesions in canine allergic skin disease; its effect on canine T cells is not well-characterized. HYPOTHESIS/OBJECTIVES: To evaluate the impact of oclacitinib on cultured T cells using peripheral blood mononuclear cells from dogs. ANIMALS: Six bluetick coonhounds. METHODS AND MATERIALS: Lymphocyte-enriched cells were incubated with or without the T-cell mitogen concanavalin A (Con A), oclacitinib (0.5, 1 or 10 µM), ciclosporin (200 ng/mL), Con A + oclacitinib 1 µM and Con A + ciclosporin. We assessed both T-cell proliferation and the secretion of cytokines. RESULTS: Ciclosporin and oclacitinib both inhibited the spontaneous proliferation of T cells; this effect was significant only after incubation with oclacitinib at 10 µM. At this concentration, oclacitinib significantly reduced the spontaneous secretion of clonal activator cytokines [interleukin (IL)-2, IL-15], pro-inflammatory cytokines (interferon-gamma (IFN-γ), IL-18) and the regulatory cytokine IL-10; tumour necrosis factor alpha (TNF-α) and IL-6 cytokine production was mildly inhibited. After Con A stimulation, only T cells co-treated with ciclosporin achieved a significant proliferation inhibition and reduction of IL-2, IL-10, IL-15, IL-18, IFN-γ and TNF-α. Surprisingly, oclacitinib at 1 µM (337 ng/mL, corresponding to the oral dosage of 0.4-0.6 mg/kg) did not significantly affect Con A-stimulated T-cell proliferation nor cytokine production (IL-2, IL-10, IL-15, IL-18, IFN-γ and TNF-α). CONCLUSIONS: Although a limited number of dogs were investigated, these preliminary results suggest that oclacitinib appears to have immunosuppressive properties, but only at dosages above those used to treat allergic pruritus in dogs.


Assuntos
Citocinas/metabolismo , Fatores Imunológicos/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Ciclosporina/farmacologia , Cães , Feminino , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-15/metabolismo , Interleucina-18/metabolismo , Interleucina-2/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Fator de Necrose Tumoral alfa/metabolismo
15.
BMC Genomics ; 19(1): 918, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30545299

RESUMO

BACKGROUND: The molecular mechanisms underlying stress-influenced immune function of chicken (Gallus Gallus) are not clear. The stress models can be established effectively by feeding chickens corticosterone (CORT) hormone. The bursa of Fabricius is a unique central immune organ of birds. RNA-Seq technology was used to investigate differences in the expression profiles of immune-related genes and associated pathways in the bursa of Fabricius to clarify molecular mechanisms. The aim of this study was to broaden the understanding of the stress-influenced immune function in chickens. RESULTS: Differentially expressed genes (DEGs) in the bursa of Fabricius between experimental group (basal diet with added CORT 30 mg/kg; C_B group) and control group (basal diet; B_B group) were identified by using RNA-seq technology. In total, we found 1434 significant DEGs (SDEGs), which included 199 upregulated and 1235 downregulated genes in the C_B group compared with the B_B group. The immune system process GO term was the top significantly GO term, including MYD88, TLR4, IL15, VEGFA gene and so on. The cytokine-cytokine receptor interaction pathway and the Toll-like receptor signaling pathway were the key pathways affected by stress. The protein-protein interaction (PPI) analysis of the SDEGs showed that VEGFA, MyD88 and IL15 were hub genes and module analysis showed that MYD88, TLR4 and VEGFA play important roles in response to stress. CONCLUSION: This study showed that the VEGFA and ILs (such as IL15) via the cytokine-cytokine receptor interaction pathway, MYD88 and TLR4 via the Toll-like receptor signaling pathway may play important roles in the regulation of immune function under stress condition with CORT administration. The results of this study provide a reference for further studies of the molecular mechanisms of stress-influenced immune function.


Assuntos
Bolsa de Fabricius/metabolismo , Galinhas/genética , Corticosterona/farmacologia , Imunidade/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Bolsa de Fabricius/efeitos dos fármacos , Bolsa de Fabricius/imunologia , Galinhas/imunologia , Análise por Conglomerados , Dieta , Imunidade/genética , Interleucina-15/genética , Interleucina-15/metabolismo , Modelos Animais , Mapas de Interação de Proteínas/efeitos dos fármacos , RNA/química , RNA/isolamento & purificação , RNA/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
16.
Apunts, Med. esport (Internet) ; 53(200): 155-162, oct.-dic. 2018. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-180020

RESUMO

Malos hábitos como el sedentarismo, obesidad o sobrealimentación, se relacionan a la evolución de estados pro-inflamatorios crónicos, principal factor de riesgo para el desarrollo de enfermedades crónicas no transmisibles (ECNT). Sin embargo, modificar únicamente el peso corporal no reduce el riesgo, es necesario también aumentar la masa muscular, dando a entender que existe una relación benéfica asociada a este tejido que no está totalmente dilucidada. Durante los últimos años, las explicaciones celulares más interesantes se han enfocado en la producción de citokinas musculares denominadas miokinas, dentro de las que se destacan la interleucina 6, el factor inhibidor de la leucemia, entre otras recientemente estudiadas como lo son la mionectina y la musclina. Debido a los múltiples avances, se realiza una revisión que pretende: presentar los hallazgos más recientes y representativos acerca de las miokinas, corregir conceptos y demostrar su aplicabilidad en la prescripción del ejercicio físico para la salud


Bad habits such as sedentary lifestyle, obesity or overfeeding, are related to the production of chronic pro-inflammatory states, the main risk factor for the development of chronic noncommunicable diseases (CNCD). However, modifying only the body weight does not reduce the risk, it is necessary to increase muscle mass, this implies there is a beneficial relationship associated with the muscle tissue that is not fully elucidated. During the last years, the most interesting cellular explanations have focused on the production of muscle cytokines called myokines, among which stand out interleukin 6, the inhibitory factor of leukemia, with others recently studied such as mionectine and muscline. Due to the multiple advances, this intends to present the most recent and representative findings about myokines, correct concepts and demonstrate their applicability in the prescription of physical exercise for health


Assuntos
Humanos , Exercício/fisiologia , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Interleucina-6/metabolismo , Interleucina-15/metabolismo , Estilo de Vida , Índice de Massa Corporal , Leucemia/enzimologia , Leucemia/metabolismo
17.
Sci Rep ; 8(1): 16113, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30382157

RESUMO

The adipose tissue includes various stromal cells, such as preadipocytes, endothelial cells, fibroblasts, and immune cells, which are involved in adipose tissue functions. We previously reported that, in obese mice, the sodium-glucose cotransporter 2 inhibitor ipragliflozin (Ipra) promoted the expansion of the epididymal adipose tissue (Epi) with increase of serum ketone body concentration. The Ipra-induced adipose tissue expansion did not deteriorate adipose inflammation, or systemic glucose/lipid metabolism, referred to as "healthy adipose tissue expansion." Here we found that Ipra promoted healthy adipose tissue expansion with a reduced ratio of pro-inflammatory M1-like adipose tissue macrophages (ATMs) to anti-inflammatory M2-like ATMs. Ipra downregulated the gene expression of interleukin (IL)-15 (Il15) in stromal cells of Epi. IL-15 inhibited lipogenesis in 3T3-L1 cells associated with downregulation of the lipogenic gene. Ketone body ß-hydroxybutyrate suppressed Il15 gene induction in M1-polarized cultured macrophages, and a ketogenic diet reproduced the adipose tissue expansion without deteriorating systemic glucose metabolism in mice. Our data indicate that the phenotypic switch of ATMs could mediate healthy adipose tissue expansion by treatment with Ipra, and it may offer new insights into the pathophysiological mechanisms of adipose tissue expansion.


Assuntos
Tecido Adiposo/citologia , Polaridade Celular , Macrófagos/citologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Células 3T3-L1 , Animais , Anisóis/administração & dosagem , Anisóis/farmacologia , Polaridade Celular/efeitos dos fármacos , Ceramidas/metabolismo , Dieta Hiperlipídica , Regulação para Baixo/efeitos dos fármacos , Glucosídeos/farmacologia , Interleucina-15/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Corpos Cetônicos/metabolismo , Lipídeos/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptores CCR2/deficiência , Receptores CCR2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esfingomielinas/metabolismo , Tiofenos/farmacologia , Regulação para Cima/efeitos dos fármacos
18.
Blood Adv ; 2(22): 3177-3192, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30482760

RESUMO

Engineered autologous acute myeloid leukemia (AML) cells present multiple leukemia-associated and patient-specific antigens and as such hold promise as immunotherapeutic vaccines. However, prior vaccines have not reliably induced effective antileukemic immunity, in part because AML blasts have immune inhibitory effects and lack expression of the critical costimulatory molecule CD80. To enhance induction of leukemia-specific cytolytic activity, 32Dp210 murine AML cells were engineered to express either CD80 alone, or the immunostimulatory cytokine interleukin-15 (IL-15) with its receptor α (IL-15Rα), or heterodimeric IL-15/IL-15Rα together with CD80 and tested as irradiated cell vaccines. IL-15 is a γc-chain cytokine, with unique properties suited to stimulating antitumor immunity, including stimulation of both natural killer and CD8+ memory T cells. Coexpression of IL-15 and IL-15Rα markedly increases IL-15 stability and secretion. Non-tumor-bearing mice vaccinated with irradiated 32Dp210-IL-15/IL-15Rα/CD80 and challenged with 32Dp210 leukemia had greater survival than did mice treated with 32Dp210-CD80 or 32Dp210-IL-15/IL-15Rα vaccines, whereas no unvaccinated mice inoculated with leukemia survived. In mice with established leukemia, treatment with 32Dp210-IL-15/IL-15Rα/CD80 vaccination stimulated unprecedented antileukemic immunity enabling 80% survival, an effect that was abrogated by anti-CD8 antibody-mediated depletion in vivo. Because, clinically, AML vaccines are administered as postremission therapy, we established a novel model in which mice with high leukemic burdens were treated with cytotoxic therapy to induce remission (<5% marrow blasts). Postremission vaccination with 32Dp210-IL-15/IL-15Rα/CD80 achieved 50% overall survival in these mice, whereas all unvaccinated mice achieving remission subsequently relapsed. These studies demonstrate that combined expression of IL-15/IL-15Rα and CD80 by syngeneic AML vaccines stimulates effective and long-lasting antileukemic immunity.


Assuntos
Antígeno B7-1/metabolismo , Vacinas Anticâncer/imunologia , Subunidade alfa de Receptor de Interleucina-15/metabolismo , Interleucina-15/metabolismo , Leucemia Mieloide Aguda/terapia , Animais , Antígeno B7-1/genética , Vacinas Anticâncer/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Interleucina-15/genética , Subunidade alfa de Receptor de Interleucina-15/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Endogâmicos C3H , Neoplasia Residual , Taxa de Sobrevida , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Homólogo
19.
Oncol Rep ; 40(6): 3335-3345, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30272301

RESUMO

Leukocyte­derived microparticles (LMPs) include neutrophil­, lymphocyte­ and monocyte­derived MPs. LMPs act as proinflammatory mediators in autoimmune diseases, infectious diseases and vascular diseases. The present study examined the hypothesis that the percentage of LMPs was increased in patients with inflamed odontogenic keratocysts (OKCs), and investigated the biological effects of Jurkat cell­derived MPs on the fibroblasts of OKCs in vitro. Cyst fluid MPs, obtained by centrifugation of samples from 20 patients with inflamed OKCs, 3 patients with uninflamed OKCs, 15 patients with radicular cysts (RCs) and 12 patients with inflamed dentigerous cysts (DCs), were analyzed by transmission electron microscopy, dynamic light scattering and immunofluorescence staining. The percentages and concentrations of cyst fluid LMPs were further determined by flow cytometry. The cytokine levels of apoptotic Jurkat cell­derived MPs and Jurkat cell supernatants were compared by cytokine antibody arrays. Fibroblasts were isolated from 3 patients with OKC and co­cultured with apoptotic Jurkat cell­derived MPs with or without interleukin (IL)­15Rα to detect the levels of matrix metallopeptidase 9 (MMP­9) and receptor activator of nuclear factor­κB ligand (RANKL) by reverse transcription­quantitative polymerase chain reaction and enzyme­linked immunosorbent assay. The supernatant from Jurkat MPs­treated fibroblasts was collected to make conditioned medium in which the osteoclastogenesis of Raw264.7 cells was determined. Antibodies against human soluble (s)RANKL were added to the conditioned medium to investigate the inhibitory effects. Mean percentages of lymphocyte­ and neutrophil­derived MPs were significantly higher in inflamed OKCs than in DCs. Significant elevations in IL­15 were detected in apoptotic Jurkat cell­derived MPs compared with that in Jurkat cell supernatant. Furthermore, higher levels of MMP­9 and RANKL were detected in Jurkat cell MP­treated OKC fibroblasts, and this was partially blocked by IL­15Rα. Increased osteoclast­like cell formation was observed in the Jurkat MPs­treated fibroblast supernatant and Raw264.7 co­culture groups. The anti­human sRANKL antibody in the Jurkat MPs­treated fibroblast supernatant group decreased the osteoclastogenesis of the Raw264.7 cells. These results indicate that LMPs serve as novel communication tools that contribute toward the bone resorption of inflamed OKCs by inducing RANKL of OKC fibroblasts via IL­15.


Assuntos
Micropartículas Derivadas de Células/fisiologia , Interleucina-15/metabolismo , Linfócitos/citologia , Cistos Odontogênicos/imunologia , Ligante RANK/metabolismo , Adolescente , Adulto , Idoso , Animais , Micropartículas Derivadas de Células/metabolismo , Células Cultivadas , Criança , Técnicas de Cocultura , Feminino , Humanos , Células Jurkat , Linfócitos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Células RAW 264.7 , Adulto Jovem
20.
Front Immunol ; 9: 2126, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319610

RESUMO

Recent studies have identified CD49a+Eomes- and CD49a+Eomes+ subsets of tissue-resident NK (trNK) cells in different organs of the mouse. However, the characteristics of CD49a+Eomes-/+ NK cell development and the regulation of Eomes expression in NK cells remain unclear. Here, we established an in vitro cytokine-based feeder-free system in which bone marrow progenitor cells differentiate into CD49a+ NK cells. IL-15 was identified as being the key cytokine in this system that supported the development and maintenance of CD49a+ NK cells. The CD49a+ NK cells generated were Eomes-CD49b- and shared the same phenotype as hepatic trNK cells. IL-4 induced the expression of Eomes in generated NK cells and converted them into CD49a+Eomes+ cells, which were phenotypically and functionally similar to uterine trNK cells. Moreover, the IL-4/STAT6 axis was identified as being important in the generation of CD49a+Eomes+ induced NK cells. Collectively, these studies describe an approach to generate CD49a+Eomes-/+ subsets of NK cells and demonstrate important roles for IL-15 and IL-4 in the differentiation of these cells. These findings have potential for developmental research underlying the generation of different subsets of NK cells and the application of adoptive NK cell transfer therapies.


Assuntos
Diferenciação Celular/imunologia , Integrina alfa1/metabolismo , Células Matadoras Naturais/fisiologia , Cultura Primária de Células/métodos , Proteínas com Domínio T/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Células Cultivadas , Feminino , Integrina alfa1/imunologia , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Fígado/citologia , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Fator de Transcrição STAT6/imunologia , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/imunologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia
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