Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 384
Filtrar
1.
Mol Immunol ; 111: 145-151, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31054408

RESUMO

Tuberculosis (TB) is a global epidemic with devastating consequences. Emerging evidence suggests that B-cells have the ability to modulate the immune response and understanding these roles during Mycobacterium tuberculosis (M.tb) infection can help to find new strategies to treat TB. The immune system of individuals with pulmonary TB form granulomas in the lung which controls the infection by inhibiting the M.tb growth and acts as a physical barrier. Thereafter, surviving M.tb become dormant and in most cases the host's immunity prevents TB reactivation. B-cells execute several immunological functions and are regarded as protective regulators of immune responses by antibody and cytokine production, as well as presenting antigen. Some of these B-cells, or regulatory B-cells, have been shown to express death-inducing ligands, such as Fas ligand (FasL). This expression and binding to the Fas receptor leads to apoptosis, a major immune regulation mechanism, in addition to the ability to induce T-cell tolerance. Here, I discuss the relevance of B-cells, in particular their non-humoral functions by addressing their regulatory properties during M.tb infection.


Assuntos
Linfócitos B/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Latência Viral/imunologia , Apoptose/imunologia , Proteína Ligante Fas/imunologia , Ativação Linfocitária/imunologia , Receptor fas/imunologia
2.
Transplant Proc ; 51(3): 942-950, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30979487

RESUMO

BACKGROUND: Intrasplenic transplantation of xenogeneic hepatic oval cells (HOCs) may provide metabolic support for acute liver injury. However, xenoreactive lymphocyte-mediated immune response hinders HOCs' survival in the xeno-spleen parenchyma. Cytotoxic T-lymphocyte associated protein 4-Fas ligand (CTLA4.FasL), a fusion product integrating 2 inhibitory elements against lymphocytes into 1 molecule, effectively inhibited the proliferation of allogeneic and autoimmune lymphocytes. The purpose of this study was to explore the effect of CTLA4.FasL on the proliferation of xenoreactive lymphocytes and evaluate the therapeutic efficacy of CTLA4.FasL-modified HOC transplantation on acute liver injury in rats. METHODS: The effect of CTLA4.FasL-modified mouse liver epithelial progenitor cells (CTLA4.FasL-LEPCs) on the proliferation of rat lymphocytes in xeno-mixed lymphocyte reaction was investigated. Furthermore, CTLA4.FasL-LEPCs were intrasplenically transplanted in carbon tetrachloride- and partial hepatectomy-treated rats, and the therapeutic effect was evaluated using hematoxylin and eosin staining and alanine aminotransferase and aspartate aminotransferase assays. The hepatocytic differentiation of CTLA4.FasL-LEPCs in xenogeneic spleen was monitored by immunohistochemical staining for albumin. RESULTS: In xeno-mixed lymphocyte reaction, CTLA4.FasL-LEPCs substantially inhibited the rat lymphocytes proliferation. CTLA4.FasL-LEPC transplantation significantly ameliorated liver injury compared with mCherry-modified LEPC and LEPC transplantation, as assessed by hematoxylin and eosin staining, alanine aminotransferase, and aspartate aminotransferase assays. Albumin positive cells appeared only in CTLA4.FasL-LEPCs group, but not in the mCherry-modified LEPCs group and LEPCs group. CONCLUSIONS: Our results indicate CTLA4.FasL-LEPCs substantially improved liver function and structure in carbon tetrachloride- and partial hepatectomy-induced acute liver injury rats through long-term hepatocytic differentiation.


Assuntos
Lesão Pulmonar Aguda/cirurgia , Antígeno CTLA-4/imunologia , Proteína Ligante Fas/imunologia , Hepatócitos/transplante , Linfócitos T Citotóxicos/imunologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Antígeno CTLA-4/metabolismo , Diferenciação Celular , Proliferação de Células , Modelos Animais de Doenças , Proteína Ligante Fas/metabolismo , Feminino , Hepatócitos/citologia , Hepatócitos/metabolismo , Injeções , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Ratos , Ratos Sprague-Dawley , Baço
3.
Int J Mol Sci ; 20(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925759

RESUMO

Hepatic intrasinusoidal (HI) natural killer (NK) cells from liver perfusate have unique features that are similar to those of liver-resident NK cells. Previously, we have reported that HI CD56bright NK cells effectively degranulate against SNU398 hepatocellular carcinoma (HCC) cells. Thus, the aim of this study was to further investigate the phenotype and function of HI NK cells. We found that HI CD56bright NK cells degranulated much less to Huh7 cells. HI CD56bright NK cells expressed NKG2D, NKp46, TNF-related apoptosis-inducing ligand (TRAIL), and FAS ligand (FASL) at higher levels than CD56dim cells. SNU398 cells expressed more NKG2D ligands and FAS and less PD-L1 than Huh7 cells. Blockade of NKG2D, TRAIL, and FASL significantly reduced the cytotoxicity of HI NK cells against SNU398 cells, but blockade of PD-L1 did not lead to any significant change. However, HI NK cells produced IFN-γ well in response to Huh7 cells. In conclusion, the cytotoxicity of HI CD56bright NK cells was attributed to the expression of NKG2D, TRAIL, and FASL. The results suggest the possible use of HI NK cells for cancer immunotherapy and prescreening of HCC cells to help identify the most effective NK cell therapy recipients.


Assuntos
Antígeno CD56/imunologia , Carcinoma Hepatocelular/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Hepáticas/imunologia , Adulto , Antígeno CD56/análise , Linhagem Celular Tumoral , Proteína Ligante Fas/análise , Proteína Ligante Fas/imunologia , Feminino , Proteínas Ligadas por GPI/análise , Proteínas Ligadas por GPI/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/análise , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Interferon gama/análise , Interferon gama/imunologia , Masculino , Ligante Indutor de Apoptose Relacionado a TNF/análise , Ligante Indutor de Apoptose Relacionado a TNF/imunologia
4.
Birth Defects Res ; 111(4): 197-211, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30702213

RESUMO

The prototype death receptor CD95 (Fas) and its ligand, CD95L (FasL), have been thoroughly studied due to their role in immune homeostasis and elimination of infected and transformed cells. The fact that CD95 is present in female reproductive cells and modulated during embryogenesis and pregnancy has raised interest in its role in immune tolerance to the fetoplacental unit. CD95 has been shown to be critical for proper embryonic formation and survival. Moreover, altered expression of CD95 or its ligand causes autoimmunity and has also been directly involved in recurrent pregnancy losses and pregnancy disorders. The objective of this review is to summarize studies that evaluate the mechanisms involved in the activation of CD95 to provide an updated global view of its effect on the regulation of the maternal immune system. Modulation of the CD95 system components may be the immune basis of several common pregnancy disorders.


Assuntos
Apoptose/imunologia , Desenvolvimento Embrionário/imunologia , Proteína Ligante Fas/imunologia , Complicações na Gravidez/imunologia , Receptor fas/imunologia , Feminino , Humanos , Gravidez
5.
J Clin Invest ; 129(4): 1551-1565, 2019 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-30694219

RESUMO

Across clinical trials, T cell expansion and persistence following adoptive cell transfer (ACT) have correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis to identify actionable ligand-receptor pairs capable of compromising T cell durability following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments (TMEs). Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T cells used for clinical ACT. We hypothesized that a cognate Fas-FasL interaction within the TME might limit both T cell persistence and antitumor efficacy. We discovered that genetic engineering of Fas variants impaired in the ability to bind FADD functioned as dominant negative receptors (DNRs), preventing FasL-induced apoptosis in Fas-competent T cells. T cells coengineered with a Fas DNR and either a T cell receptor or chimeric antigen receptor exhibited enhanced persistence following ACT, resulting in superior antitumor efficacy against established solid and hematologic cancers. Despite increased longevity, Fas DNR-engineered T cells did not undergo aberrant expansion or mediate autoimmunity. Thus, T cell-intrinsic disruption of Fas signaling through genetic engineering represents a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies.


Assuntos
Transferência Adotiva , Engenharia Genética , Neoplasias Experimentais/terapia , Receptores de Antígenos Quiméricos , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Animais , Proteína Ligante Fas/genética , Proteína Ligante Fas/imunologia , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Transdução de Sinais/genética , Microambiente Tumoral/genética , Receptor fas/genética , Receptor fas/imunologia
6.
Eur J Pharmacol ; 843: 226-232, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30445020

RESUMO

Graft-versus host disease (GVHD) remains the most significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dissociation of graft versus-leukemia (GVL) activity from GVHD has yet to be achieved. In this study, we used γ-secretase inhibitor (GSIs, DAPT) to inhibit Notch signaling in GVHD and GVL murine model. We found that CD11c+CD80+ dendritic cells (DCs) were up-regulated but did not enhance GVHD. Regulatory T cells (Tregs) and central memory T cells that express high levels of CD62L and CD44 had an expansion after Notch inhibition. Reduced Tumor Necrosis Factor-α and increased Interferon-γ production were found, which might be ascribed to the expansion of Tregs and central memory T cells, and result in increased sensitivity of tumor cells to cytotoxic T lymphocyte activity. Fas Receptor-Fas Ligand interaction plays a critical role in GVL instead of aGVHD. Fas Ligand expressions were similar in recipients with or without Notch inhibition, suggesting that GVL activity was maintained. We showed that Notch inhibition could enhances GVL while reducing GVHD via modulating host DCs and donor T cell activity, and the production of inflammatory cytokines.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Leucemia/imunologia , Receptores Notch/antagonistas & inibidores , Animais , Citocinas/imunologia , Células Dendríticas/imunologia , Proteína Ligante Fas/imunologia , Doença Enxerto-Hospedeiro/patologia , Intestinos/patologia , Fígado/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptores Notch/imunologia , Pele/patologia , Linfócitos T/imunologia
7.
IUBMB Life ; 71(3): 376-384, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30537230

RESUMO

Tilorone hydrochloride, a low-molecular-weight synthetic compound, induces interferon production and has been reported to have both antiviral and antitumor activities. Here, we have demonstrated the ability of tilorone to activate NK cells and specific subpopulations of cytotoxic CD4+ and CD8+ T lymphocytes that recognize immune-evasive tumor cells and kill them via the FasL-Fas interaction. We have also performed a comparative analysis of characteristics between lymphocytes activated in the fraction of human peripheral blood mononuclear cells (PBMCs) upon treatment with different stimulants of the immune response: tilorone, innate immunity protein Tag7, and cytokine IL-2, a regulator of adaptive immunity. The results show that all the three stimulants, regardless of their nature, activate lymphocytes that are identical with respect to the spectrum of target cells, phenotype, and mechanism of cytotoxic action However, these stimulants induce different mechanisms of lymphocyte activation at early stages of the immune response. © 2018 IUBMB Life, 71(3):376-384, 2019.


Assuntos
Antineoplásicos/farmacologia , Regulação Leucêmica da Expressão Gênica , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Tilorona/farmacologia , Animais , Linhagem Celular , Técnicas de Cocultura , Meios de Cultivo Condicionados/farmacologia , Citocinas/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Proteína Ligante Fas/genética , Proteína Ligante Fas/imunologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Células HeLa , Humanos , Imunidade Inata/efeitos dos fármacos , Interleucina-2/farmacologia , Células K562 , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Camundongos , Cultura Primária de Células , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Receptor fas/genética , Receptor fas/imunologia
8.
J Autoimmun ; 95: 159-170, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30274824

RESUMO

The immunomodulatory effect of IL-10 as an immunosuppressive and anti-inflammatory cytokine is well known. Taking advantage of our established mouse model of autoimmune cholangitis using 2-octynoic acid conjugated ovalbumin (2-OA-OVA) induction, we compared liver pathology, immune cell populations and antimitochondrial antibodies between IL-10 knockout and wild type mice immunized with 2-OA-OVA. At 10 weeks post immunization, portal inflammation and fibrosis were more severe in 2-OA-OVA immunized IL-10 knockout mice than in wild type mice. This was accompanied by significant higher levels of collagen I and III expression, T, NK and NKT subsets in liver and IgG anti-mitochondrial autoantibodies (AMAs) compared to 2-OA-OVA immunized wild type mice, suggesting that endogenous IL-10 is necessary for the maintenance of immune tolerance in primary biliary cholangitis (PBC). Further, we investigated whether administration of exogenous IL-10 could prevent PBC by administration of IL-10 expressing recombinant adeno-associated virus (AAV-IL-10) either 3 days before or 3 weeks after the establishment of liver pathology. Interestingly, administration of AAV-IL-10 resulted in increased liver inflammation and fibrosis, accompanied by increases in IFN-γ in liver CD4+ T cell, granzyme B, FasL, and CD107a in liver CD8+ T and NKT cells, and granzyme B and FasL in liver NK cells of AAV-IL-10 administered mice compared with control mice. Furthermore, administration of AAV-IL-10 significantly increased levels of proinflammatory cytokines and chemokines (IFN-γ, TNF-α, CXCL9 and CXCL10) and collagen I and III production in naïve mice, together with increase in immune cell infiltration and collagen deposition in the liver, suggesting a role of IL-10 in fibrosis. In conclusion, our data demonstrate that endogenous IL-10 is critical in the maintenance of immune tolerance but exogenous administration of IL-10 exacerbates liver inflammation and fibrosis. Furthermore, the distinctive presence of inflammatory immune cell populations and collagen expression in AAV-IL-10 treated naïve mice cautions against the clinical use of exogenous IL-10 in patients with autoimmune cholangitis.


Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/genética , Tolerância Imunológica , Interleucina-10/imunologia , Cirrose Hepática Biliar/imunologia , Animais , Doenças Autoimunes/sangue , Doenças Autoimunes/patologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Colágeno Tipo I/genética , Colágeno Tipo I/imunologia , Colágeno Tipo III/genética , Colágeno Tipo III/imunologia , Dependovirus/genética , Dependovirus/imunologia , Modelos Animais de Doenças , Proteína Ligante Fas/genética , Proteína Ligante Fas/imunologia , Feminino , Regulação da Expressão Gênica , Vetores Genéticos/administração & dosagem , Vetores Genéticos/química , Vetores Genéticos/imunologia , Granzimas/genética , Granzimas/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/administração & dosagem , Interleucina-10/deficiência , Interleucina-10/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Fígado/imunologia , Fígado/patologia , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
9.
Front Immunol ; 9: 2201, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319645

RESUMO

Inflammasomes have emerged as critical innate sensors of host immune that defense against pathogen infection, metabolism syndrome, cellular stress and cancer metastasis in the liver. The assembly of inflammasome activates caspase-1, which promotes the maturation of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18), and initiates pyroptotic cell death (pyroptosis). IL-18 exerts pleiotropic effects on hepatic NK cells, priming FasL-mediated cytotoxicity, and interferon-γ (IFN-γ)-dependent responses to prevent the development of liver diseases. However, considerable attention has been attracted to the pathogenic role of inflammasomes in various acute and chronic liver diseases, including viral hepatitis, nanoparticle-induced liver injury, alcoholic and non-alcoholic steatohepatitis. In this review, we summarize the latest advances on the physiological and pathological roles of inflammasomes for further development of inflammasome-based therapeutic strategies for human liver diseases.


Assuntos
Imunidade Inata , Inflamassomos/imunologia , Células Matadoras Naturais/imunologia , Hepatopatias/imunologia , Piroptose/imunologia , Caspase 1/imunologia , Caspase 1/metabolismo , Proteína Ligante Fas/imunologia , Proteína Ligante Fas/metabolismo , Humanos , Imunoterapia/métodos , Inflamassomos/metabolismo , Inflamassomos/uso terapêutico , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-18/imunologia , Interleucina-18/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Células Matadoras Naturais/metabolismo , Fígado/citologia , Fígado/imunologia , Fígado/patologia , Hepatopatias/patologia , Hepatopatias/terapia
10.
Front Immunol ; 9: 2068, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30254642

RESUMO

The role of HIV-specific CD8 T cell activity in the course of HIV infection and the way it affects the virus that resides in the latent reservoir resting memory cells is debated. The PBMC of HIV-infected patients contain HIV-specific CD8 T cells and their potential targets, CD4 T cells latently infected by HIV. CD4 T cells and CD8 T cells procured from PBMC of HIV-infected patients were co-incubated and analyzed: Formation of CD8 T cells and HIV-infected CD4 T cell conjugates and apoptosis of these CD4 T cells were observed by fluorescence microscopy with in situ PCR of HIV LTR DNA. Furthermore, conjugation of CD8 T cells with CD4 T cells and apoptosis of CD4 T cells was observed and quantified by imaging flow cytometry using anti-human activated caspase 3 antibody and TUNEL assay. The conjugation activity and apoptosis were found to be much higher in patients with acute HIV infection or AIDS compared to patients in chronic infection on antiretroviral therapy (ART) or not. Patients on ART had low grade conjugation and apoptosis of isolated CD69, CD25, and HLA-DR-negative CD4 T cells (latent reservoir cells) by CD8 T cells. Using in situ PCR The latent reservoir CD4 T cells were shown to contain most of the HIV DNA. We demonstrate in HIV-infected patients, that CD8 T cells conjugate with and kill HIV-infected CD4 T cells, including HIV-infected resting memory CD4 T cells, throughout the course of HIV infection. We propose that in HIV-infected patients CD4 T cell annihilation is caused in part by ongoing activity of HIV-specific CD8 T cells. HIV Nef protein interacts with ASK 1 and inhibits its pro-apoptotic death signaling by Fas/FasL, thus protecting HIV-infected cells from CD8 T cells killing. A peptide that interrupts Nef-ASK1 interaction that had been delivered into CD4 T cells procured from patients on ART resulted in the increase of their apoptosis inflicted by autologous CD8 T cells. We suggest that elimination of the HIV-infected latent reservoir CD4 T cells can be achieved by Nef inhibition.


Assuntos
Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Imunidade Celular , Produtos do Gene nef do Vírus da Imunodeficiência Humana/imunologia , Adulto , Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , DNA Viral/imunologia , Proteína Ligante Fas/imunologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Memória Imunológica/efeitos dos fármacos , MAP Quinase Quinase Quinase 5/imunologia , Masculino , Pessoa de Meia-Idade , Peptídeos/farmacologia , Receptor fas/imunologia
11.
Immunology ; 155(4): 499-504, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30099739

RESUMO

There is a need for more detailed elucidation of T-cell immunity in chikungunya infection. CD8 T cells are one of main actors against viruses. Here, we analysed CD8+ T lymphocytes from patients in the acute and chronic phases of chikungunya disease (CHIKD). Our results demonstrate that CD8+ T cells expressed higher ex vivo granzyme B, perforin and CD107A expression in patients in the acute phase of CHIKD compared with healthy individuals and higher ex vivo expression of CD69, interleukin-17A, interleukin-10 and CD95 ligand, and co-expression of CD95/CD95 ligand. These results elucidate the importance of these lymphocytes, demonstrating immune mechanisms mediated in human chikungunya infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Febre de Chikungunya/imunologia , Vírus Chikungunya/imunologia , Citocinas/biossíntese , Ativação Linfocitária/imunologia , Antígenos CD/biossíntese , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/biossíntese , Antígenos de Diferenciação de Linfócitos T/imunologia , Febre de Chikungunya/patologia , Febre de Chikungunya/virologia , Citocinas/imunologia , Citotoxicidade Imunológica/imunologia , Proteína Ligante Fas/biossíntese , Proteína Ligante Fas/imunologia , Granzimas/biossíntese , Granzimas/imunologia , Humanos , Interleucina-10/biossíntese , Interleucina-10/imunologia , Interleucina-17/biossíntese , Interleucina-17/imunologia , Lectinas Tipo C/biossíntese , Lectinas Tipo C/imunologia , Proteína 1 de Membrana Associada ao Lisossomo/biossíntese , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Perforina/biossíntese , Perforina/imunologia , Receptor fas/biossíntese , Receptor fas/imunologia
12.
Int J Mol Sci ; 19(8)2018 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-30103522

RESUMO

The pathogenesis of Sjögren's syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas ligand system is a leading player with activation of the death domain and caspase 8/3 cleavage, the role of soluble Fas/FasL (including its polymorphism) in apoptosis is controversial. The tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of salivary gland epithelial cells (SGECs) involves a mitochondrial pathway that includes caspase 9 cleavage. The involvement of innate immunity cells such as toll-like receptors (TLRs) has been investigated; TLR2-4 and TLR7-9 are associated with the induction of inflammation in exocrine glands of SS patients. TLR3 has the potential to induce the apoptosis of SS patients' SGECs. Linkage of epidermal growth factor (EGF) was shown in exocrine glands in SS, and it inhibited the Fas/FasL system with the help of cell-survival factors. TLR3 has dual actions to cause inflammation as well as apoptosis, which are inhibited by EGF. In conclusion, apoptosis in exocrine glands of SS patients is tightly controlled by balance of pro-apoptotic signals and growth factor.


Assuntos
Apoptose , Fator de Crescimento Epidérmico/imunologia , Glândulas Exócrinas/imunologia , Proteína Ligante Fas/imunologia , Síndrome de Sjogren/imunologia , Receptor fas/imunologia , Animais , Caspase 9/imunologia , Sobrevivência Celular , Glândulas Exócrinas/patologia , Humanos , Síndrome de Sjogren/patologia , Receptores Toll-Like/imunologia
13.
Cancer Immunol Res ; 6(10): 1186-1198, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30108045

RESUMO

The chemokine receptor, CXCR4, is involved in cancer growth, invasion, and metastasis. Several promising CXCR4 antagonists have been shown to halt tumor metastasis in preclinical studies, and clinical trials evaluating the effectiveness of these agents in patients with cancer are ongoing. However, the impact of targeting CXCR4 specifically on immune cells is not clear. Here, we demonstrate that genetic deletion of CXCR4 in myeloid cells (CXCR4MyeΔ/Δ) enhances the antitumor immune response, resulting in significantly reduced melanoma tumor growth. Moreover, CXCR4MyeΔ/Δ mice exhibited slowed tumor progression compared with CXCR4WT mice in an inducible melanocyte BrafV600E/Pten -/- mouse model. The percentage of Fas ligand (FasL)-expressing myeloid cells was reduced in CXCR4MyeΔ/Δ mice as compared with myeloid cells from CXCR4WT mice. In contrast, there was an increased percentage of natural killer (NK) cells expressing FasL in tumors growing in CXCR4MyeΔ/Δ mice. NK cells from CXCR4MyeΔ/Δ mice also exhibited increased tumor cell killing capacity in vivo, based on clearance of NK-sensitive Yac-1 cells. NK cell-mediated killing of Yac-1 cells occurred in a FasL-dependent manner, which was partially dependent upon the presence of CXCR4MyeΔ/Δ neutrophils. Furthermore, enhanced NK cell activity in CXCR4MyeΔ/Δ mice was also associated with increased production of IL18 by specific leukocyte subpopulations. These data suggest that CXCR4-mediated signals from myeloid cells suppress NK cell-mediated tumor surveillance and thereby enhance tumor growth. Systemic delivery of a peptide antagonist of CXCR4 to tumor-bearing CXCR4WT mice resulted in enhanced NK-cell activation and reduced tumor growth, supporting potential clinical implications for CXCR4 antagonism in some cancers. Cancer Immunol Res; 6(10); 1186-98. ©2018 AACR.


Assuntos
Citotoxicidade Imunológica , Proteína Ligante Fas/imunologia , Células Matadoras Naturais/imunologia , Melanoma Experimental/terapia , Receptores CXCR4/antagonistas & inibidores , Animais , Transplante de Medula Óssea , Linhagem Celular Tumoral , Interleucina-18/imunologia , Macrófagos/imunologia , Melanoma Experimental/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neutrófilos/imunologia , Receptores CXCR4/genética , Receptores CXCR4/imunologia
14.
Cancer Immunol Res ; 6(10): 1274-1287, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30087115

RESUMO

Tumor antigen heterogeneity limits success of chimeric antigen receptor (CAR) T-cell therapies. Embryonal carcinomas (EC) and mixed testicular germ cell tumors (TGCT) containing EC, which are the most aggressive TGCT subtypes, are useful for dissecting this issue as ECs express the CD30 antigen but also contain CD30-/dim cells. We found that CD30-redirected CAR T cells (CD30.CAR T cells) exhibit antitumor activity in vitro against the human EC cell lines Tera-1, Tera-2, and NCCIT and putative EC stem cells identified by Hoechst dye staining. Cytolytic activity of CD30.CAR T cells was complemented by their sustained proliferation and proinflammatory cytokine production. CD30.CAR T cells also demonstrated antitumor activity in an in vivo xenograft NOD/SCID/γcnull (NSG) mouse model of metastatic EC. We observed that CD30.CAR T cells, while targeting CD30+ EC tumor cells through the CAR (i.e., antigen-dependent targeting), also eliminated surrounding CD30- EC cells in an antigen-independent manner, via a cell-cell contact-dependent Fas/FasL interaction. In addition, ectopic Fas (CD95) expression in CD30+ Fas- EC was sufficient to improve CD30.CAR T-cell antitumor activity. Overall, these data suggest that CD30.CAR T cells might be useful as an immunotherapy for ECs. Additionally, Fas/FasL interaction between tumor cells and CAR T cells can be exploited to reduce tumor escape due to heterogeneous antigen expression or to improve CAR T-cell antitumor activity. Cancer Immunol Res; 6(10); 1274-87. ©2018 AACR.


Assuntos
Imunoterapia Adotiva , Antígeno Ki-1/imunologia , Neoplasias Embrionárias de Células Germinativas/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Neoplasias Testiculares/terapia , Animais , Linhagem Celular Tumoral , Proteína Ligante Fas/imunologia , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Ensaios Antitumorais Modelo de Xenoenxerto , Receptor fas/imunologia
15.
Int Immunopharmacol ; 63: 129-136, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30086535

RESUMO

Evolution and progression of cancer always leads to CD8+ T cells dysfunction/exhaustion. Controversy remains as to the role of Notch signaling pathway in CD8+ T cells regulation in tumorigenesis. Thus, the aim of this study was to investigate the immunomodulatory activity of Notch signaling pathway to peripheral and lung-resident CD8+ T cells in patients with lung adenocarcinoma. Forty-eight lung adenocarcinoma patients and twenty healthy individuals were enrolled in the current study, and CD8+ T cells were purified from both peripheral bloods and bronchoalveolar lavage fluids. Notch receptor mRNA expression was semi-quantified by real-time PCR. Cytolytic and noncytolytic activity of CD8+ T cells evaluated in direct and indirect contact co-culture with A549 cells in response to Notch signaling inhibition by measuring of lactate dehydrogenase release and cytokines production. Expression of Fas ligand (FasL), perforin, and granzyme B were also assessed by flow cytometry. Notch2 mRNA expression was elevated in both peripheral and lung-resident CD8+ T cells in lung adenocarcinoma patients, however, did not correlated with tumor stages or epidermal growth factor receptor mutation. Peripheral CD8+ T cells from healthy individuals exhibited stronger cytotoxicity in direct contact co-culture system, which was not influenced by Notch signaling inhibition. Moreover, suppression of Notch signaling augmented cytotoxicity of peripheral and lung-resident CD8+ T cells from lung adenocarcinoma patients in direct contact co-culture system, and promoted interferon-γ production in both systems. This process was accompanied by increased expression of FasL and perforin within CD8+ T cells. The current data revealed a potential immunosuppressive property of Notch signaling pathway to CD8+ T cells probably via inhibition of FasL and perforin in lung adenocarcinoma patients.


Assuntos
Adenocarcinoma de Pulmão/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Pulmonares/imunologia , Receptor Notch2/imunologia , Células A549 , Adenocarcinoma de Pulmão/genética , Adulto , Técnicas de Cocultura , Proteína Ligante Fas/imunologia , Feminino , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Perforina/imunologia , Receptor Notch1/genética , Receptor Notch1/imunologia , Receptor Notch2/genética , Transdução de Sinais
16.
J Immunother Cancer ; 6(1): 71, 2018 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-30005714

RESUMO

Adoptive transfer of T cells transduced with Chimeric Antigen Receptors (CAR) are now FDA-approved for the treatment of B-cell malignancies. Yet, the functionality of the endogenous TCR in CART cells has not been fully assessed. Here, we demonstrate that CART cells progressively upregulate Fas, FasL, DR5 and TRAIL, which result in their programmed cell death, independently of antigen-mediated TCR or CAR activation. CART cell apoptosis occurs even when the CAR contains a single (co-)activatory domain such as CD3ζ, CD28 or 4-1BB. Importantly, the dominant role of the Fas and DR5 pathways in CART cell apoptosis is demonstrated by the significant rescue of CART cells upon in vivo blockade by combined Fas-Fc and DR5-Fc recombinant proteins. These observations are of crucial importance for the long-term persistence of CART cells and for the development of new applications including the combined TCR and CAR activation against solid tumors.


Assuntos
Imunoterapia Adotiva , Melanoma Experimental/terapia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Neoplasias Cutâneas/terapia , Receptor fas/imunologia , Animais , Morte Celular , Proteína Ligante Fas/imunologia , Feminino , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Cutâneas/patologia , Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Carga Tumoral
17.
Front Immunol ; 9: 1052, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29868013

RESUMO

Natural killer group 2D (NKG2D) is a well-characterized activating receptor expressed on many immune cells, including invariant natural killer T (iNKT) cells. These cells were shown to be responsible of liver injury in the model of concanavalin A (Con A)-induced hepatitis, considered to be an experimental model of human autoimmune hepatitis. In this study, we investigated whether NKG2D plays a role in the hepatitis induced by iNKT cell-mediated immune response to Con A. By using killer cell lectin-like receptor subfamily K, member 1 deficient (Klrk1-/-) mice, we found that the absence of NKG2D reduced the hepatic injury upon Con A administration. This was not due to an intrinsic functional defect of NKG2D-deficient iNKT cells as mice missing NKG2D have normal distribution and function of iNKT cells. Furthermore, increased resistance to Con A-induced hepatitis was confirmed using neutralizing anti-NKG2D antibodies. The reduced pathogenic effect of Con A in the absence of NKG2D correlates with a reduction in pathogenic cytokine production and FAS-Ligand (FAS-L) expression by iNKT cells. We also found that Con A administration led to an increase in the retinoic acid early inducible (RAE-1) surface expression on wild-type hepatocytes. Finally, we found that Con A has no direct action on FAS-L expression or cytokine production by iNKT cells and thus propose that NKG2D-L expression on stressed hepatocytes promote cytotoxic activity of iNKT cells via its interaction with NKG2D contributing to hepatic injury. In conclusion, our results highlight NKG2D as an essential receptor required for the activation of iNKT cells in Con A-induced hepatitis and indicate that it represents a potential drug target for prevention of autoimmune hepatitis.


Assuntos
Hepatite Animal/imunologia , Fígado/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Células T Matadoras Naturais/imunologia , Animais , Concanavalina A , Citocinas/imunologia , Proteína Ligante Fas/imunologia , Hepatite Animal/induzido quimicamente , Hepatite Autoimune , Hepatócitos/imunologia , Fígado/citologia , Ativação Linfocitária , Camundongos , Camundongos Knockout , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia
18.
Clin Immunol ; 194: 34-42, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29940333

RESUMO

To test the relative roles of perforin (pfp) vs. FasL in CTL control of autoreactive B cell expansion, we used the parent-into-F1 model of murine graft-vs.-host disease in which donor CD8 CTL prevent lupus like disease by eliminating activated autoreactive B cells. F1 mice receiving either pfp or FasL defective donor T cells exhibited an intermediate short-term phenotype. Pairing of purified normal CD4 T cells with either pfp or FasL defective CD8 T cell subsets resulted in impaired host B cell elimination and mild lupus like disease that was roughly equivalent in the two experimental groups. Thus, in addition to major roles in tumor and intracellular pathogen control, pfp mediated CD8 CTL killing plays a significant role in controlling autoreactive B cell expansion and lupus downregulation that is comparable to that mediated by FasL killing. Importantly, both pathways are required for optimal elimination of activated autoreactive B cells.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteína Ligante Fas/imunologia , Proteínas Citotóxicas Formadoras de Poros/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Doença Enxerto-Hospedeiro/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Mol Med Rep ; 18(1): 920-930, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29845202

RESUMO

Post-menopausal osteoporosis is a bone formation disorder induced by estrogen deficiency. Estrogen deficiency facilitates the differentiation and maturation of osteoclasts by activating T lymphocytes. In our previous study, it was demonstrated that estrogen promotes bone marrow mesenchymal stem cell (BMMSC)­induced osteoclast apoptosis through downregulation of microRNA (miR)­181a and subsequent Fas ligand (FasL) protein accumulation. In the present study, the regulatory effects of miR­181a on FasL expression in BMMSCs and the apoptotic effects of BMMSCs on cluster of differentiation (CD)4+T lymphocytes were investigated. An ovariectomized mouse model of osteoporosis (OVX) was established and CD4+T lymphocytes were isolated from the bones of these mice. The results demonstrated that the number of CD4+T lymphocytes was increased in the OVX group compared within the control group, thus suggesting that estrogen deficiency may increase CD4+T lymphocyte number. CD4+T lymphocytes were subsequently co­cultured with estrogen­treated BMMSCs, after which it was demonstrated that estrogen significantly promoted the apoptosis of CD4+T lymphocytes. Western blot analysis indicated that estrogen promoted the apoptosis of CD4+T lymphocytes through regulation of FasL expression in BMMSCs in a concentration­dependent manner. Finally, miR­181a was transfected into BMMSCs, which were co­cultured with CD4+T lymphocytes in vitro and in vivo. The results revealed that miR­181a exerted a negative regulatory effect on BMMSC­induced CD4+T lymphocyte apoptosis by regulating FasL protein expression in BMMSCs; this maybe a key mechanism underlying the development of estrogen deficiency­induced osteoporosis.


Assuntos
Apoptose/imunologia , Células da Medula Óssea/imunologia , Linfócitos T CD4-Positivos/imunologia , Estrogênios/deficiência , Proteína Ligante Fas/imunologia , Regulação da Expressão Gênica/imunologia , Células-Tronco Mesenquimais/imunologia , MicroRNAs/imunologia , Osteoporose/imunologia , Animais , Células da Medula Óssea/patologia , Linfócitos T CD4-Positivos/patologia , Proteína Ligante Fas/genética , Feminino , Regulação da Expressão Gênica/genética , Células-Tronco Mesenquimais/patologia , Camundongos , MicroRNAs/genética , Osteoporose/genética , Osteoporose/patologia
20.
Immun Inflamm Dis ; 6(2): 312-321, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29642281

RESUMO

INTRODUCTION: T cell and NK cell cytotoxicity can be mediated via the perforin/granzyme system and Fas Ligand (FasL, CD178). FasL is synthesized as a type II transmembrane protein that binds its cognate receptor Fas (CD95). Membrane-bound FasL is expressed on the plasma membrane of activated lymphocytes and is the main form of FasL with cytotoxic activity, but whether FasL is delivered to the immune synapse along with granzyme and perforin-containing granules is unclear. METHODS: We stably expressed FasL-fluorescent fusion proteins into human NK cells and examined the localization of FasL relative to other intracellular markers by confocal and immunoelectron microscopy, and examined the trafficking of FasL during formation of immune synapses with HLA-deficient B cells. RESULTS: FasL co-localized with CD63 more strongly than perforin or Lamp1+ in cytolytic granules. Electron microscopy revealed that FasL is enriched on intraluminal vesicles (ILVs) adjacent to the dense-core within cytolytic granules. In NK cells forming immune synapses with HLA-deficient B cells, a portion of FasL-containing granules re-localize toward the immune synapse, while a distinct pool of FasL remains at the distal pole of the cell. CONCLUSIONS: Localization of FasL to intra-luminal vesicles within cytolytic granules facilitates FasL trafficking to immune synapses and cytotoxic function in NK cells.


Assuntos
Grânulos Citoplasmáticos/metabolismo , Proteína Ligante Fas/metabolismo , Sinapses Imunológicas/metabolismo , Células Matadoras Naturais/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Grânulos Citoplasmáticos/imunologia , Grânulos Citoplasmáticos/ultraestrutura , Proteína Ligante Fas/imunologia , Proteína Ligante Fas/ultraestrutura , Granzimas/metabolismo , Antígenos HLA/metabolismo , Humanos , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/ultraestrutura , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/ultraestrutura , Microscopia Eletrônica , Perforina/metabolismo , Tetraspanina 30/imunologia , Tetraspanina 30/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA