As CD40 transduces activation signals involved in inflammatory and immune disorders,we explored the expression and response to CD40 engagement in human glioma cell lines in this study.The CD40 expression in BT-325 and...As CD40 transduces activation signals involved in inflammatory and immune disorders,we explored the expression and response to CD40 engagement in human glioma cell lines in this study.The CD40 expression in BT-325 and U251 cells was flow cytometrically detected.The cells were incubated with srhCD40L for 72 h to assess its effects on cell growth in vitro.TNF-α expression was quantified by real-time PCR,and protein expression was analyzed by ELISA.The I-κb mRNA was detected by RT-PCR.I-κB expression decreased after stimulation with 1 μg/mL srhCD40L,but it was upregulated after the cells were pretreated with CD40 antibody.srhCD40L significantly inhibited the proliferation of the CD40+ human glioma cells.The stimulation of CD40+ glioma cells with soluble CD40L (CD154) up-regulated the expression of TNF-α at both mRNA and protein levels.We are led to conclude that CD40L/CD40 could inhibit human glioma cells through I-κb signaling pathway.Interferon-γ can augment CD40 expression and the inhibitory effect of CD40 ligand on cell growth in vitro.These results suggest that srhCD40L may benefit the therapy strategy of glioma.展开更多
CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vacci...CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 （PD-1） and lymphocyte-activation gene-3 （LAG-3） and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-7 production and cytolytic effects. Naive CD8＋ T cells upregulated inhibitory PD-ligand 1 （PD-L1）, B- and T-lymphocyte attenuator and T-cell anergy-associated molecules （Grail and Itch） while down-regulating the proliferative response upon stimulation in mice with chronic infection. Remarkably, the OVA-Texo vaccine counteracted T-cell anergy and converted CTL exhaustion. The latter was associated with （i） the upregulation of a marker for CTL functionality, diacetylated histone-H3 （diAcH3）, （ii） a fourfold increase in CTLs, occurring independent of host DCs or CD4＋ T cells, and （iii） the restoration of CTL IFN-7 production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, elF4E and T-bet, and treatment of the CTLs with an mTORC1 inhibitor, rapamycin, significantly reduced the OVA-Texo- induced increase in CTLs. Interestingly, OVA-Texo-mediated CD40L signaling played a critical role in the observed immunological effects. Importantly, the Gag-Texo vaccine induced Gag-specific therapeutic immunity in chronic infection. Therefore, this study should have a serious impact on the development of new therapeutic vaccines for human immunodeficiency virus （HIV-1） infection.展开更多
CD40 and its cognate ligand （CD40L） are a pair of regulators of pro-inflammatory and immune responses. In the central nervous system （CNS）, CD40 is expressed on a variety of cells, including vascular endothelial c...CD40 and its cognate ligand （CD40L） are a pair of regulators of pro-inflammatory and immune responses. In the central nervous system （CNS）, CD40 is expressed on a variety of cells, including vascular endothelial cells, smooth muscle cells, astrocytes and microglia （the brain macrophages, being the most sensitive cell type to respond to CD40 ligand）. Interaction between CD40 on microglia and CD40L presented by infiltrating T lymphocytes and other resident CNS cells triggers a series of intracellular signaling events that promote the production of a wide array of cytokines, chemokines and neurotoxins. Thus, both molecules serve as amplifiers of pro-inflammatory and immune responses in the CNS and constitute important molecular targets for therapeutic intervention of diseases.Cellular ＆ Molecular Immunology. 2006;3（3）：163-169.展开更多
基金supported by a grant from the Ministry ofEducation for New Teachers,China (No.20070487132)
文摘As CD40 transduces activation signals involved in inflammatory and immune disorders,we explored the expression and response to CD40 engagement in human glioma cell lines in this study.The CD40 expression in BT-325 and U251 cells was flow cytometrically detected.The cells were incubated with srhCD40L for 72 h to assess its effects on cell growth in vitro.TNF-α expression was quantified by real-time PCR,and protein expression was analyzed by ELISA.The I-κb mRNA was detected by RT-PCR.I-κB expression decreased after stimulation with 1 μg/mL srhCD40L,but it was upregulated after the cells were pretreated with CD40 antibody.srhCD40L significantly inhibited the proliferation of the CD40+ human glioma cells.The stimulation of CD40+ glioma cells with soluble CD40L (CD154) up-regulated the expression of TNF-α at both mRNA and protein levels.We are led to conclude that CD40L/CD40 could inhibit human glioma cells through I-κb signaling pathway.Interferon-γ can augment CD40 expression and the inhibitory effect of CD40 ligand on cell growth in vitro.These results suggest that srhCD40L may benefit the therapy strategy of glioma.
文摘CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 （PD-1） and lymphocyte-activation gene-3 （LAG-3） and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-7 production and cytolytic effects. Naive CD8＋ T cells upregulated inhibitory PD-ligand 1 （PD-L1）, B- and T-lymphocyte attenuator and T-cell anergy-associated molecules （Grail and Itch） while down-regulating the proliferative response upon stimulation in mice with chronic infection. Remarkably, the OVA-Texo vaccine counteracted T-cell anergy and converted CTL exhaustion. The latter was associated with （i） the upregulation of a marker for CTL functionality, diacetylated histone-H3 （diAcH3）, （ii） a fourfold increase in CTLs, occurring independent of host DCs or CD4＋ T cells, and （iii） the restoration of CTL IFN-7 production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, elF4E and T-bet, and treatment of the CTLs with an mTORC1 inhibitor, rapamycin, significantly reduced the OVA-Texo- induced increase in CTLs. Interestingly, OVA-Texo-mediated CD40L signaling played a critical role in the observed immunological effects. Importantly, the Gag-Texo vaccine induced Gag-specific therapeutic immunity in chronic infection. Therefore, this study should have a serious impact on the development of new therapeutic vaccines for human immunodeficiency virus （HIV-1） infection.
文摘CD40 and its cognate ligand （CD40L） are a pair of regulators of pro-inflammatory and immune responses. In the central nervous system （CNS）, CD40 is expressed on a variety of cells, including vascular endothelial cells, smooth muscle cells, astrocytes and microglia （the brain macrophages, being the most sensitive cell type to respond to CD40 ligand）. Interaction between CD40 on microglia and CD40L presented by infiltrating T lymphocytes and other resident CNS cells triggers a series of intracellular signaling events that promote the production of a wide array of cytokines, chemokines and neurotoxins. Thus, both molecules serve as amplifiers of pro-inflammatory and immune responses in the CNS and constitute important molecular targets for therapeutic intervention of diseases.Cellular ＆ Molecular Immunology. 2006;3（3）：163-169.
