CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))subpopulatio...CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))subpopulations.Inhibitor of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell immunity.However,the role of Id2 in CD8^(+)T-cell exhaustion is unclear.Here,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm cells.Genetic deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor susceptibility.Mechanistically,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1.Therefore,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog cells.An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice.Inhibition of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T cells.This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.展开更多
In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2,no specific and effective drugs for treating this disease have been reported until today.Angiotensin-converting enzyme 2(ACE2),a ...In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2,no specific and effective drugs for treating this disease have been reported until today.Angiotensin-converting enzyme 2(ACE2),a receptor of SARS-CoV-2,mediates the virus infection by binding to spike protein.Although ACE2 is expressed in the lung,kidney,and intestine,its expressing levels are rather low,especially in the lung.Considering the great infectivity of COVID-19,we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection.Here,we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein.The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody,Meplazumab,inhibits SARSCoV-2 amplification.Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells,which can be neutralized by CD147 extracellular fragment.Viral loads are detectable in the lungs of human CD147(hCD147)mice infected with SARS-CoV-2,but not in those of virus-infected wild type mice.Interestingly,virions are observed in lymphocytes of lung tissue from a COVID-19 patient.Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dosedependent manner,which is specifically inhibited by Meplazumab.Furthermore,CD147 mediates virus entering host cells by endocytosis.Together,our study reveals a novel virus entry route,CD147-spike protein,which provides an important target for developing specific and effective drug against COVID-19.展开更多
The uncontrollable synthesis of Prussian blue (PB) and its weak stability toward OH -are great challenges affecting its electrochemical biosensing application. Herein we utilize the unique properties of chitosan (CS) ...The uncontrollable synthesis of Prussian blue (PB) and its weak stability toward OH -are great challenges affecting its electrochemical biosensing application. Herein we utilize the unique properties of chitosan (CS) to realize the facile and controllable synthesis of a CS-PB nanocomposite and combine it with the urease-catalyzed deposition of polydopamine (PDA) for amplifying the electrochemical signal inhibition of PB to develop a novel immunosensing method for protein detection. The immunosensor was constructed on a CS-PB modified electrode, and a urease-functionalized silica nanoprobe was prepared for tracing its sandwich immunoassay toward the model analyte of carcinoembryonic antigen. Besides the electrochem- ical impedance effect of the quantitatively captured nanoprobes, their enzymatic reaction can release numerous OH -to destroy the PB crystals and also induce the PDA deposition onto the immunosensor. These caused drastic electrochemical signal inhibition to PB. Based on the above multi-signal amplification mechanism, the method exhibits a very low detection limit of 0.042 pg mL^(-1) along with a very wide linear range of six-order of magnitude. In addition, the CS-PB based immunosensor has excellent specificity, repeatability, stability and reliability. Thus this PB nanocomposite and the proposed electrochemical immunosensing method reveal a promising potential for future applications.展开更多
In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2,no specific and effective drugs for treating this disease have been reported until today.Angiotensin-converting enzyme 2(ACE2),a ...In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2,no specific and effective drugs for treating this disease have been reported until today.Angiotensin-converting enzyme 2(ACE2),a receptor of SARS-CoV-2,mediates the virus infection by binding to spike protein.Although ACE2 is expressed in the lung,kidney,and intestine,its expressing levels are rather low,especially in the lung.Considering the great infectivity of COVID-19,we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection.Here,we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein.The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody,Meplazumab,inhibits SARSCoV-2 amplification.Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells,which can be neutralized by CD147 extracellular fragment.Viral loads are detectable in the lungs of human CD147(hCD147)mice infected with SARS-CoV-2,but not in those of virus-infected wild type mice.Interestingly,virions are observed in lymphocytes of lung tissue from a COVID-19 patient.Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dosedependent manner,which is specifically inhibited by Meplazumab.Furthermore,CD147 mediates virus entering host cells by endocytosis.Together,our study reveals a novel virus entry route,CD147-spike protein,which provides an important target for developing specific and effective drug against COVID-19.展开更多
基金supported by the Major Program of the National Natural Science Foundation of China(No.82293635,No.92169211)the National Key Research and Development Program of China(No.2019YFC1316302,No.2023YFC2306400)+1 种基金the National Natural Science Foundation of China(No.81972711)supported by the Science Fund Program for Distinguished Young Scholars(LC).
文摘CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))subpopulations.Inhibitor of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell immunity.However,the role of Id2 in CD8^(+)T-cell exhaustion is unclear.Here,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm cells.Genetic deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor susceptibility.Mechanistically,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1.Therefore,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog cells.An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice.Inhibition of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T cells.This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.
基金supported by the National Science and Technology Major Project of China(2019ZX09732-001)the Key R&D Plan Projects in Shaanxi Province(2020ZDXM2-SF-01)Young Talent fund of the University Association for Science and Technology in Shaanxi,China(20200304).
文摘In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2,no specific and effective drugs for treating this disease have been reported until today.Angiotensin-converting enzyme 2(ACE2),a receptor of SARS-CoV-2,mediates the virus infection by binding to spike protein.Although ACE2 is expressed in the lung,kidney,and intestine,its expressing levels are rather low,especially in the lung.Considering the great infectivity of COVID-19,we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection.Here,we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein.The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody,Meplazumab,inhibits SARSCoV-2 amplification.Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells,which can be neutralized by CD147 extracellular fragment.Viral loads are detectable in the lungs of human CD147(hCD147)mice infected with SARS-CoV-2,but not in those of virus-infected wild type mice.Interestingly,virions are observed in lymphocytes of lung tissue from a COVID-19 patient.Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dosedependent manner,which is specifically inhibited by Meplazumab.Furthermore,CD147 mediates virus entering host cells by endocytosis.Together,our study reveals a novel virus entry route,CD147-spike protein,which provides an important target for developing specific and effective drug against COVID-19.
基金financially supported by the National Natural Science Foundation of China (No. 22076043)the Science and Technology Foundation for Excellent Creative Research Group of Hubei Provincial Department of Education (No. T201810)。
文摘The uncontrollable synthesis of Prussian blue (PB) and its weak stability toward OH -are great challenges affecting its electrochemical biosensing application. Herein we utilize the unique properties of chitosan (CS) to realize the facile and controllable synthesis of a CS-PB nanocomposite and combine it with the urease-catalyzed deposition of polydopamine (PDA) for amplifying the electrochemical signal inhibition of PB to develop a novel immunosensing method for protein detection. The immunosensor was constructed on a CS-PB modified electrode, and a urease-functionalized silica nanoprobe was prepared for tracing its sandwich immunoassay toward the model analyte of carcinoembryonic antigen. Besides the electrochem- ical impedance effect of the quantitatively captured nanoprobes, their enzymatic reaction can release numerous OH -to destroy the PB crystals and also induce the PDA deposition onto the immunosensor. These caused drastic electrochemical signal inhibition to PB. Based on the above multi-signal amplification mechanism, the method exhibits a very low detection limit of 0.042 pg mL^(-1) along with a very wide linear range of six-order of magnitude. In addition, the CS-PB based immunosensor has excellent specificity, repeatability, stability and reliability. Thus this PB nanocomposite and the proposed electrochemical immunosensing method reveal a promising potential for future applications.
基金This work was supported by the National Science and Technology Major Project of China(2019ZX09732-001)the Key R&D Plan Projects in Shaanxi Province(2020ZDXM2-SF-01)Young Talent fund of the University Association for Science and Technology in Shaanxi,China(20200304).
文摘In face of the everlasting battle toward COVID-19 and the rapid evolution of SARS-CoV-2,no specific and effective drugs for treating this disease have been reported until today.Angiotensin-converting enzyme 2(ACE2),a receptor of SARS-CoV-2,mediates the virus infection by binding to spike protein.Although ACE2 is expressed in the lung,kidney,and intestine,its expressing levels are rather low,especially in the lung.Considering the great infectivity of COVID-19,we speculate that SARS-CoV-2 may depend on other routes to facilitate its infection.Here,we first discover an interaction between host cell receptor CD147 and SARS-CoV-2 spike protein.The loss of CD147 or blocking CD147 in Vero E6 and BEAS-2B cell lines by anti-CD147 antibody,Meplazumab,inhibits SARSCoV-2 amplification.Expression of human CD147 allows virus entry into non-susceptible BHK-21 cells,which can be neutralized by CD147 extracellular fragment.Viral loads are detectable in the lungs of human CD147(hCD147)mice infected with SARS-CoV-2,but not in those of virus-infected wild type mice.Interestingly,virions are observed in lymphocytes of lung tissue from a COVID-19 patient.Human T cells with a property of ACE2 natural deficiency can be infected with SARS-CoV-2 pseudovirus in a dosedependent manner,which is specifically inhibited by Meplazumab.Furthermore,CD147 mediates virus entering host cells by endocytosis.Together,our study reveals a novel virus entry route,CD147-spike protein,which provides an important target for developing specific and effective drug against COVID-19.