Research into the suppressive activity of CD4＋FoxP3＋ T regulatory cells （Treg） has defined a sublineage of CD4＋ cells that contribute to self-tolerance and resistance to autoimmune disease. Much less attention ha...Research into the suppressive activity of CD4＋FoxP3＋ T regulatory cells （Treg） has defined a sublineage of CD4＋ cells that contribute to self-tolerance and resistance to autoimmune disease. Much less attention has been given to the potential contribution of regulatory sublineages of CD8＋ cells. Analysis of a small fraction of CD8＋ cells that target autoreactive CD4＋ cells through recognition of the MHC class Ib molecule Qa-1 in mouse and HLA-E in human has revitalized interest in CD8＋ Treg. Here we summarize recent progress and future directions of research into the role of this CD8＋ sublineage in resistance to autoimmune disease. Cellular ＆ Molecular Immunology. 2008; 5（6）：401-406.展开更多
Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus(SLE),which makes B-cell depletion a potential strategy for SLE treatment.The clinical success of anti-CD19 CAR-T cells in treating B-c...Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus(SLE),which makes B-cell depletion a potential strategy for SLE treatment.The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers.In this study,we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model.We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice.Furthermore,anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention.According to our observations,compared with antibody treatment,the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice.The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression.We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif,CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment.Taken together,these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE,indicating its potential for clinical use in patients.展开更多
Chemical and biological sensing play important roles in healthcare,environmental science,food-safety tests,and medical applications.Flexible organic electrochemical transistors(OECTs)have shown great promise in the fi...Chemical and biological sensing play important roles in healthcare,environmental science,food-safety tests,and medical applications.Flexible organic electrochemical transistors(OECTs)have shown great promise in the field of chemical and biological sensing,owing to their superior sensitivity,high biocompatibility,low cost,and light weight.Herein,we summarize recent progress in the fabrication of flexible OECTs and their applications in chemical and biological sensing.We start with a brief introduction to the working principle,configuration,and sensing mechanism of the flexible OECT-based sensors.Then,we focus on the fabrication of flexible OECT-based sensors,including material selection and structural engineering of the components in OECTs:the substrate,electrodes,electrolyte,and channel.Particularly,the gate modification is discussed extensively.Then,the applications of OECT-based sensors in chemical and biological sensing are reviewed in detail.Especially,the array-based and integrated OECT sensors are also introduced.Finally,we present the conclusions and remaining challenges in the field of flexible OECT-based sensing.Our timely review will deepen the understanding of the flexible OECT-based sensors and promote the further development of the fast-growing field of flexible sensing.展开更多
Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obe...Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obese status.In a weight gain-loss-regain model,we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain.This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice.Surprisingly,such obesity memory was abrogated by dexamethasone treatment,whereas immunodeficient Rag1−/−and H2A−/−mice failed to establish such memory.Rag1−/−mice repossessed the obesity memory when immune cells or CD4+T cells isolated from previously obese mice were transferred.Furthermore,depletion of CD4+T cells led to obesity memory ablation.Taken together,we conclude that CD4+T cells mediate obesity memory and promote weight regain.展开更多
The nucleotide-binding domain,leucine-rich-repeat containing family,pyrin domain-containing 3(NLRP3)inflammasome is essential in inflammation and inflammatory disorders.Phosphorylation at various sites on NLRP3 differ...The nucleotide-binding domain,leucine-rich-repeat containing family,pyrin domain-containing 3(NLRP3)inflammasome is essential in inflammation and inflammatory disorders.Phosphorylation at various sites on NLRP3 differentially regulates inflammasome activation.The Ser725 phosphorylation site on NLRP3 is depicted in multiple inflammasome activation scenarios,but the importance and regulation of this site has not been clarified.The present study revealed that the phosphorylation of Ser725 was an essential step for the priming of the NLRP3 inflammasome in macrophages.We also showed that Ser725 was directly phosphorylated by misshapen(Msn)/NIK-related kinase 1(MINK1),depending on the direct interaction between MINK1 and the NLRP3 LRR domain.MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis.Reactive oxygen species(ROS)upregulated the kinase activity of MINK1 and subsequently promoted inflammasome priming via NLRP3 Ser725 phosphorylation.Eliminating ROS suppressed NLRP3 activation and reduced sepsis and peritonitis symptoms in a MINK1-dependent manner.Altogether,our study reveals a direct regulation of the NLRP3 inflammasome by Msn family kinase MINK1 and suggests that modulation of MINK1 activity is a potential intervention strategy for inflammasomerelated diseases.展开更多
Double-positive(DP)thymocytes undergo positive selection to become mature single-positive CD4+and CD8+T cells in response to T cell receptor(TCR)signaling.Unlike mature T cells,DP cells must respond to low-affinity se...Double-positive(DP)thymocytes undergo positive selection to become mature single-positive CD4+and CD8+T cells in response to T cell receptor(TCR)signaling.Unlike mature T cells,DP cells must respond to low-affinity self-peptide-MHC ligands before full upregulation of their surface TCR expression can occur.Thus,DP thymocytes must be more sensitive to ligands than mature T cells.A number of molecules have been found that are able to enhance the strength of the TCR signal to facilitate positive selection.However,almost all of these molecules are also active in mature T cells.Themis(thymocyte expressed molecule involved in selection)and Tespa1(thymocyte expressed positive selection associated 1)are two recently discovered molecules essential for optimal TCR signaling and thymocyte development.A deficiency in both molecules leads to defects in positive selection.Here,we compared the relative contributions of Themis and Tespa1 to positive selection in thymocytes.We show that Tespa1 deficiency led to more limited and specific gene expression profile changes in cells undergoing positive selection.In mixed bone marrow transfer experiments,Tespa1^(−/−)cells showed more severe defects in thymocyte development than Themis^(−/−)cells.However,Tespa1^(−/−)cells showed a substantial degree of homeostatic expansion and became predominant in the peripheral lymphoid organs,suggesting that Tespa1 is a thymic-specific TCR signaling regulator.This hypothesis is further supported by our observations in Tespa1 conditional knockout mice,as Tespa1 deletion in peripheral T cells did not affect TCR signaling or cell proliferation.The different regulatory effects of Tespa1 and Themis are in accordance with their nonredundant roles in thymocyte selection,during which Tespa1 and Themis double knockouts showed additive defects.展开更多
CD4 T cells play central roles in both immune response and regulation.They can either serve as the mediators of adaptive immune response against infections, or act as gate keepers to maintain immune homeostasis. Upon ...CD4 T cells play central roles in both immune response and regulation.They can either serve as the mediators of adaptive immune response against infections, or act as gate keepers to maintain immune homeostasis. Upon activation by antigens, naive T cells proliferate and differentiate into different T helper （Th） cells with distinct effector functions. Thl cells, induced by tran- scription factor T-bet and produce interferon- y, are crucial for clearing intracellular patho- gens. In contrast, IL-4 expressing Th2 cells driven by GATA-3 are responsible for the clearing of extraceUular pathogens. Thl7 cells, an additional subset ofT cells expressing tran- scription factor RORyt and cytokine ILl 7, are considered as the main drivers of autoimmune tissue injury.展开更多
Calcium is an important cell signaling intermediate known to play a critical role in T-cell receptor(TCR)-mediated activation of both developing thymocytes and mature peripheral T cells.Upon antigen engagement,the TCR...Calcium is an important cell signaling intermediate known to play a critical role in T-cell receptor(TCR)-mediated activation of both developing thymocytes and mature peripheral T cells.Upon antigen engagement,the TCR recruits PLCγ1 to the proximal signaling complex to be phosphorylated and activated by the membrane-bound kinase Itk.Activated PLCγ1 mediates the cleavage of the cell membrane lipid component PIP2 into the lipids diacylglycerol(DAG)and inositol 1,4,5-triphosphate(IP3).展开更多
In a recent study from NEJM,Mougiakakos et al.reported a case in which autologous anti-CD19 CAR-T cell therapy was used in the treatment of a refractory SLE patient[1].Rapid remission of severe SLE was observed in thi...In a recent study from NEJM,Mougiakakos et al.reported a case in which autologous anti-CD19 CAR-T cell therapy was used in the treatment of a refractory SLE patient[1].Rapid remission of severe SLE was observed in this case,indicating the potential of application of B cell-targeting CAR-T cell therapy in severe autoimmune diseases.展开更多
基金supported in part by research grants from the NIH (AI037562)National Multiple Sclerosis Society and a gift from the Schecter Family Research Foundation to HC LL is a Claudia Adams Barr Investigator and NIH NRSA Fellow (T32 AI07386)
文摘Research into the suppressive activity of CD4＋FoxP3＋ T regulatory cells （Treg） has defined a sublineage of CD4＋ cells that contribute to self-tolerance and resistance to autoimmune disease. Much less attention has been given to the potential contribution of regulatory sublineages of CD8＋ cells. Analysis of a small fraction of CD8＋ cells that target autoreactive CD4＋ cells through recognition of the MHC class Ib molecule Qa-1 in mouse and HLA-E in human has revitalized interest in CD8＋ Treg. Here we summarize recent progress and future directions of research into the role of this CD8＋ sublineage in resistance to autoimmune disease. Cellular ＆ Molecular Immunology. 2008; 5（6）：401-406.
基金This work was supported by grants from the National Natural Science Foundation of China(31770954,31530019 to L.L.and 31900628 to Q.X.)the Fundamental Research Funds for the Central Universities(2018XZZX001-12 to L.L.).
文摘Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus(SLE),which makes B-cell depletion a potential strategy for SLE treatment.The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers.In this study,we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model.We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice.Furthermore,anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention.According to our observations,compared with antibody treatment,the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice.The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression.We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif,CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment.Taken together,these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE,indicating its potential for clinical use in patients.
基金the National Key R&D Program of China(No.2017YFA0204700)the National Natural Science Foundation of China(No.11974180)+2 种基金the Joint Research Funds of Department of Science&Technology of Shaanxi Province and Northwestern Polytechnical University(No.2020GXLH-Z-021)the China-Sweden Joint Mobility Project(No.51811530018)the Fundamental Research Funds for the Central Universities.
文摘Chemical and biological sensing play important roles in healthcare,environmental science,food-safety tests,and medical applications.Flexible organic electrochemical transistors(OECTs)have shown great promise in the field of chemical and biological sensing,owing to their superior sensitivity,high biocompatibility,low cost,and light weight.Herein,we summarize recent progress in the fabrication of flexible OECTs and their applications in chemical and biological sensing.We start with a brief introduction to the working principle,configuration,and sensing mechanism of the flexible OECT-based sensors.Then,we focus on the fabrication of flexible OECT-based sensors,including material selection and structural engineering of the components in OECTs:the substrate,electrodes,electrolyte,and channel.Particularly,the gate modification is discussed extensively.Then,the applications of OECT-based sensors in chemical and biological sensing are reviewed in detail.Especially,the array-based and integrated OECT sensors are also introduced.Finally,we present the conclusions and remaining challenges in the field of flexible OECT-based sensing.Our timely review will deepen the understanding of the flexible OECT-based sensors and promote the further development of the fast-growing field of flexible sensing.
基金This work was supported by the National Natural Science Foundation of China(Grant 31301217)the Ministry of Science and Technology of China(Grants 2015BAI08B02 and 2014BAI02B01).
文摘Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obese status.In a weight gain-loss-regain model,we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain.This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice.Surprisingly,such obesity memory was abrogated by dexamethasone treatment,whereas immunodeficient Rag1−/−and H2A−/−mice failed to establish such memory.Rag1−/−mice repossessed the obesity memory when immune cells or CD4+T cells isolated from previously obese mice were transferred.Furthermore,depletion of CD4+T cells led to obesity memory ablation.Taken together,we conclude that CD4+T cells mediate obesity memory and promote weight regain.
基金This work was supported by grants from the National Natural Science Foundation of China(31930038,31770954,and 31530019 to L.L.).
文摘The nucleotide-binding domain,leucine-rich-repeat containing family,pyrin domain-containing 3(NLRP3)inflammasome is essential in inflammation and inflammatory disorders.Phosphorylation at various sites on NLRP3 differentially regulates inflammasome activation.The Ser725 phosphorylation site on NLRP3 is depicted in multiple inflammasome activation scenarios,but the importance and regulation of this site has not been clarified.The present study revealed that the phosphorylation of Ser725 was an essential step for the priming of the NLRP3 inflammasome in macrophages.We also showed that Ser725 was directly phosphorylated by misshapen(Msn)/NIK-related kinase 1(MINK1),depending on the direct interaction between MINK1 and the NLRP3 LRR domain.MINK1 deficiency reduced NLRP3 activation and suppressed inflammatory responses in mouse models of acute sepsis and peritonitis.Reactive oxygen species(ROS)upregulated the kinase activity of MINK1 and subsequently promoted inflammasome priming via NLRP3 Ser725 phosphorylation.Eliminating ROS suppressed NLRP3 activation and reduced sepsis and peritonitis symptoms in a MINK1-dependent manner.Altogether,our study reveals a direct regulation of the NLRP3 inflammasome by Msn family kinase MINK1 and suggests that modulation of MINK1 activity is a potential intervention strategy for inflammasomerelated diseases.
基金supported by grants from the National Natural Science Foundation of China(31530019,31770954,and 31325009 to L.L.)the National Key R&D Program of China(2018YFC1105102)the Fundamental Research Funds for the Central Universities(2018XZZX001-12).
文摘Double-positive(DP)thymocytes undergo positive selection to become mature single-positive CD4+and CD8+T cells in response to T cell receptor(TCR)signaling.Unlike mature T cells,DP cells must respond to low-affinity self-peptide-MHC ligands before full upregulation of their surface TCR expression can occur.Thus,DP thymocytes must be more sensitive to ligands than mature T cells.A number of molecules have been found that are able to enhance the strength of the TCR signal to facilitate positive selection.However,almost all of these molecules are also active in mature T cells.Themis(thymocyte expressed molecule involved in selection)and Tespa1(thymocyte expressed positive selection associated 1)are two recently discovered molecules essential for optimal TCR signaling and thymocyte development.A deficiency in both molecules leads to defects in positive selection.Here,we compared the relative contributions of Themis and Tespa1 to positive selection in thymocytes.We show that Tespa1 deficiency led to more limited and specific gene expression profile changes in cells undergoing positive selection.In mixed bone marrow transfer experiments,Tespa1^(−/−)cells showed more severe defects in thymocyte development than Themis^(−/−)cells.However,Tespa1^(−/−)cells showed a substantial degree of homeostatic expansion and became predominant in the peripheral lymphoid organs,suggesting that Tespa1 is a thymic-specific TCR signaling regulator.This hypothesis is further supported by our observations in Tespa1 conditional knockout mice,as Tespa1 deletion in peripheral T cells did not affect TCR signaling or cell proliferation.The different regulatory effects of Tespa1 and Themis are in accordance with their nonredundant roles in thymocyte selection,during which Tespa1 and Themis double knockouts showed additive defects.
文摘CD4 T cells play central roles in both immune response and regulation.They can either serve as the mediators of adaptive immune response against infections, or act as gate keepers to maintain immune homeostasis. Upon activation by antigens, naive T cells proliferate and differentiate into different T helper （Th） cells with distinct effector functions. Thl cells, induced by tran- scription factor T-bet and produce interferon- y, are crucial for clearing intracellular patho- gens. In contrast, IL-4 expressing Th2 cells driven by GATA-3 are responsible for the clearing of extraceUular pathogens. Thl7 cells, an additional subset ofT cells expressing tran- scription factor RORyt and cytokine ILl 7, are considered as the main drivers of autoimmune tissue injury.
文摘Calcium is an important cell signaling intermediate known to play a critical role in T-cell receptor(TCR)-mediated activation of both developing thymocytes and mature peripheral T cells.Upon antigen engagement,the TCR recruits PLCγ1 to the proximal signaling complex to be phosphorylated and activated by the membrane-bound kinase Itk.Activated PLCγ1 mediates the cleavage of the cell membrane lipid component PIP2 into the lipids diacylglycerol(DAG)and inositol 1,4,5-triphosphate(IP3).
基金Our work was supported by grants from the National Natural Science Foundation of China(31930038,31770954,and 31530019 to LL).
文摘In a recent study from NEJM,Mougiakakos et al.reported a case in which autologous anti-CD19 CAR-T cell therapy was used in the treatment of a refractory SLE patient[1].Rapid remission of severe SLE was observed in this case,indicating the potential of application of B cell-targeting CAR-T cell therapy in severe autoimmune diseases.
