T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an init...T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an initial signal of T-cell activation,has been found to occur before IS for-mation.The mechanism for triggering the calcium signaling and relationship bet ween calciumrelease and IS format ion remains unclear.Herein,using live-cell imaging,we found that int ercellularadhesion molecule 1(ICAM-1),an essential mdlecule for IS formation,accumulated and then wasdepleted at the center of the synapse before complete IS formation.During the proces of ICAM1depletion,calcium was released.if ICAM-1 failed to be depleted from the center of the synapse,thesustained calcium signaling could not be induced.Moreover,depletion of ICAM-1 in ISs preferen-tially ccurred with the contact of antigen-specific T-cels and dendritic clls(DCs).Blocking thebinding ofICA M-1 and lymphocy te finction-associated antigen 1(LFA-1),ICAM-1 failed to depleteat the center of the synapse,and calcium release in T-clls decreased.In studying the mechanism ofhow the depletion ofiCA M1 could influence calcium release in T-clls,we found that the movementof ICAM-1 was associat ed with the localization of LFA-1 in the IS,which afected the localization ofcalcium microdomains,ORAIl and mitochondria in IS.Therefore,the depletion of ICAM-1 in the center of the synapse is an important factor for an initial sust ained calcium release in T-cells.展开更多
The immunological synapse(IS)serves as the fundamental architectural framework for direct interactions and secretory crosstalk between immune cells,as well as between immune cells and other cells.Its dysregulation is ...The immunological synapse(IS)serves as the fundamental architectural framework for direct interactions and secretory crosstalk between immune cells,as well as between immune cells and other cells.Its dysregulation is thought to be a key underlying cause of immune evasion or inflammation observed in various diseases,including tumors and infections.Numerous recent studies have addressed key signaling mechanisms and reported novel targets related to IS,further broadening our understanding of its function and regulatory factors.However,a comprehensive review that highlights recent progress and consolidates past knowledge is still lacking.In this study,we delineated the pre-and postsynaptic structures constituting the IS between T cells,natural killer(NK)cells,dendritic cells(DCs),and macrophages.We also detail the specific signaling mechanisms and pathways that modulate the formation and disassembly of the IS,including cytoskeletal remodeling,membrane reshaping,integrin signaling,and force transduction.Following these experimental findings,we systematically review the central roles of IS in maintaining homeostasis and health and outline various diseases arising from IS disorders.Finally,we thoroughly explore targets and treatments related to IS on the basis of preclinical evidence and clinical trials,with the aim of providing further investigatory and therapeutic insights for researchers and clinicians.展开更多
Chimeric antigen receptor(CAR)T cell therapy has transformed cancer care and is under investigation for autoimmune,infectious,and chronic inflammatory diseases[1,2].Seven CAR-T cell products have been approved by the ...Chimeric antigen receptor(CAR)T cell therapy has transformed cancer care and is under investigation for autoimmune,infectious,and chronic inflammatory diseases[1,2].Seven CAR-T cell products have been approved by the USA Food and Drug Administration(FDA),demonstrating promising clinical outcomes in the treatment of CD19^(+)B cell malignancies,including acute lymphoblastic leukemia(ALL),non-Hodgkin lymphoma(NHL),chronic lymphocytic leukemia(CLL),and BCMA^(+)multiple myeloma(MM)[3].Key performance indicators for CAR-T cell products encompass high yield,purity,and CAR transduction rates,all of which are crucial for the therapeutic efficacy of the final product.展开更多
CAR-T-cell therapy has made significant strides in treating hematological malignancies,yet its efficacy is often hampered by suboptimal T-cell functionality,marked by weak antitumor capabilities and a lack of durabili...CAR-T-cell therapy has made significant strides in treating hematological malignancies,yet its efficacy is often hampered by suboptimal T-cell functionality,marked by weak antitumor capabilities and a lack of durability.The immunological synapse,a key determinant of T-cell function,is influenced by the CD58-CD2 axis.The dynamic regulation of CD2 expression on T cells impacts the quality of CAR-mediated immunological synapses,affecting CAR-T-cell functional outcomes and differentiation.Our study demonstrated that CD2 expression levels are closely linked to the quality of immunological synapses formed by CAR-T cells and their antitumor potency.Exogenous CD2 supplementation enhances the ability of CAR-T cells to form high-quality synapses,reduces T-cell exhaustion,and increases sustained antitumor efficacy.Additionally,ectopic CD2 expression increases CAR-T-cell sensitivity to low-density antigens.Thus,replenishing CD2 in CAR-T cells is a promising strategy to increase the therapeutic efficacy of CAR-T-cell therapy.展开更多
Cytotoxic T lymphocytes （CTLs） and natural killer （NK） cells contribute to the body＇s immune defenses. Current chimeric antigen receptor （CAR）-modified T cell immunotherapy shows strong promise for treating var...Cytotoxic T lymphocytes （CTLs） and natural killer （NK） cells contribute to the body＇s immune defenses. Current chimeric antigen receptor （CAR）-modified T cell immunotherapy shows strong promise for treating var- ious cancers and infectious diseases. Although CAR- modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cyto- toxic cell-mediated immunotherapies are urgently nee- ded. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the for- mation of the immunological synapse （IS） between CAR- modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat can- cer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus （HIV）, and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-medi- ated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.展开更多
Dear editor,Bispecific T-cell engagers(also referred to as BiTEs)are bi/multispecific antibodies that are a clinically used cancer immunotherapy,which enforce formation of an immunological synapse between T-cells and ...Dear editor,Bispecific T-cell engagers(also referred to as BiTEs)are bi/multispecific antibodies that are a clinically used cancer immunotherapy,which enforce formation of an immunological synapse between T-cells and tumour cells by antigenic engagement on the respective cells,resulting in cancer cell apoptosis.1,2 Tumour heterogeneity,however,is a major challenge for identifying the most appropriate cancer target antigen for each patient.Discovery of new tumour targets outweighs new BiTE approval,calling for rapid screening tools to evaluate novel targets and BiTE combinational formats.展开更多
T cells react to foreign or self-antigens through T cell receptor(TCR)signaling.Several decades of research have delineated the mechanism of TCR signal transduction and its impact on T cell performance.This knowledge ...T cells react to foreign or self-antigens through T cell receptor(TCR)signaling.Several decades of research have delineated the mechanism of TCR signal transduction and its impact on T cell performance.This knowledge provides the foundation for chimeric antigen receptor T cell(CAR-T cell)technology,by which T cells are redirected in a major histocompatibility complex-unrestricted manner.TCR and CAR signaling plays a critical role in determining the T cell state,including exhaustion and memory.Given its artificial nature,CARs might affect or rewire signaling differently than TCRs.A better understanding of CAR signal transduction would greatly facilitate improvements to CAR-T cell technology and advance its usefulness in clinical practice.Herein,we systematically review the knowns and unknowns of TCR and CAR signaling,from the contact of receptors and antigens,proximal signaling,immunological synapse formation,and late signaling outcomes.Signaling through different T cell subtypes and how signaling is translated into practice are also discussed.展开更多
Natural killer(NK)cells participate in early immune defenses against pathogens and tumors and play a major role as immune effector and regulatory cells.The NK cell-mediated elimination of an infected or cancerous cell...Natural killer(NK)cells participate in early immune defenses against pathogens and tumors and play a major role as immune effector and regulatory cells.The NK cell-mediated elimination of an infected or cancerous cell is a highly regulated process that requires the formation of a cell contact,the establishment of an immunological synapse and the polarization and release of lytic granules.Additionally,the detachment of NK cells from target cells is important for NK cells to bind and kill other cells in a process called serial killing.However,very little is known about this detachment process.Here,we show that NK detachment is directly connected to the successful killing of a target cell.The inhibition of killing due to reduced NK cell cytotoxicity or increased target cell resistance results in defective detachment and prolonged contact times.This effect leads to sustained Ca^(2+) flux in NK cells and the hypersecretion of proinflammatory cytokines.Linking defective cytotoxicity with enhanced cytokine secretion via reduced detachment may explain inflammatory pathologies in several diseases.展开更多
基金supported by the National Major Scientic Research Program of China(Grant No.2011CB910404)the National Nature Science Foundation of China(Grant Nos.61227017,31400772 and 81273215)+3 种基金the National Science Fund for Distinguished Young Scholars(Grant No.61425006)the grants of the Project for Laureate of Taishan Scholar(Grant No.ts201511075)the Innovation Project of Shandong Academy of Medical Sciences,the Projects of medical and health technology development program in Shandong province(No.2015WS0194)the science and technology program from Shandong Academy of Medical Sciences(No.2015-25).
文摘T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an initial signal of T-cell activation,has been found to occur before IS for-mation.The mechanism for triggering the calcium signaling and relationship bet ween calciumrelease and IS format ion remains unclear.Herein,using live-cell imaging,we found that int ercellularadhesion molecule 1(ICAM-1),an essential mdlecule for IS formation,accumulated and then wasdepleted at the center of the synapse before complete IS formation.During the proces of ICAM1depletion,calcium was released.if ICAM-1 failed to be depleted from the center of the synapse,thesustained calcium signaling could not be induced.Moreover,depletion of ICAM-1 in ISs preferen-tially ccurred with the contact of antigen-specific T-cels and dendritic clls(DCs).Blocking thebinding ofICA M-1 and lymphocy te finction-associated antigen 1(LFA-1),ICAM-1 failed to depleteat the center of the synapse,and calcium release in T-clls decreased.In studying the mechanism ofhow the depletion ofiCA M1 could influence calcium release in T-clls,we found that the movementof ICAM-1 was associat ed with the localization of LFA-1 in the IS,which afected the localization ofcalcium microdomains,ORAIl and mitochondria in IS.Therefore,the depletion of ICAM-1 in the center of the synapse is an important factor for an initial sust ained calcium release in T-cells.
基金supported by the National Natural Science Foundation of China(Nos.823B2064,Nos.82373333)。
文摘The immunological synapse(IS)serves as the fundamental architectural framework for direct interactions and secretory crosstalk between immune cells,as well as between immune cells and other cells.Its dysregulation is thought to be a key underlying cause of immune evasion or inflammation observed in various diseases,including tumors and infections.Numerous recent studies have addressed key signaling mechanisms and reported novel targets related to IS,further broadening our understanding of its function and regulatory factors.However,a comprehensive review that highlights recent progress and consolidates past knowledge is still lacking.In this study,we delineated the pre-and postsynaptic structures constituting the IS between T cells,natural killer(NK)cells,dendritic cells(DCs),and macrophages.We also detail the specific signaling mechanisms and pathways that modulate the formation and disassembly of the IS,including cytoskeletal remodeling,membrane reshaping,integrin signaling,and force transduction.Following these experimental findings,we systematically review the central roles of IS in maintaining homeostasis and health and outline various diseases arising from IS disorders.Finally,we thoroughly explore targets and treatments related to IS on the basis of preclinical evidence and clinical trials,with the aim of providing further investigatory and therapeutic insights for researchers and clinicians.
文摘Chimeric antigen receptor(CAR)T cell therapy has transformed cancer care and is under investigation for autoimmune,infectious,and chronic inflammatory diseases[1,2].Seven CAR-T cell products have been approved by the USA Food and Drug Administration(FDA),demonstrating promising clinical outcomes in the treatment of CD19^(+)B cell malignancies,including acute lymphoblastic leukemia(ALL),non-Hodgkin lymphoma(NHL),chronic lymphocytic leukemia(CLL),and BCMA^(+)multiple myeloma(MM)[3].Key performance indicators for CAR-T cell products encompass high yield,purity,and CAR transduction rates,all of which are crucial for the therapeutic efficacy of the final product.
基金supported by grants from the National Natural Science Foundation of China(82430012 and 82341208 to W.H.)the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2023ZD0501300).
文摘CAR-T-cell therapy has made significant strides in treating hematological malignancies,yet its efficacy is often hampered by suboptimal T-cell functionality,marked by weak antitumor capabilities and a lack of durability.The immunological synapse,a key determinant of T-cell function,is influenced by the CD58-CD2 axis.The dynamic regulation of CD2 expression on T cells impacts the quality of CAR-mediated immunological synapses,affecting CAR-T-cell functional outcomes and differentiation.Our study demonstrated that CD2 expression levels are closely linked to the quality of immunological synapses formed by CAR-T cells and their antitumor potency.Exogenous CD2 supplementation enhances the ability of CAR-T cells to form high-quality synapses,reduces T-cell exhaustion,and increases sustained antitumor efficacy.Additionally,ectopic CD2 expression increases CAR-T-cell sensitivity to low-density antigens.Thus,replenishing CD2 in CAR-T cells is a promising strategy to increase the therapeutic efficacy of CAR-T-cell therapy.
文摘Cytotoxic T lymphocytes （CTLs） and natural killer （NK） cells contribute to the body＇s immune defenses. Current chimeric antigen receptor （CAR）-modified T cell immunotherapy shows strong promise for treating var- ious cancers and infectious diseases. Although CAR- modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cyto- toxic cell-mediated immunotherapies are urgently nee- ded. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the for- mation of the immunological synapse （IS） between CAR- modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat can- cer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus （HIV）, and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-medi- ated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.
基金supported by the Novo Nordisk Foundation Grant,CEMBID(Center for Multifunctional Biomolecular Drug Design,Grant Number:NNF17OC0028070)the National Key Research and Development Programme(2024 YFA0918600)+1 种基金Venus Project from China-Japan Union Hospital of Jilin University(Funding No.:XHQMX20242)the Science and Technology Development Plan Project of Jilin Province(Grant No.:20230402040GH).
文摘Dear editor,Bispecific T-cell engagers(also referred to as BiTEs)are bi/multispecific antibodies that are a clinically used cancer immunotherapy,which enforce formation of an immunological synapse between T-cells and tumour cells by antigenic engagement on the respective cells,resulting in cancer cell apoptosis.1,2 Tumour heterogeneity,however,is a major challenge for identifying the most appropriate cancer target antigen for each patient.Discovery of new tumour targets outweighs new BiTE approval,calling for rapid screening tools to evaluate novel targets and BiTE combinational formats.
文摘T cells react to foreign or self-antigens through T cell receptor(TCR)signaling.Several decades of research have delineated the mechanism of TCR signal transduction and its impact on T cell performance.This knowledge provides the foundation for chimeric antigen receptor T cell(CAR-T cell)technology,by which T cells are redirected in a major histocompatibility complex-unrestricted manner.TCR and CAR signaling plays a critical role in determining the T cell state,including exhaustion and memory.Given its artificial nature,CARs might affect or rewire signaling differently than TCRs.A better understanding of CAR signal transduction would greatly facilitate improvements to CAR-T cell technology and advance its usefulness in clinical practice.Herein,we systematically review the knowns and unknowns of TCR and CAR signaling,from the contact of receptors and antigens,proximal signaling,immunological synapse formation,and late signaling outcomes.Signaling through different T cell subtypes and how signaling is translated into practice are also discussed.
文摘Natural killer(NK)cells participate in early immune defenses against pathogens and tumors and play a major role as immune effector and regulatory cells.The NK cell-mediated elimination of an infected or cancerous cell is a highly regulated process that requires the formation of a cell contact,the establishment of an immunological synapse and the polarization and release of lytic granules.Additionally,the detachment of NK cells from target cells is important for NK cells to bind and kill other cells in a process called serial killing.However,very little is known about this detachment process.Here,we show that NK detachment is directly connected to the successful killing of a target cell.The inhibition of killing due to reduced NK cell cytotoxicity or increased target cell resistance results in defective detachment and prolonged contact times.This effect leads to sustained Ca^(2+) flux in NK cells and the hypersecretion of proinflammatory cytokines.Linking defective cytotoxicity with enhanced cytokine secretion via reduced detachment may explain inflammatory pathologies in several diseases.
