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
Dear Editor,The 2002–2003 global pandemic caused by severe acute respiratory syndrome coronavirus(SARS-CoV)infected around 8,000 people with 10%mortality(http://www.who.int/csr/sars/en/).The virus has a positivestran...Dear Editor,The 2002–2003 global pandemic caused by severe acute respiratory syndrome coronavirus(SARS-CoV)infected around 8,000 people with 10%mortality(http://www.who.int/csr/sars/en/).The virus has a positivestranded RNA genome that encodes a large polyprotein(1a and 1ab),four structural proteins,including spike(S),展开更多
Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely understood.In this study,Sin1,a key component of mTOR complex 2(mTORC2...Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely understood.In this study,Sin1,a key component of mTOR complex 2(mTORC2),specifically regulates B cell growth and metabolism.Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism.Sin1 deficiency also severely impairs B-cell proliferation,antibody responses,and anti-viral immunity.At the molecular level,Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2,respectively.Therefore,our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.展开更多
A human immunodeficiency virus type-1 (HIV-1) vaccine which is able to effectively prevent infection would be the most powerful method of extinguishing pandemic of the acquired immunodeficiency syndrome (AIDS). Ye...A human immunodeficiency virus type-1 (HIV-1) vaccine which is able to effectively prevent infection would be the most powerful method of extinguishing pandemic of the acquired immunodeficiency syndrome (AIDS). Yet, achieving such vaccine remains great challenges. The membrane-proximal external region (MPER) is a highly conserved region of the envelope glycoprotein (Env) gp41 subunit near the viral envelope surface, and it plays a key role in membrane fusion. It is also the target of some reported broadly neutralizing antibodies (bNAbs). Thus, MPER is deemed to be one of the most attractive vaccine targets. However, no one can induce these bNAbs by immunization with immunogens con- taining the MPER sequence(s). The few attempts at developing a vaccine have only resulted in the induction of neutralizing antibodies with quite low potency and limited breadth. Thus far, vaccine failure can be attrib- uted to various characteristics of MPER, such as those involving structure and immunology; therefore, we will focus on these and review the recent progress in the field from the following perspectives: (1) MPER structure and its role in membrane fusion, (2) the epitopes and neutralization mechanisms of MPER-specific bNAbs, as well as the limitations in eliciting neutralizing antibodies, and (3) different strategies for MPER vaccine design and current harvests.展开更多
To successfully infect host cells and evade the host immune response, a type III secretion system (T3SS) is commonly used by enteric bacterial pathogens such as enteropathogenic Escherichia coil (EPEC). Recent fin...To successfully infect host cells and evade the host immune response, a type III secretion system (T3SS) is commonly used by enteric bacterial pathogens such as enteropathogenic Escherichia coil (EPEC). Recent findings have revealed that various effectors are injected into host cells through the T3SS and exert an inhibitory effect on inflammatory signaling pathways, subverting the immune responses to these pathogens. Here we review recent studies aimed at addressing the modulation of several important inflammatory signaling pathways modulated by EPEC effector proteins, such as the nuclear factor-KB (NF-KB) and mitogen-activated protein kinase (MAPK) pathways, which provides insight into the unfinished work in this unexplored field and helps to identify novel positions in inflammatory signaling networks for EPEC effectors.展开更多
Human immunodeficiency virus(HIV)-infected individuals exhibit remarkable transcriptomic variation.Transcriptome analyses of antiretroviral therapy(ART)-free chronically infected HIV-1 patients with different clinical...Human immunodeficiency virus(HIV)-infected individuals exhibit remarkable transcriptomic variation.Transcriptome analyses of antiretroviral therapy(ART)-free chronically infected HIV-1 patients with different clinical outcomes are likely to aid the development of vaccine and immune therapies.Here,we performed microarray analyses on whole-blood derived RNA from 89 ART-free HIV-1-infected individuals from 2 cohorts.The differentially expressed genes were analyzed between long-term non-progressors,viremic non-progressors and typical progressors,and between elite controllers and non-elite controllers among the long-term nonprogressors.Several genes related to T-cell growth,proliferation and differentiation and antiapoptosis were upregulated,whereas interferon-stimulated genes and inflammatory genes were significantly downregulated in long-term non-progressors and viremic non-progressors.The observations above were further confirmed in the set of 261 genes that correlated with disease progression during a 5-year follow-up,which included 51 genes significantly associated with slower disease progression,and 210 genes associated with aggressive disease progression.Overall,our data suggest that it is vital to maintain the homeostasis of the immune system when mounting antiviral immune responses.Immune therapeutics able to reconstruct immune homeostasis are likely to be required for immune reconstitution in the context of ART,such as the administration of interleukin-7,healthy allogenic CD4^(+)T cells(providing CD4^(+)T-cell growth factors),or Tregs.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(81290341,31621061 to Zheng-Li Shi)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDPB0301 to Zheng-Li Shi)+2 种基金National Institute of Allergy and Infectious Diseases of National Institutes of Health grant(R01AI110964 to Zheng-Li Shi)the National Key Research and Development Program of China(2016YFC1201000 to Shibo Jiang)NIH grant(R01AI098775 to Shibo Jiang and Lanying Du)
文摘Dear Editor,The 2002–2003 global pandemic caused by severe acute respiratory syndrome coronavirus(SARS-CoV)infected around 8,000 people with 10%mortality(http://www.who.int/csr/sars/en/).The virus has a positivestranded RNA genome that encodes a large polyprotein(1a and 1ab),four structural proteins,including spike(S),
基金This study was partially supported by grant PR093728(DoD to B.S.)the National Natural Science Foundation of China(grant numbers 31470845 and 81430033 to B.S.,31422020 to F.L.and 31600704 to H.H.Z.)+2 种基金grant 13JC1404700 from the Program of Science and Technology Commission of Shanghai Municipality(B.S.)the Ministry of Science and Technology of China(Program 2014CB943600,F.L.)Chinese Mega Project on Infectious Diseases(No.2018ZX10302301).
文摘Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity,but the underlying molecular mechanisms remain incompletely understood.In this study,Sin1,a key component of mTOR complex 2(mTORC2),specifically regulates B cell growth and metabolism.Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism.Sin1 deficiency also severely impairs B-cell proliferation,antibody responses,and anti-viral immunity.At the molecular level,Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2,respectively.Therefore,our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.
文摘A human immunodeficiency virus type-1 (HIV-1) vaccine which is able to effectively prevent infection would be the most powerful method of extinguishing pandemic of the acquired immunodeficiency syndrome (AIDS). Yet, achieving such vaccine remains great challenges. The membrane-proximal external region (MPER) is a highly conserved region of the envelope glycoprotein (Env) gp41 subunit near the viral envelope surface, and it plays a key role in membrane fusion. It is also the target of some reported broadly neutralizing antibodies (bNAbs). Thus, MPER is deemed to be one of the most attractive vaccine targets. However, no one can induce these bNAbs by immunization with immunogens con- taining the MPER sequence(s). The few attempts at developing a vaccine have only resulted in the induction of neutralizing antibodies with quite low potency and limited breadth. Thus far, vaccine failure can be attrib- uted to various characteristics of MPER, such as those involving structure and immunology; therefore, we will focus on these and review the recent progress in the field from the following perspectives: (1) MPER structure and its role in membrane fusion, (2) the epitopes and neutralization mechanisms of MPER-specific bNAbs, as well as the limitations in eliciting neutralizing antibodies, and (3) different strategies for MPER vaccine design and current harvests.
文摘To successfully infect host cells and evade the host immune response, a type III secretion system (T3SS) is commonly used by enteric bacterial pathogens such as enteropathogenic Escherichia coil (EPEC). Recent findings have revealed that various effectors are injected into host cells through the T3SS and exert an inhibitory effect on inflammatory signaling pathways, subverting the immune responses to these pathogens. Here we review recent studies aimed at addressing the modulation of several important inflammatory signaling pathways modulated by EPEC effector proteins, such as the nuclear factor-KB (NF-KB) and mitogen-activated protein kinase (MAPK) pathways, which provides insight into the unfinished work in this unexplored field and helps to identify novel positions in inflammatory signaling networks for EPEC effectors.
基金This work was supported by the National Grand Program on Key Infectious Disease Control(No.2017ZX10202102)the National Nature Science Foundation of China(No.81561128008).
文摘Human immunodeficiency virus(HIV)-infected individuals exhibit remarkable transcriptomic variation.Transcriptome analyses of antiretroviral therapy(ART)-free chronically infected HIV-1 patients with different clinical outcomes are likely to aid the development of vaccine and immune therapies.Here,we performed microarray analyses on whole-blood derived RNA from 89 ART-free HIV-1-infected individuals from 2 cohorts.The differentially expressed genes were analyzed between long-term non-progressors,viremic non-progressors and typical progressors,and between elite controllers and non-elite controllers among the long-term nonprogressors.Several genes related to T-cell growth,proliferation and differentiation and antiapoptosis were upregulated,whereas interferon-stimulated genes and inflammatory genes were significantly downregulated in long-term non-progressors and viremic non-progressors.The observations above were further confirmed in the set of 261 genes that correlated with disease progression during a 5-year follow-up,which included 51 genes significantly associated with slower disease progression,and 210 genes associated with aggressive disease progression.Overall,our data suggest that it is vital to maintain the homeostasis of the immune system when mounting antiviral immune responses.Immune therapeutics able to reconstruct immune homeostasis are likely to be required for immune reconstitution in the context of ART,such as the administration of interleukin-7,healthy allogenic CD4^(+)T cells(providing CD4^(+)T-cell growth factors),or Tregs.