According to the World Health Organization(WHO)newly updated situation report on March 18th,2020,the coronavirus disease 2019(COVID-19)pandemic has confirmed 191,127 cases and claimed 7807 deaths worldwide.1 The etiol...According to the World Health Organization(WHO)newly updated situation report on March 18th,2020,the coronavirus disease 2019(COVID-19)pandemic has confirmed 191,127 cases and claimed 7807 deaths worldwide.1 The etiological agent of COVID-19 has been identified as a novel coronavirus,the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),belonging to Sarbecovirus subgenus(genus Betacoronavirus,family Coronaviridae)and showing 79.6 and 96.2%sequence identity in nucleotide to SARS-CoV and a bat coronavirus(BatCoV RaTG13),respectively.2–4 Like SARS-CoV infection,a substantial fraction of COVID-19 patients exhibits severe respiratory symptoms and has to be hospitalized in intensive care unit.5–8 Although the mortality rate of COVID-19 is significantly lower than that of SARS-CoV infection,SARS-CoV-2 shows much higher human-to-human transmission rate,rapidly leading to a global pandemic declared by WHO on March 11th,2020.展开更多
COVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection.It is currently unknown as to the correlation between the magnitude of neutralizing antibody(NAb)responses and the disease severity in...COVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection.It is currently unknown as to the correlation between the magnitude of neutralizing antibody(NAb)responses and the disease severity in COVID-19 patients.In a cohort of 59 recovered patients with disease severity including severe,moderate,mild,and asymptomatic,we observed the positive correlation between serum neutralizing capacity and disease severity,in particular,the highest NAb capacity in sera from the patients with severe disease,while a lack of ability of asymptomatic patients to mount competent NAbs.Furthermore,the compositions of NAb subtypes were also different between recovered patients with severe symptoms and with mild-tomoderate symptoms.These results reveal the tremendous heterogeneity of SARS-CoV-2-specific NAb responses and their correlations to disease severity,highlighting the needs of future vaccination in COVID-19 patients recovered from asymptomatic or mild illness.展开更多
Epigenetic modifications to histones dictate the differentiation of naïve CD4^(+) T cells into different subsets of effector T helper(TH)cells.The histone methyltransferase enhancer of zeste homolog 2(EZH2)has be...Epigenetic modifications to histones dictate the differentiation of naïve CD4^(+) T cells into different subsets of effector T helper(TH)cells.The histone methyltransferase enhancer of zeste homolog 2(EZH2)has been implicated in the mechanism regulating the differentiation of TH1,TH2 and regulatory T(Treg)cells.However,whether and how EZH2 regulates follicular helper T(TFH)cell differentiation remain unknown.Using a mouse model of acute lymphocytic choriomeningitis virus(LCMV)infection,we observed abundant EZH2 expression and associated H3K27me3 modifications preferentially in the early committed virus-specific TFH cells compared to those in TH1 cells.Ablation of EZH2 in LCMV-specific CD4^(+) T cells leads to a selective impairment of early TFH cell fate commitment,but not late TFH differentiation or memory TFH maintenance.Mechanistically,EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for TFH fate commitment,particularly B cell lymphoma 6(Bcl6),and thus directs TFH cell commitment.Therefore,we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early TFH differentiation during acute viral infection.展开更多
The adaptive immunity that protects patients from coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is not well characterized.In particular,the asymptomatic patie...The adaptive immunity that protects patients from coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is not well characterized.In particular,the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses,but the underlying mechanisms remain unknown;meanwhile,the protective immunity that guide the recovery of these asymptomatic patients is elusive.Here,we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity(mild,n=10,moderate,n=32,severe,n=12)and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center(GC)B cell responses that result in robust and prolonged humoral immunity,assessed by GC response indicators including follicular helper T(TFH)cell and memory B cell responses as well as serum CXCL13 levels.Alternatively,these patients mounted potent virus-specific TH1 and CD8+T cell responses.In sharp contrast,patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated TFH responses;however,the virus-specific TH1 and CD8+T cells were minimally induced in these patients.These results,therefore,uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity,providing important insights into rational design of effective COVID-19 vaccines.展开更多
The functional exhaustion of CD8^(+)T cells represents a fundamental hallmark of chronic viral infection and cancer and,in both scenarios,is driven by prolonged exposure to persistent cognate antigens in the context o...The functional exhaustion of CD8^(+)T cells represents a fundamental hallmark of chronic viral infection and cancer and,in both scenarios,is driven by prolonged exposure to persistent cognate antigens in the context of an immunoinhibitory microenvironment.Exhausted CD8^(+)T cells upregulate the expression of a wide diversity of coinhibitory immunoreceptors(also referred to as immune checkpoint receptors),such as PD-1,Tim-3,LAG-3,and TIGIT.Concomitantly,exhausted CD8^(+)T cells lose their potential to differentiate into functional memory cells and are characterized by hierarchical loss of effector function,leading to compromised tumor control and viral eradication[1,2].展开更多
基金supported by grants from the National Natural Science Fund for Distinguished Young Scholars(No.31825011 to L.Y.)the Chongqing Special Research Project for Novel Coronavirus Pneumonia Prevention and Control(No.cstc2020jscx-2 to L.Y.,No.cstc2020jscx-fyzx0074 to Y.C.,cstc2020jscx-fyzx0135 to Y.C.).
文摘According to the World Health Organization(WHO)newly updated situation report on March 18th,2020,the coronavirus disease 2019(COVID-19)pandemic has confirmed 191,127 cases and claimed 7807 deaths worldwide.1 The etiological agent of COVID-19 has been identified as a novel coronavirus,the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),belonging to Sarbecovirus subgenus(genus Betacoronavirus,family Coronaviridae)and showing 79.6 and 96.2%sequence identity in nucleotide to SARS-CoV and a bat coronavirus(BatCoV RaTG13),respectively.2–4 Like SARS-CoV infection,a substantial fraction of COVID-19 patients exhibits severe respiratory symptoms and has to be hospitalized in intensive care unit.5–8 Although the mortality rate of COVID-19 is significantly lower than that of SARS-CoV infection,SARS-CoV-2 shows much higher human-to-human transmission rate,rapidly leading to a global pandemic declared by WHO on March 11th,2020.
基金supported by grants from the National Science and Technology Major Project(No.2017ZX10202102-006-002 to L.Y.)the National Natural Science Fund for Distinguished Young Scholars(No.31825011 to L.Y.)the National Science and Technology Major Project(2016ZX09J16105-001-002 to L.Y.).
文摘COVID-19 patients exhibit differential disease severity after SARS-CoV-2 infection.It is currently unknown as to the correlation between the magnitude of neutralizing antibody(NAb)responses and the disease severity in COVID-19 patients.In a cohort of 59 recovered patients with disease severity including severe,moderate,mild,and asymptomatic,we observed the positive correlation between serum neutralizing capacity and disease severity,in particular,the highest NAb capacity in sera from the patients with severe disease,while a lack of ability of asymptomatic patients to mount competent NAbs.Furthermore,the compositions of NAb subtypes were also different between recovered patients with severe symptoms and with mild-tomoderate symptoms.These results reveal the tremendous heterogeneity of SARS-CoV-2-specific NAb responses and their correlations to disease severity,highlighting the needs of future vaccination in COVID-19 patients recovered from asymptomatic or mild illness.
基金This study was supported by grants from the National Key Research Development Plan(No.2016YFA0502202 to L.Y.)the Open Research Fund of State Key Laboratory of Veterinary Biotechnology(No.SKLVBF2018XX to L.Ye)+3 种基金the National Natural Science Foundation of China(No.31825011 to L.Y.No.31800742 to Q.T.No.31700774 to L.Xu and No.31470870 to X.Z.)Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust(to J.H.).
文摘Epigenetic modifications to histones dictate the differentiation of naïve CD4^(+) T cells into different subsets of effector T helper(TH)cells.The histone methyltransferase enhancer of zeste homolog 2(EZH2)has been implicated in the mechanism regulating the differentiation of TH1,TH2 and regulatory T(Treg)cells.However,whether and how EZH2 regulates follicular helper T(TFH)cell differentiation remain unknown.Using a mouse model of acute lymphocytic choriomeningitis virus(LCMV)infection,we observed abundant EZH2 expression and associated H3K27me3 modifications preferentially in the early committed virus-specific TFH cells compared to those in TH1 cells.Ablation of EZH2 in LCMV-specific CD4^(+) T cells leads to a selective impairment of early TFH cell fate commitment,but not late TFH differentiation or memory TFH maintenance.Mechanistically,EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for TFH fate commitment,particularly B cell lymphoma 6(Bcl6),and thus directs TFH cell commitment.Therefore,we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early TFH differentiation during acute viral infection.
基金This work was supported by grants from the National Science and Technology Major Project(No.2017ZX10202102-006-002 to L.Y.)National Key Research Development Plan(No.2016YFA0502202 to L.Ye)+1 种基金the National Natural Science Fund for Distinguished Young Scholars(No.31825011 to L.Y.)the Chongqing Special Research Project for Novel Coronavirus Pneumonia Prevention and Control(No.cstc2020jscx-2 to L.Y.,No.cstc2020jscx-fyzx0074 to Y.C.,ocstc2020jscx-fyzx0135 to Y.C.).
文摘The adaptive immunity that protects patients from coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is not well characterized.In particular,the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses,but the underlying mechanisms remain unknown;meanwhile,the protective immunity that guide the recovery of these asymptomatic patients is elusive.Here,we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity(mild,n=10,moderate,n=32,severe,n=12)and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center(GC)B cell responses that result in robust and prolonged humoral immunity,assessed by GC response indicators including follicular helper T(TFH)cell and memory B cell responses as well as serum CXCL13 levels.Alternatively,these patients mounted potent virus-specific TH1 and CD8+T cell responses.In sharp contrast,patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated TFH responses;however,the virus-specific TH1 and CD8+T cells were minimally induced in these patients.These results,therefore,uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity,providing important insights into rational design of effective COVID-19 vaccines.
基金the National Key Research and Development Program of China(no.2021YFC-2300602 to LY)the Key Program of the National Natural Science Foundation of China(no.32030041 to LY)+2 种基金the National Science Foundation for Outstanding Young Scholars of China(no.82122028 to LX)the National Natural Science Foundation of China(no.82173094 to LX,no.31900643 to QH)the Chongqing Postdoctoral Science Foundation Project(no.cstc2021jcyj-bshX0232 to QL).
文摘The functional exhaustion of CD8^(+)T cells represents a fundamental hallmark of chronic viral infection and cancer and,in both scenarios,is driven by prolonged exposure to persistent cognate antigens in the context of an immunoinhibitory microenvironment.Exhausted CD8^(+)T cells upregulate the expression of a wide diversity of coinhibitory immunoreceptors(also referred to as immune checkpoint receptors),such as PD-1,Tim-3,LAG-3,and TIGIT.Concomitantly,exhausted CD8^(+)T cells lose their potential to differentiate into functional memory cells and are characterized by hierarchical loss of effector function,leading to compromised tumor control and viral eradication[1,2].
