Tumor-specific memory CD8^(+)T cells are strictly resident in draining lymph nodes during tumorigenesis

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].

肿瘤引流淋巴结抗原特异性记忆CD8^(+)T细胞是PD-1/PD-L1免疫检查点阻断治疗的关键响应者

CD8^(+)T细胞耗竭是机体免疫系统不能有效清除慢性病毒感染及恶性肿瘤的关键原因.相较于急性感染或者疫苗免疫情形下诱导形成的记忆性CD8^(+)T细胞,耗竭的CD8^(+)T细胞表面持续表达包括PD-1在内的免疫检查点分子,其增殖潜力、效应及杀伤功能等都较为低下,且易于凋亡.

Human monoclonal antibodies block the binding of SARS-CoV-2 spike protein to angiotensin converting enzyme 2 receptor

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.

The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection

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.

The dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity

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.

A potent human monoclonal antibody with pan-neutralizing activities directly dislocates S trimer of SARS-CoV-2 through binding both up and down forms of RBD

The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused a global pandemic of novel coronavirus disease(COVID-19).The neutralizing monoclonal antibodies(mAbs)targeting the receptor-binding domain(RBD)of SARS-CoV-2 are among the most promising strategies to prevent and treat COVID-19.However,SARS-CoV-2 variants of concern(VOCs)profoundly reduced the efficacies of most of mAbs and vaccines approved for clinical use.Herein,we demonstrated mAb 35B5 efficiently neutralizes both wild-type(WT)SARS-CoV-2 and VOCs.

Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19

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.

The lncRNA Snhgl-Vpsl3D vesicle trafficking system promotes memory CD8 T cell establishment via regulating the dual effects of IL-7 signaling

The efficient induction and long-term persistence of pathogen-specific memory CD8 T cells are pivotal to rapidly curb the reinfection.Recent studies indicated that long-noncoding RNAs expression is highly cell-and stage-specific during T cell development and differentiation,suggesting their potential roles in T cell programs.However,the key lncRNAs playing crucial roles in memory CD8 T cell establishment remain to be clarified.Through CD8 T cell subsets profiling of lncRNAs,this study found a key lncRNA-Snhgl with the conserved naivehl-effectorlo-memoryh,expression pattern in CD8 T cells of both mice and human,that can promote memory formation while impeding effector CD8 in acute viral infection.Further,Snhgl was found interacting with the conserved vesicle trafficking protein Vps13D to promote IL-7Ra membrane location specifically.With the deep mechanism probing,the results show Snhgl-Vps13D regulated IL-7 signaling with its dual effects in memory CD8 generation,which not just because of the sustaining role of STAT5-BCL-2 axis for memory survival,but more through the STAT3-TCF1-Blimp1 axis for transcriptional launch program of memory differentiation.Moreover,we performed further study with finding a similar high-low-high expression pattern of human SNHG1A/PS13D/IL7R/TCF7 in CD8 T cell subsets from PBMC samples of the convalescent COVID-19 patients.The central role of Snhgl-Vps13D-IL-7R-TCF1 axis in memory CD8 establishment makes it a potential target for improving the vaccination effects to control the ongoing pandemic.