Progressive exhaustion:A qualitative study on the experiences of Iranian family caregivers regarding patients undergoing hemodialysis

Objective:The aim of this study was to explore the burden of care for patients undergoing hemodialysis from the experiences of family caregivers.Methods:In this qualitative study,a content analysis approach was used for data collection and analysis.Participants were 16 family caregivers selected through purposive sampling from four medical education centers affiliated with Ahvaz Jundishapur University of Medical Sciences,Iran.Semi-structured interviews were held to collect data.Results:Four categories were developed as follows:‘care challenges’,‘psychological vulnerabilities’,‘the chronic nature of care’and“care in the shade”.The categories led to the development of the main theme of‘progressive exhaustion’experienced by the family caregivers during the provision of care to patients undergoing hemodialysis.Conclusion:Family caregivers have a significant role in the process of patient care,and this role leads them to progressive exhaustion;therefore,the overall health of the caregivers should be taken into account and more attention should be paid to their quality of life,social welfare,and satisfaction level.

The Effects of Job Insecurity, Emotional Exhaustion, and Met Expectations on Hotel Employees’ Pro-Environmental Behaviors: Test of a Serial Mediation Model

There are a plethora of empirical pieces about employees’pro-environmental behaviors.However,the extant literature has either ignored or not fully examined various factors(e.g.,negative or positive non-green workplace factors)that might affect employees’pro-environmental behaviors.Realizing these voids,the present paper proposes and tests a serial mediation model that examines the interrelationships of job insecurity,emotional exhaustion,met expectations,and proactive pro-environmental behavior.We used data gathered from hotel customer-contact employees with a time lag of one week and their direct supervisors in China.After presenting support for the psychometric properties of the measures via confirmatory analysis in LISREL 8.30,the abovementioned linkages were gauged using the PROCESS plug-in for statistical package for social sciences.The findings delineated support for the hypothesized associations.Specifically,emotional exhaustion and met expectations partly mediated the effect of job insecurity on proactive pro-environmental behavior.More importantly,emotional exhaustion and met expectations serially mediated the influence of job insecurity on proactive pro-environmental behavior.These findings have important theoretical implications as well as significant implications for diminishing job insecurity,managing emotional exhaustion,increasing met expectations,and enhancing ecofriendly behaviors.

The Mechanisms of CD8+ T Cells Exhaustion in the Tumor Microenvironment and Immune Therapy

In the tumor immune microenvironment, CD8+ T cells differentiate towards functional failure. The exhaustion of CD8+ T cells (Tex) showed varying degrees of effect dysfunction, loss of proliferation ability, and sustained high expression of a variety of inhibitory receptors, with metabolic and epigenetic changes. Tex cells are heterogeneous, including several subsets with different characteristics at different stages of differentiation. Immune checkpoint inhibitors (ICIs) can restore the effect or function of Tex cells, indicating that this T cell subset plays a key role in tumor immunotherapy. The understanding of the mechanism of CD8+ T cell exhaustion will be helpful to the implementation of tumor immunotherapy. This article reviews the production, differentiation and functional characteristics of Tex cells and their relationship with tumor immunotherapy.

OBSERVATION ON THERAPEUTIC EFFECTS OF FENGJIU THERAPY IN 300 CASES OF EXHAUSTION SYNDROME

Fengjiu Yi(Model FJY - 1) is a patent medical and health instrument newly developed by the authors. It incorporates the drug action and physiotherapy into an integral whole, exerting comprehensive regulation and it is an effective therapeutic method. In the present paper, 300 cases of exhaustion syndrome were all cured by the instrument after 7 - 17 sessions of treatment.

A Health Impairment Process of Sickness Presenteeism in Norwegian Physicians: The Mediating Role of Exhaustion

Although work factors have been associated with both presenteeism and exhaustion among hospital physicians, we lack knowledge on the dynamic relationship between demands in the work context and presenteeism and how this can be mediated by symptoms of exhaustion when controlling for job resources. The objective of this study is to examine a health impairment process of presenteeism among university hospital physicians. A cross-sectional survey of 545 university hospital physicians in Norway was conducted. Variables included in the model were presenteeism, exhaustion, work-family conflict, role conflict, social support and control over work pace. Findings from structural equation modeling indicated that exhaustion mediates the relationship between job demands and presenteeism. Job resources had no direct effect on presenteeism in the hypothesized model. The variables in the study explained 17% of the variance in presenteeism. The study is one of the first to demonstrate that the relationship between job demands and presenteeism is mediated by exhaustion when controlling for job resources. The results highlight the importance of considering the link between health symptoms and job demands to reduce the negative effects of presenteeism.

Transgene IL-21-Engineered T Cell-Based Vaccine Potently Converts CTL Exhaustion via the Activation of the mTORC1 Pathway in Chronic Infection

CD8+ cytotoxic T lymphocyte (CTL) exhaustion is one of the major obstacles for the effectiveness of virus control in chronic infectious diseases. We previously generated novel ovalbumin (OVA)-specific 41BBL-expressing OVA-TEXO and human immunodeficiency virus (HIV-1) Gag-specific Gag-TEXO vaccines, inducing therapeutic immunity in wild-type C57BL/6 (B6) mice, and converting CTL exhaustion in recombinant OVA-specific adenovirus AdVOVA-infected B6 (AdVOVA-B6) mice with chronic infection. IL-21 cytokine plays an important role in controlling chronic infections. Therefore, in this study, we constructed recombinant transgene IL-21-expressing AdVIL-21, and generated IL-21-expressing OVA-TEXO/IL-21 and Gag-TEXO/IL21 vaccines, or control vaccines (OVA-TEXO/Null and Gag-TEXO/Null) by infecting OVA-TEXO and Gag-TEXO cells with AdVIL-21 or the control AdVNull, lacking transgene, and assessed their effects in B6 or AdVOVA-B6 mice. We demonstrate that both OVA-TEXO/IL-21 and control OVA-TEXO/Null vaccines are capable of converting CTL exhaustion in chronic infection. However, the OVA-TEXO/IL-21 vaccine more efficiently rescues exhausted CTLs by increasing stronger CTL proliferation and effector cytokine IFN-γ expression than the control OVA-TEXO/Null vaccine in AdVOVA-B6 mice with chronic infection, though both vaccines stimulated comparable OVA-specific CTL responses and protective immunity against OVA-expressing BL6-10OVA melanoma lung metastasis in wild-type B6 mice. In vivo, the OVA-TEXO/IL-21-stimulated CTLs more efficiently up-regulate phosphorylation of mTORC1-controlled EIF4E and expression of mTORC1- regulated T-bet molecule than the control OVA-TEXO/Null-stimulated ones. Importantly, the Gag-TEXO/IL21 vaccine induces stronger Gag-specific therapeutic immunity against established Gag-expressing BL6-10Gag melanoma lung metastases than the control Gag-TEXO/Null vaccine in chronic infection. Therefore, this study should have a strong impact on developing new therapeutic vaccines for patients with chronic infections.

An Evaluation Study of a Nature Based Rehabilitation in Sweden for Patients with Exhaustion Disorder

The aim of this study was to evaluate a Nature Based Rehabilitation (NBR) for a group of patients with Exhaustion Disorder (ED) in the southwest Sweden. A multidisciplinary team consisting of an occupational therapist, a physiotherapist, a medical doctor practising symbolic drama and a nurse with gardening experience provided NBR in an agricultural environment. Patients were offered 14 weeks of rehabilitation in a group of eight persons, three mornings per week. Seventeen patients participated in the study and 15 completed the study. A semi-structured interview was conducted at the beginning of the rehabilitation and at the end and a follow-up interview by telephone was done one year after completion of the rehabilitation. The interviews were recorded and transcribed. Assessment scales used included: Stress and Crisis Inventory (SCI-93), Coping Resources Inventory (CRI) and Visual Analogue Scale (VAS). Weekly notes from the staff members were reviewed and compared with the patient’s own experience. The interviews and the staff notes were analysed with semantic thematic analysis. Result showed that this kind of NBR with a multidisciplinary team promotes improved health and improved quality of life for patients with ED and may thus constitute a good alternative to treatment, provided the ED has not become chronic.

C12-3.43/0.981 Type 12MW Exhaustion and Condensing Stean Turbine

TheQingdaoJienengPowerGroupCompanyinShandongmanufactUreseightseriesofsteamtIJrbinesin140varieties,witheachturbinebelow25MaTheC12-3.43/0.98type12MWexhaustionandcondensingsteamturbinehasthefollowingfeatures:12mW:ipa,435C,0.981Mpa,andh/h,whichcanbeusedi...

System analysis based on the T cell exhaustion‑related genes identifies CD38 as a novel therapy target for ovarian cancer

Ovarian cancer(OV)is highly heterogeneous tumor with a very poor prognosis.Studies increasingly show that T cell exhaustion is prognostically relevant in OV.The aim of this study was to dissect the heterogeneity of T cell subclusters in OV through single cell transcriptomic analysis.The single RNA-sequencing(scRNA-seq)data of five OV patients were analyzed,and six major cell clusters were identified after threshold screening.Further clustering of T cell-associated clusters revealed four subtypes.Pathways related to oxidative phosphorylation,G2M checkpoint,JAK-STAT and MAPK signaling were significantly activated,while the p53 pathway was inhibited in the CD8+exhausted T cells.The standard marker genes of CD8+T cell exhaustion were screened to develop a T-cell related gene score(TRS)based on random forest plots in TCGA cohort.The patients with low TRS have better prognosis compared to the patients with high TRS in both TCGA and GEO.In addition,most genes included in the TRS showed significant differences in expression levels between the high-and low-risk groups.Immune cell infiltration was analyzed using the MCPcounter and xCell algorithms,which revealed significant differences between the two risk groups,indicating that the different prognoses may stem from the respective immune landscapes.In addition,CD38 knockdown in OV cell lines increased apoptosis and inhibited invasion in vitro.Finally,we performed a drug sensitivity analysis and identified six potential drug candidates for OV.To summarize,we identified the heterogeneity and clinical significance of T cell exhaustion in OV and built a superior prognostic model based on T cell exhaustion genes,which can contribute to the development of more precise and effective therapies.

Design of Manure Gas Exhaustion to Reduce Ammonia Concentrations in Loose-Housing Systems for Laying Hens

Uniformity of air flow in extraction openings in exhaust air channels for manure gas exhaustion is determined by the distribution of pressure. The areas required in extraction vents and in extraction ducts are determined by the uniformity of air flow desired along the duct and by the loss of pressure that can be accepted. The area ratio between the vents and the cross section of the exhaust air duct will have a strong influence on both uniformity of flow and loss of pressure. The following ventilation properties were studied： Uniformity of air flow; Variations in static pressure along a duct; Air velocity at different distances from the vents. The area ratio should be about 1 for uniform exhaustion. The studies showed that the relative variation in air velocity is independent of the level of the ventilation rate. The uniformity of the exhaust distance is influenced in about the same way by the area ratio as the air velocity in the exhaust vents. Thus, it is important that the area ratio is not too high if a good exhaust function should be guaranteed. The studies also demonstrated that the uniformity of the exhaust distance is independent of the ventilation flow rate. The exhaust ventilation range is, maximally 0.3 m from the vents. The static friction coefficient was on average 0.80.

Unlocking T cell exhaustion:Insights and implications for CAR-T cell therapy

Chimeric antigen receptor T(CAR-T)cell therapy as a form of adoptive cell therapy(ACT)has shown significant promise in cancer treatment,demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen(BCMA)for hematological malignancies,albeit with moderate outcomes in solid tumors.However,despite these advancements,the efficacy of CAR-T therapy is often compromised by T cell exhaustion,a phenomenon that impedes the persistence and effector function of CAR-T cells,leading to a relapse rate of up to 75%in patients treated with CD19 or CD22 CAR-T cells for hematological malignancies.Strategies to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing technologies.In this review,we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell therapy.These insights,combined with lessons learned from benchmarking CAR-T based products in recent clinical trials,aim to address the challenges posed by T cell exhaustion,potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.

Id2 epigenetically controls CD8^(+)T-cell exhaustion by disrupting the assembly of the Tcf3-LSD1 complex

CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))subpopulations.Inhibitor of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell immunity.However,the role of Id2 in CD8^(+)T-cell exhaustion is unclear.Here,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm cells.Genetic deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor susceptibility.Mechanistically,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1.Therefore,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog cells.An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice.Inhibition of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T cells.This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

Gene engineered exosome reverses T cell exhaustion in cancer immunotherapy

Cancer patients by immune checkpoint therapy have achieved long-term remission,with no recurrence of clinical symptoms of cancer for many years.Nevertheless,more than half of cancer patients are not responsive to this therapy due to immune exhaustion.Here,we report a novel gene engineered exosome which is rationally designed by engineering PD1 gene and simultaneously enveloping an immune adjuvant imiquimod(PD1-Imi Exo)for boosting response of cancer immune checkpoint blockage therapy.The results showed that PD1-Imi Exo had a vesicular round shape(approximately 139 nm),revealed a significant targeting and a strong binding effect with both cancer cell and dendritic cell,and demonstrated a remarkable therapeutic efficacy in the melanoma-bearing mice and in the breast cancer-bearing mice.The mechanism was associated with two facts that PD1-Imi Exo blocked the binding of CD8^(+)T cell with cancer cell,displaying a PD1/PDL1 immune checkpoint blockage effect,and that imiquimod released from PD1-Imi Exo promoted the maturation of immature dendritic cell,exhibiting a reversing effect on the immune exhaustion through activating and restoring function of CD8^(+)T cell.In conclusion,the gene engineered exosome could be used for reversing T cell exhaustion in cancer immunotherapy.This study also offers a promising new strategy for enhancing PD1/PDL1 therapeutic efficacy,preventing tumor recurrence or metastasis after surgery by rebuilding the patients’immunity,thus consolidating the overall prognosis.

Local TSH/TSHR signaling promotes CD8^(+) T cell exhaustion and immune evasion in colorectal carcinoma

Dysfunction of CD8^(+)T cells in the tumor microenvironment(TME)contributes to tumor immune escape and immunotherapy tolerance.The effects of hormones such as leptin,steroid hormones,and glucocorticoids on T cell function have been reported previously.However,the mechanism underlying thyroid-stimulating hormone(TSH)/thyroid-stimulating hormone receptor(TSHR)signaling in CD8^(+)T cell exhaustion and tumor immune evasion remain poorly understood.This study was aimed at investigating the effects of TSH/TSHR signaling on the function of CD8^(+)T cells and immune evasion in colorectal cancer(CRC).Methods:TSHR expression levels in CD8^(+)T cells were assessed with immunofluorescence and flow cytometry.Functional investigations involved manipulation of TSHR expression in cellular and mouse models to study its role in CD8^(+)T cells.Mechanistic insights were mainly gained through RNAsequencing,Western blotting,chromatin immunoprecipitation and luciferase activity assay.Immunofluorescence,flow cytometry and Western blotting were used to investigate the source of TSH and TSHR in CRC tissues.Results:TSHR was highly expressed in cancer cells and CD8^(+)T cells in CRC tissues.TSH/TSHR signaling was identified as the intrinsic pathway promoting CD8^(+)T cell exhaustion.Conditional deletion of TSHR in CD8^(+)tumorinfiltrating lymphocytes(TILs)improved effector differentiation and suppressed the expression of immune checkpoint receptors such as programmed cell death 1(PD-1)and hepatitis A virus cellular receptor 2(HAVCR2 or TIM3)through the protein kinase A(PKA)/cAMP-response element binding protein(CREB)signaling pathway.CRC cells secreted TSHR via exosomes to increase the TSHR level in CD8^(+)T cells,resulting in immunosuppression in the TME.Myeloid-derived suppressor cells(MDSCs)was the main source of TSH within the TME.Low expression of TSHR in CRC was a predictor of immunotherapy response.Conclusions:The present findings highlighted the role of endogenous TSH/TSHR signaling in CD8^(+)T cell exhaustion and immune evasion in CRC.TSHR may be suitable as a predictive and therapeutic biomarker in CRC immunotherapy.

Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment

The failure of a massive influx of tumor-infiltrating T lymphocytes to eradicate tumor cells in the tumor microenvironment is mainly due to the dysfunction of T cells hyporesponsive to tumors.T-cell exhaustion and senescence induced by malignant tumors are two important dysfunctional states that coexist in cancer patients,hindering effective antitumor immunity and immunotherapy and sustaining the suppressive tumor microenvironment.Although exhausted and senescent T cells share a similar dysfunctional role in antitumor immunity,they are distinctly different in terms of generation,development,and metabolic and molecular regulation during tumor progression.Here,we discuss the unique phenotypic and functional characteristics of these two types of dysfunctional T cells and their roles in tumor development and progression.In addition,we further discuss the potential molecular and metabolic signaling pathways responsible for the control of T-cell exhaustion and senescence in the suppressive tumor microenvironment.Understanding these critical and fundamental features should facilitate rethinking the unresponsiveness to current immunotherapies in clinical patients and lead to further development of novel and effective strategies that target different types of dysfunctional T cells to enhance cancer immunotherapy.

A preliminary analysis of fishery resource exhaustion in the context of biodiversity decline

Marine biodiversity in almost all oceans is being threatened at the genetic, species, and ecosystem levels. The marine ecosystem is being degraded and the extinction rate of marine organisms has accelerated. In this paper, the potential causes of fishery resource exhaustion in the East China Sea are analyzed, including the change in the stoichiometric composition of seawater with regard to the concentrations of N and P, toxic effects of marine pollution, marine habitat destruction, increased seawater temperatures caused by climate warming, ocean acidification, pressure from overfishing, and the spread of marine pathogenic bacteria. It is believed that the factors mentioned above have significant impact on the exhaustion of fishery resources in the East China Sea. However, considering the cumulative, synergistic, and superimposed effects as well as the amplification effects resulting from their interactions, the actual risk of ecological extinction of marine organisms might be even more severe than that previously estimated. Hence, ecosystem management and research focused on a single risk factor or influencing factor is not enough to prevent marine ecosystem degradation and fishery resource exhaustion. A comprehensive, systematic, effective, and ecosystem-based management policy is imperative for healthy and sustainable fishery development in the East China Sea.

Novel exosome-targeted T-cell-based vaccine counteracts T-cell anergy and converts CTL exhaustion in chronic infection via CD40L signaling through the mTORC1 pathway

CD8＋ cytotoxic T lymphocyte （CTL） exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin （OVA）-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 （PD-1） and lymphocyte-activation gene-3 （LAG-3） and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-7 production and cytolytic effects. Naive CD8＋ T cells upregulated inhibitory PD-ligand 1 （PD-L1）, B- and T-lymphocyte attenuator and T-cell anergy-associated molecules （Grail and Itch） while down-regulating the proliferative response upon stimulation in mice with chronic infection. Remarkably, the OVA-Texo vaccine counteracted T-cell anergy and converted CTL exhaustion. The latter was associated with （i） the upregulation of a marker for CTL functionality, diacetylated histone-H3 （diAcH3）, （ii） a fourfold increase in CTLs, occurring independent of host DCs or CD4＋ T cells, and （iii） the restoration of CTL IFN-7 production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, elF4E and T-bet, and treatment of the CTLs with an mTORC1 inhibitor, rapamycin, significantly reduced the OVA-Texo- induced increase in CTLs. Interestingly, OVA-Texo-mediated CD40L signaling played a critical role in the observed immunological effects. Importantly, the Gag-Texo vaccine induced Gag-specific therapeutic immunity in chronic infection. Therefore, this study should have a serious impact on the development of new therapeutic vaccines for human immunodeficiency virus （HIV-1） infection.

Increased circulating level of interleukin-6 and CD8+T cell exhaustion are associated with progression of COVID-19

Background: Coronavirus disease 2019(COVID-19)is pandemic.It is critical to identify COVID-19 patients who are most likely to develop a severe disease.This study was designed to determine the clinical and epidemiological features of COVID-19 patients associated with the development of pneumonia and factors associated with disease progression.Methods:: Seventy consecutive patients with etiologically confirmed COVID-19 admitted to PLA General Hospital in Beijing,China from December 27,2019 to March 12,2020 were enrolled in this study and followed-up to March 16,2020.Differences in clinical and laboratory findings between COVID-19 patients with pneumonia and those without were determined by theχ2 test or the Fisher exact test(categorical variables)and independent group t test or Mann–Whitney U test(continuous variables).The Cox proportional hazard model and Generalized Estimating Equations were applied to evaluate factors that predicted the progression of COVID-19.Results: The mean incubation was 8.67(95%confidence interval,6.78–10.56)days.Mean duration from the first test severe acute respiratory syndrome coronavirus 2-positive to conversion was 11.38(9.86–12.90)days.Compared to pneumonia-free patients,pneumonia patients were 16.5 years older and had higher frequencies of having hypertension,fever,and cough and higher circulating levels of neutrophil proportion,interleukin-6,low count(<190/µl)of CD8+T cells,and neutrophil/lymphocyte ratio.Thirteen patients deteriorated during hospitalization.Cox regression analysis indicated that older age and higher serum levels of interleukin-6,C-reactive protein,procalcitonin,and lactate at admission significantly predicted the progression of COVID-19.During hospitalization,circulating counts of T lymphocytes,CD4+T cells,and CD8+T cells were lower,whereas neutrophil proportion,neutrophil/lymphocyte ratio,and the circulating levels of interleukin-6,C-reactive protein,and procalcitonin were higher,in pneumonia patients than in pneumonia-free patients.CD8+lymphocyte count in pneumonia patients did not recover when discharged.Conclusions: Older age and higher levels of C-reactive protein,procalcitionin,interleukin-6,and lactate might predict COVID-19 progression.T lymphocyte,especially CD8+cell-mediated immunity is critical in recovery of COVID-19.This study may help in predicting disease progression and designing immunotherapy for COVID-19.

Activation or exhaustion of CD8^(+) T cells in patients with COVID-19

In addition to CD4^(+)T cells and neutralizing antibodies,CD8^(+)T cells contribute to protective immune responses against SARS-CoV-2 in patients with coronavirus disease 2019(COVID-19),an ongoing pandemic disease.In patients with COVID-19,CD8^(+)T cells exhibiting activated phenotypes are commonly observed,although the absolute number of CD8^(+)T cells is decreased.In addition,several studies have reported an upregulation of inhibitory immune checkpoint receptors,such as PD-1,and the expression of exhaustion-associated gene signatures in CD8^(+)T cells from patients with COVID-19.However,whether CD8^(+)T cells are truly exhausted during COVID-19 has been a controversial issue.In the present review,we summarize the current understanding of CD8^(+)T-cell exhaustion and describe the available knowledge on the phenotypes and functions of CD8^(+)T cells in the context of activation and exhaustion.We also summarize recent reports regarding phenotypical and functional analyses of SARS-CoV-2-specific CD8^(+)T cells and discuss long-term SARS-CoV-2-specific CD8^(+)T-cell memory.

Transcriptional suppression of CD8^(+)T cell exhaustion for improving T cell immunotherapy

As the major effector of cellular adaptive immune response,CD8^(+) T cells play crucial roles in the host’s defense against tumor and infection.Two recent studies revealed that basic leucine zipper ATF-like transcriptional factor(BATF)not only blocks the exhaustion of CD8^(+) engineered chimeric antigen receptor(CAR)-T cells,but also regulates the differentiation of stem-like CD8^(+) T precursor cells into effector cells during chronic infection[1,2].These results emphasized the important roles of transcriptional regulation in promoting T cell effector functions and preventing T cell exhaustion as well,suggesting the potential application of motivating transcriptional regulators such as BATF to improve the efficacy of adaptive T cell immunotherapy of cancer and chronic infection.