Exhausted CD8
T (T
) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T
...) or memory (T
) CD8
T cells. T
cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T
cells are a distinct immune subset, with a unique chromatin landscape compared with T
and T
cells. However, the mechanisms that govern the transcriptional and epigenetic development of T
cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T
cells in mice. TOX is largely dispensable for the formation of T
and T
cells, but it is critical for exhaustion: in the absence of TOX, T
cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in T
cells. Robust expression of TOX therefore results in commitment to T
cells by translating persistent stimulation into a distinct T
cell transcriptional and epigenetic developmental program.
TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the ...transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1+Ly108+PD-1+ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1Hi effectors while fostering KLRG1Lo Tex precursor cells, and PD-1 stabilized this TCF-1+ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset.
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•scRNA-seq defines an effector versus exhausted Tex cell-fate decision•TCF-1 plays a central role in initially establishing Tex precursor cells•PD-1 supports the TCF-1+ Tex precursor cells at early phase of chronic infection•Eomes and c-Myb play key roles in Tex cell persistence downstream of TCF-1
The initiation of the T cell exhaustion program remains poorly understood. In this study, Chen et al. define an effector (Teff) versus exhausted (Tex) CD8 T cell binary-fate decision during chronic infection and find that TCF-1 supports the Tex precursor development by antagonizing Teff-like cell differentiation through multiple transcription factors.
Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) ...may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment.
Among multiple subtypes of tissue or cell, subtype-specific differentially-expressed genes (SDEGs) are defined as being most-upregulated in only one subtype but not in any other. Detecting SDEGs ...plays a critical role in the molecular characterization and deconvolution of multicellular complex tissues. Classic differential analysis assumes a null hypothesis whose test statistic is not subtype-specific, thus can produce a high false positive rate and/or lower detection power. Here we first introduce a One-Versus-Everyone Fold Change (OVE-FC) test for detecting SDEGs. We then propose a scaled test statistic (OVE-sFC) for assessing the statistical significance of SDEGs that applies a mixture null distribution model and a tailored permutation test. The OVE-FC/sFC test was validated on both type 1 error rate and detection power using extensive simulation data sets generated from real gene expression profiles of purified subtype samples. The OVE-FC/sFC test was then applied to two benchmark gene expression data sets of purified subtype samples and detected many known or previously unknown SDEGs. Subsequent supervised deconvolution results on synthesized bulk expression data, obtained using the SDEGs detected from the independent purified expression data by the OVE-FC/sFC test, showed superior performance in deconvolution accuracy when compared with popular peer methods.
BACKGROUNDSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 1 million deaths worldwide; thus, there is an urgent need to develop preventive and therapeutic strategies. ...The antituberculosis vaccine bacillus Calmette-Guérin (BCG) demonstrates nonspecific, protective innate immune-boosting effects. Here, we determined whether a history of BCG vaccination was associated with decreased SARS-CoV-2 infection and seroconversion in a longitudinal, retrospective observational study of a diverse cohort of health care workers (HCWs).METHODSWe assessed SARS-CoV-2 seroprevalence and collected medical questionnaires, which included information on BCG vaccination status and preexisting demographic and clinical characteristics, from an observational cohort of HCWs in a multisite Los Angeles health care organization. We used multivariate analysis to determine whether a history of BCG vaccination was associated with decreased rates of SARS-CoV-2 infection and seroconversion.RESULTSOf the 6201 HCWs, 29.6% reported a history of BCG vaccination, whereas 68.9% had not received BCG vaccination. Seroprevalence of anti-SARS-CoV-2 IgG as well as the incidence of self-reported clinical symptoms associated with coronavirus disease 2019 (COVID-19) were markedly decreased among HCWs with a history of BCG vaccination compared with those without BCG vaccination. After adjusting for age and sex, we found that a history of BCG vaccination, but not meningococcal, pneumococcal, or influenza vaccination, was associated with decreased SARS-CoV-2 IgG seroconversion.CONCLUSIONSA history of BCG vaccination was associated with a decrease in the seroprevalence of anti-SARS-CoV-2 IgG and a lower number of participants who self-reported experiencing COVID-19-related clinical symptoms in this cohort of HCWs. Therefore, large randomized, prospective clinical trials of BCG vaccination are urgently needed to confirm whether BCG vaccination can confer a protective effect against SARS-CoV-2 infection.
OBJECTIVE:The purpose of this study was to determine the relationship between the Timed Up and Go test and postoperative morbidity and 1-year mortality, and to compare the Timed Up and Go to the ...standard-of-care surgical risk calculators for prediction of postoperative complications.
METHODS:In this prospective cohort study, patients 65 years and older undergoing elective colorectal and cardiac operations with a minimum of 1-year follow-up were included. The Timed Up and Go test was performed preoperatively. This timed test starts with the subject standing from a chair, walking 10 feet, returning to the chair, and ends after the subject sits. Timed Up and Go results were grouped as fast ≤ 10 seconds, intermediate = 11–14 seconds, and slow ≥ 15 seconds. Receiver operating characteristic curves were used to compare the 3 Timed Up and Go groups to current standard-of-care surgical risk calculators at forecasting postoperative complications.
RESULTS:This study included 272 subjects (mean age of 74 ± 6 years). Slower Timed Up and Go was associated with increased postoperative complications after colorectal (fast 13%, intermediate 29%, and slow 77%; P < 0.001) and cardiac (fast 11%, intermediate 26%, and slow 52%; P < 0.001) operations. Slower Timed Up and Go was associated with increased 1-year mortality following both colorectal (fast 3%, intermediate 10%, and slow 31%; P = 0.006) and cardiac (fast 2%, intermediate 3%, and slow 12%; P = 0.039) operations. Receiver operating characteristic area under curve of the Timed Up and Go and the risk calculators for the colorectal group was 0.775 (95% CI0.670–0.880) and 0.554 (95% CI0.499–0.609), and for the cardiac group was 0.684 (95% CI0.603–0.766) and 0.552 (95% CI0.477–0.626).
CONCLUSIONS:Slower Timed Up and Go forecasted increased postoperative complications and 1-year mortality across surgical specialties. Regardless of operation performed, the Timed Up and Go compared favorably to the more complex risk calculators at forecasting postoperative complications.
Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the ...transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer.
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•OpTICS In vivo CD8+ T cell CRISPR screening platform developed for focused gene discovery•OpTICS identifies genes involved in effector versus exhausted CD8+ T cells•The Fli1 transcription factor represses optimal effector CD8+ T cells during exhaustion•Fli1 antagonizes epigenetic accessibility at ETS-RUNX sites limiting Runx3 activity
An in vivo T cell CRISPR screening platform identifies Fli1 as a factor modulating CD8+ T cell effector differentiation with limited effects on memory or exhaustion.
Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. Here, we employed a combination of behavioral, molecular and ...computational techniques to test the role of the microbiota in mediating despair behavior. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. Specifically, we observed reduced Lactobacillus and increased circulating kynurenine levels as the most prominent changes in stressed mice. Restoring intestinal Lactobacillus levels was sufficient to improve the metabolic alterations and behavioral abnormalities. Mechanistically, we identified that Lactobacillus-derived reactive oxygen species may suppress host kynurenine metabolism, by inhibiting the expression of the metabolizing enzyme, IDO1, in the intestine. Moreover, maintaining elevated kynurenine levels during Lactobacillus supplementation diminished the treatment benefits. Collectively, our data provide a mechanistic scenario for how a microbiota player (Lactobacillus) may contribute to regulating metabolism and resilience during stress.
Clinical evaluation of immune reconstitution and health status during HIV-1 infection and anti-retroviral therapy (ART) is largely based on CD4+ T cell counts and viral load, measures that fail to ...take into account the CD8+ T cell subset, known to show features of accelerated aging in HIV disease. Here, we compare adenosine deaminase (ADA), glucose uptake receptor 1 (GLUT1), and leucine-rich repeat neuronal 3 (LRRN3) to CD38 expression and telomerase activity, two strong predictors of HIV disease progression. Our analysis revealed that reduced ADA, telomerase activity and LRRN3 gene expression were significantly associated with high CD38 and HLA-DR in CD8+ T cells, with % ADA+ cells being the most robust predictor of CD8+ T cell activation. Our results suggest that ADA, LRRN3 and telomerase activity in CD8+ T cells may serve as novel, clinically relevant biomarkers of immune status in HIV-1 infection, specifically by demonstrating the degree to which CD8+ T cells have progressed to the end stage of replicative senescence. Since chronological aging itself leads to the accumulation of senescent CD8+ T cells, the prolonged survival and resultant increased age of the HIV+ population may synergize with the chronic immune activation to exacerbate both immune decline and age-associated pathologies. The identification and future validation of these new biomarkers may lead to fresh immune-based HIV treatments.
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