Aging gene signature of memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

BACKGROUND: Memory CD8+ T cells expand with age. We previously demonstrated an age-associated expansion of effector memory (EM) CD8+ T cells expressing low levels of IL-7 receptor alpha (IL-7Rαlow) and the presence of its gene signature (i.e., IL-7Rαlow aging genes) in peripheral blood of older adults without Alzheimer's disease (AD). Considering age as the strongest risk factor for AD and the recent finding of EM CD8+ T cell expansion, mostly IL-7Rαlow cells, in AD, we investigated whether subjects with AD have alterations in IL-7Rαlow aging gene signature, especially in relation to genes possibly associated with AD and disease severity. RESULTS: We identified a set of 29 candidate genes (i.e., putative AD genes) which could be differentially expressed in peripheral blood of patients with AD through the systematic search of publicly available datasets. Of the 29 putative AD genes, 9 genes (31%) were IL-7Rαlow aging genes (P < 0.001), suggesting the possible implication of IL-7Rαlow aging genes in AD. These findings were validated by RT-qPCR analysis of 40 genes, including 29 putative AD genes, additional 9 top IL-7R⍺low aging but not the putative AD genes, and 2 inflammatory control genes in peripheral blood of cognitively normal persons (CN, 38 subjects) and patients with AD (40 mild cognitive impairment and 43 dementia subjects). The RT-qPCR results showed 8 differentially expressed genes between AD and CN groups; five (62.5%) of which were top IL-7Rαlow aging genes (FGFBP2, GZMH, NUAK1, PRSS23, TGFBR3) not previously reported to be altered in AD. Unbiased clustering analysis revealed 3 clusters of dementia patients with distinct expression levels of the 40 analyzed genes, including IL-7Rαlow aging genes, which were associated with neurocognitive function as determined by MoCA, CDRsob and neuropsychological testing. CONCLUSIONS: We report differential expression of "normal" aging genes associated with IL-7Rαlow EM CD8+ T cells in peripheral blood of patients with AD, and the significance of such gene expression in clustering subjects with dementia due to AD into groups with different levels of cognitive functioning. These results provide a platform for studies investigating the possible implications of age-related immune changes, including those associated with CD8+ T cells, in AD.

Defining Clinical and Immunological Predictors of Poor Immune Responses to COVID-19 mRNA Vaccines in Patients with Primary Antibody Deficiency.

Immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines in primary antibody deficiencies (PADs) are largely unknown. We investigated antibody and CD4+ T-cell responses specific for SARS-CoV-2 spike protein (S) before and after vaccination and associations between vaccine response and patients' clinical and immunological characteristics in PADs. The PAD cohort consisted of common variable immune deficiency (CVID) and other PADs, not meeting the criteria for CVID diagnosis (oPADs). Anti-S IgG, IgA, and IgG subclasses 1 and 3 increased after vaccination and correlated with neutralization activity in HCs and patients with oPADs. However, 42% of CVID patients developed such responses after the 2nd dose. A similar pattern was also observed with S-specific CD4+ T-cells as determined by OX40 and 4-1BB expression. Patients with poor anti-S IgG response had significantly lower levels of baseline IgG, IgA, CD19+ B-cells, switched memory B-cells, naïve CD8+ T-cells, and a higher frequency of EM CD8+ T-cells and autoimmunity compared to patients with adequate anti-S IgG responses. Patients with oPADs can develop humoral and cellular immune responses to vaccines similar to HCs. However, a subset of CVID patients exhibit impairment in developing such responses, which can be predicted by the baseline immune profile and history of autoimmunity.

Implication of IL-7 receptor alpha chain expression by CD8+ T cells and its signature in defining biomarkers in aging.

CD8+ T cells play an important role in host defense against infections and malignancies as well as contribute to the development of inflammatory disorders. Alterations in the frequency of naïve and memory CD8+ T cells are one of the most significant changes in the immune system with age. As the world population rapidly ages, a better understanding of aging immune function or immunosenescence could become a basis for discovering treatments of illnesses that commonly occur in older adults. In particular, biomarkers for immune aging could be utilized to identify individuals at high risk of developing age-associated conditions and help monitor the efficacy of therapeutic interventions targeting such conditions. This review details the possible role of CD8+ T cell subsets expressing different levels of the cytokine receptor IL-7 receptor alpha chain (IL-7Rα) and the gene signature associated with IL-7Rα as potential biomarkers for immune aging given the association of CD8+ T cells in host defense, inflammation, and immunosenescence.

A distinct association of inflammatory molecules with outcomes of COVID-19 in younger versus older adults.

Aging can alter immunity affecting host defense. COVID-19 has the most devastating clinical outcomes in older adults, raising the implication of immune aging in determining its severity and mortality. We investigated biological predictors for clinical outcomes in a dataset of 13,642 ambulatory and hospitalized adult COVID-19 patients, including younger (age < 65, n = 566) and older (age ≥ 65, n = 717) subjects, with in-depth analyses of inflammatory molecules, cytokines and comorbidities. Disease severity and mortality in younger and older adults were associated with discrete immune mechanisms, including predominant T cell activation in younger adults, as measured by increased soluble IL-2 receptor alpha, and increased IL-10 in older adults although both groups also had shared inflammatory processes, including acute phase reactants, contributing to clinical outcomes. These observations suggest that progression to severe disease and death in COVID-19 may proceed by different immunologic mechanisms in younger versus older subjects and introduce the possibility of age-based immune directed therapies.

Infectious Complications Predict Premature CD8+ T-cell Senescence in CD40 Ligand-Deficient Patients.

PURPOSE: CD40 ligand (CD40L)-deficient patients display increased susceptibilities to infections that can be mitigated with effective prophylactic strategies including immunoglobulin G (IgG) replacement and prophylactic antibiotics. CD8+ T-cell senescence has been described in CD40L deficiency, but it is unclear if this is an intrinsic feature of the disease or secondary to infectious exposures. To address this question, we assessed CD8+ T-cell senescence and its relationship to clinical histories, including prophylaxis adherence and infections, in CD40L-deficient patients. METHODS: Peripheral CD8+ T-cells from seven CD40L-deficient patients and healthy controls (HCs) were assessed for senescent features using T-cell receptor excision circle (TREC) analysis, flow cytometry, cytometry by time of flight (CyTOF) and in vitro functional determinations including CMV-specific proliferation and cytokine release assays. RESULTS: Three patients (5, 28, and 34 years old) who were poorly adherent to immunoglobulin G replacement and Pneumocystis jirovecii pneumonia (PJP) prophylaxis and/or experienced multiple childhood pneumonias (patient group 1) had an expansion of effector memory CD8+ T-cells with the senescent phenotype when compared to HCs. Such changes were not observed in the patient group 2 (four patients, 16, 22, 24, and 33 years old) who were life-long adherents to prophylaxis and experienced few infectious complications. CyTOF analysis of CD8+ T-cells from the 5-year-old patient and older adult HCs showed similar expression patterns of senescence-associated molecules. CONCLUSIONS: Our findings support that recurrent infections and non-adherence to prophylaxis promote early CD8+ T-cell senescence in CD40L deficiency. Premature senescence may increase malignant susceptibilities and further exacerbate infectious risk in CD40L-deficient patients.

Estimation of Excess All-cause Mortality during COVID-19 Pandemic in Korea.

BACKGROUND: Excess all-cause mortality is helpful to assess the full extent of the health impact, including direct and indirect deaths of coronavirus disease 2019 (COVID-19). The study aimed to estimate overall and regional excess all-cause mortality during the pandemic in Korea. METHODS: We obtained all-cause death data and population statistics from January 2010 to December 2020. The expected mortality in 2020 was estimated using a quasi-Poisson regression model. The model included death year, seasonal variation, cold wave (January), average death counts in the previous month, and population. Excess mortality was defined as the difference between the observed mortality and the expected mortality. Regions were classified into three areas according to the numbers of COVID-19 cases. RESULTS: There was no annual excess all-cause mortality in 2020 at the national and regional level compared to the average death for the previous ten years. The observed mortality in 2020 was 582.9 per 100,000 people, and the expected mortality was 582.3 per 100,000 people (95% confidence interval, 568.3-596.7). However, we found monthly and regional variations depending on the waves of the COVID-19 pandemic in Korea. While the mortality in August, October, and November exceeded the expected range, the mortality in September was lower than the expected range. The months in which excess deaths were identified differed by region. CONCLUSION: Our results show that the mortality in 2020 was similar to the historical trend. However, in the era of the COVID-19 pandemic, it would be necessary to regularly investigate COVID-19-related mortality and determine its direct and indirect causes.

IL-7 receptor alpha defines heterogeneity and signature of human effector memory CD8+ T cells in high dimensional analysis.

The IL-7 receptor alpha chain (IL-7Rα or CD127) can be differentially expressed in memory CD8+ T cells. Here we investigated whether IL-7Rα could serve as a key molecule in defining a comprehensive landscape of heterogeneity in human effector memory (EM) CD8+ T cells using high-dimensional Cytometry by Time-Of-Flight (CyTOF) and single-cell RNA-seq (scRNA-seq). IL-7Rα had diverse, but organized, expressional relationship in EM CD8+ T cells with molecules related to cell function and gene regulation, which rendered an immune landscape defining heterogeneous cell subsets. The differential expression of these molecules likely has biological implications as we found in vivo signatures of transcription factors and homeostasis cytokine receptors, including T-bet and IL-7Rα. Our findings indicate the existence of heterogeneity in human EM CD8+ T cells as defined by distinct but organized expression patterns of multiple molecules in relationship to IL-7Rα and its possible biological significance in modulating downstream events.

Dissecting alterations in human CD8+ T cells with aging by high-dimensional single cell mass cytometry.

We investigated the effect of aging on the multi-dimensional characteristics and heterogeneity of human peripheral CD8+ T cells defined by the expression of a set of molecules at the single cell level using the recently developed mass cytometry or Cytometry by Time-Of-Flight (CyTOF) and computational algorithms. CD8+ T cells of young and older adults had differential expression of molecules, especially those related to cell activation and migration, permitting the clustering of young and older adults through an unbiased approach. The changes in the expression of individual molecules were collectively reflected in the altered high-dimensional profiles of CD8+ T cells in older adults as visualized by the dimensionality reduction analysis tools principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE). A combination of PhenoGraph clustering and t-SNE analysis revealed heterogeneous subsets of CD8+ T cells that altered with aging. Furthermore, intermolecular quantitative relationships in CD8+ T cells appeared to change with age as determined by the computational algorithm conditional-Density Resampled Estimate of Mutual Information (DREMI). The results of our study showed that heterogeneity, multidimensional characteristics, and intermolecular quantitative relationships in human CD8+ T cells altered with age, distinctively clustering young and older adults through an unbiased approach.

DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7Rαlow and IL-7Rαhigh Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine.

DNA methylation is an epigenetic mechanism that modulates gene expression in mammalian cells including T cells. Memory T cells are heterogeneous populations. Human effector memory (EM) CD8(+) T cells in peripheral blood contain two cell subsets with distinct traits that express low and high levels of the IL-7Rα. However, epigenetic mechanisms involved in defining such cellular traits are largely unknown. In this study, we use genome-wide DNA methylation and individual gene expression to show the possible role of DNA methylation in conferring distinct traits of chemotaxis and inflammatory responses in human IL-7Rα(low) and IL-7Rα(high) EM CD8(+) T cells. In particular, IL-7Rα(low) EM CD8(+) T cells had increased expression of CX3CR1 along with decreased DNA methylation in the CX3CR1 gene promoter compared with IL-7Rα(high) EM CD8(+) T cells. Altering the DNA methylation status of the CX3CR1 gene promoter changed its activity and gene expression. IL-7Rα(low) EM CD8(+) T cells had an increased migratory capacity to the CX3CR1 ligand fractalkine compared with IL-7Rα(high) EM CD8(+) T cells, suggesting an important biological outcome of the differential expression of CX3CR1. Moreover, IL-7Rα(low) EM CD8(+) T cells induced fractalkine expression on endothelial cells by producing IFN-γ and TNF-α, forming an autocrine amplification loop. Overall, our study shows the role of DNA methylation in generating unique cellular traits in human IL-7Rα(low) and IL-7Rα(high) EM CD8(+) T cells, including differential expression of CX3CR1, as well as potential biological implications of this differential expression.

Self double-stranded (ds)DNA induces IL-1ß production from human monocytes by activating NLRP3 inflammasome in the presence of anti-dsDNA antibodies.

The pathogenic hallmark of systemic lupus erythematosus is the autoimmune response against self nuclear Ags, including dsDNA. The increased expression of the proinflammatory cytokine IL-1ß has been found in the cutaneous lesion and PBMCs from lupus patients, suggesting a potential involvement of this cytokine in the pathogenesis of lupus. IL-1ß is produced primarily by innate immune cells such as monocytes and can promote a Th17 cell response, which is increased in lupus. IL-1ß production requires cleaving pro-IL-ß into IL-1ß by the caspase-1-associated multiprotein complex called inflammasomes. In this study we show that self dsDNA induces IL-1ß production from human monocytes dependent on serum or purified IgG containing anti-dsDNA Abs by activating the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Reactive oxygen species (ROS) and K(+) efflux were involved in this activation. Knocking down the NLRP3 or inhibiting caspase-1, ROS, and K(+) efflux decreased IL-1ß production. Supernatants from monocytes treated with a combination of self dsDNA and anti-dsDNA Ab(+) serum promoted IL-17 production from CD4(+) T cells in an IL-1ß-dependent manner. These findings provide new insights in lupus pathogenesis by demonstrating that self dsDNA together with its autoantibodies induces IL-1ß production from human monocytes by activating the NLRP3 inflammasome through inducing ROS synthesis and K(+) efflux, leading to the increased Th17 cell response.

IL-6 receptor α defines effector memory CD8+ T cells producing Th2 cytokines and expanding in asthma.

RATIONALE: Cytokine receptors can be markers defining different T-cell subsets and considered as therapeutic targets. The association of IL-6 and IL-6 receptor α (IL-6Rα) with asthma was reported, suggesting their involvement in asthma. OBJECTIVES: To determine whether and how IL-6Rα defines a distinct effector memory (EM) CD8+ T-cell population in health and disease. METHODS: EM CD8+ T cells expressing IL-6Rα (IL-6Rα(high)) were identified in human peripheral blood and analyzed for function, gene, and transcription factor expression. The relationship of these cells with asthma was determined using blood and sputum. MEASUREMENTS AND MAIN RESULTS: A unique population of IL-6Rα(high) EM CD8+ T cells was found in peripheral blood. These cells that potently proliferated, survived, and produced high levels of the Th2-type cytokines IL-5 and IL-13 had increased levels of GATA3 and decreased levels of T-bet and Blimp-1 in comparison with other EM CD8+ T cells. In fact, GATA3 was required for IL-6Rα expression. Patients with asthma had an increased frequency of IL-6Rα(high) EM CD8+ T cells in peripheral blood compared with healthy control subjects. Also, IL-6Rα(high) EM CD8+ T cells exclusively produced IL-5 and IL-13 in response to asthma-associated respiratory syncytial virus and bacterial superantigens. CONCLUSIONS: Human IL-6Rα(high) EM CD8+ T cells is a unique cell subset that may serve as a reservoir for effector CD8+ T cells, particularly the ones producing Th2-type cytokines, and expand in asthma.

Edible blue-green algae reduce the production of pro-inflammatory cytokines by inhibiting NF-κB pathway in macrophages and splenocytes.

BACKGROUND: Chronic inflammation contributes to the development of pathological disorders including insulin resistance and atherosclerosis. Identification of anti-inflammatory natural products can prevent the inflammatory diseases. METHODS: Anti-inflammatory effects of blue-green algae (BGA), i.e., Nostoc commune var. sphaeroides Kützing (NO) and Spirulina platensis (SP), were compared in RAW 264.7 and mouse bone marrow-derived macrophages (BMM) as well as splenocytes from apolipoprotein E knockout (apoE(-/-)) mice fed BGA. RESULTS: When macrophages pretreated with 100µg/ml NO lipid extract (NOE) or SP lipid extract (SPE) were activated by lipopolysaccharide (LPS), expression and secretion of pro-inflammatory cytokines, such as tumor necrosis factor α (TNFα), interleukin 1ß (IL-1ß), and IL-6, were significantly repressed. NOE and SPE also significantly repressed the expression of TNFα and IL-1ß in BMM. LPS-induced secretion of IL-6 was lower in splenocytes from apoE(-/-) fed an atherogenic diet containing 5% NO or SP for 12weeks. In RAW 264.7 macrophages, NOE and SPE markedly decreased nuclear translocation of NF-κB. The degree of repression of pro-inflammatory gene expression by algal extracts was much stronger than that of SN50, an inhibitor of NF-κB nuclear translocation. Trichostatin A, a pan histone deacetylase inhibitor, increased basal expression of IL-1ß and attenuated the repression of the gene expression by SPE. SPE significantly down-regulated mRNA abundance of 11 HDAC isoforms, consequently increasing acetylated histone 3 levels. CONCLUSION: NOE and SPE repress pro-inflammatory cytokine expression and secretion in macrophages and splenocytes via inhibition of NF-κB pathway. Histone acetylation state is likely involved in the inhibition. GENERAL SIGNIFICANCE: This study underscores natural products can exert anti-inflammatory effects by epigenetic modifications such as histone acetylation.

Human monocytes have increased IFN-γ-mediated IL-15 production with age alongside altered IFN-γ receptor signaling.

IL-15 is involved in regulating host defense and inflammation. Monocytes produce the biologically active cell surface IL-15 in response to IFN-γ. Although aging can alter the immune system, little is known about whether and how aging affects IFN-γ-mediated IL-15 production in human monocytes. We showed that monocytes of healthy older adults (age ≥ 65) had increased cell surface IL-15 expression in response to IFN-γ compared to those of healthy young adults (age ≤ 40). This finding stems in part from increased IFN-γ receptor (R)1/2 expression on monocytes in older adults, leading to enhanced STAT1 activation and interferon regulatory factor 1 synthesis with increased IL15 gene expression. Our study suggests that with aging the IFN-γ-mediated IL-15 production pathway in human monocytes is uncompromised, but rather augmented, and could be considered as a therapeutic target point to modulate host defense and inflammation in older adults.

U1-small nuclear ribonucleoprotein activates the NLRP3 inflammasome in human monocytes.

The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is a caspase-1-containing cytosolic protein complex that is essential for processing and secretion of IL-1ß. The U1-small nuclear ribonucleoprotein (U1-snRNP) that includes U1-small nuclear RNA is a highly conserved intranuclear molecular complex involved in splicing pre-mRNA. Abs against this self nuclear molecule are characteristically found in autoimmune diseases like systemic lupus erythematosus, suggesting a potential role of U1-snRNP in autoimmunity. Although endogenous DNA and microbial nucleic acids are known to activate the inflammasomes, it is unknown whether endogenous RNA-containing U1-snRNP could activate this molecular complex. In this study, we show that U1-snRNP activates the NLRP3 inflammasome in CD14(+) human monocytes dependently of anti-U1-snRNP Abs, leading to IL-1ß production. Reactive oxygen species and K(+) efflux were responsible for this activation. Knocking down the NLRP3 or inhibiting caspase-1 or TLR7/8 pathway decreased IL-1ß production from monocytes treated with U1-snRNP in the presence of anti-U1-snRNP Abs. Our findings indicate that endogenous RNA-containing U1-snRNP could be a signal that activates the NLRP3 inflammasome in autoimmune diseases like systemic lupus erythematosus where anti-U1-snRNP Abs are present.

1,25-Dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region.

FOXP3-positive regulatory T (Treg) cells are a unique subset of T cells with immune regulatory properties. Treg cells can be induced from non-Treg CD4(+) T cells (induced Treg [iTreg] cells) by TCR triggering, IL-2, and TGF-ß or retinoic acid. 1,25-Dihyroxyvitamin D(3) [1,25(OH)(2)VD(3)] affects the functions of immune cells including T cells. 1,25(OH)(2)VD(3) binds the nuclear VD receptor (VDR) that binds target DNA sequences known as the VD response element (VDRE). Although 1,25(OH)(2)VD(3) can promote FOXP3 expression in CD4(+) T cells with TCR triggering and IL-2, it is unknown whether this effect of 1,25(OH)(2)VD(3) is mediated through direct binding of VDR to the FOXP3 gene without involving other molecules. Also, it is unclear whether FOXP3 expression in 1,25(OH)(2)VD(3)-induced Treg (VD-iTreg) cells is critical for the inhibitory function of these cells. In this study, we demonstrated the presence of VDREs in the intronic conserved noncoding sequence region +1714 to +2554 of the human FOXP3 gene and the enhancement of the FOXP3 promoter activity by such VDREs in response to 1,25(OH)(2)VD(3). Additionally, VD-iTreg cells suppressed the proliferation of target CD4(+) T cells and this activity was dependent on FOXP3 expression. These findings suggest that 1,25(OH)(2)VD(3) can affect human immune responses by regulating FOXP3 expression in CD4(+) T cells through direct VDR binding to the FOXP3 gene, which is essential for inhibitory function of VD-iTreg cells.

IL-1 receptor 1 signaling shapes the development of viral antigen-specific CD4+ T cell responses following COVID-19 mRNA vaccination.

BACKGROUND: The innate immune cytokine interleukin (IL)-1 can affect T cell immunity, a critical factor in host defense. In a previous study, we identified a subset of human CD4+ T cells which express IL-1 receptor 1 (IL-1R1). However, the expression of such receptor by viral antigen-specific CD4+ T cells and its biological implication remain largely unexplored. This led us to investigate the implication of IL-1R1 in the development of viral antigen-specific CD4+ T cell responses in humans, including healthy individuals and patients with primary antibody deficiency (PAD), and animals. METHODS: We characterized CD4+ T cells specific for SARS-CoV-2 spike (S) protein, influenza virus, and cytomegalovirus utilizing multiplexed single cell RNA-seq, mass cytometry and flow cytometry followed by an animal study. FINDINGS: In healthy individuals, CD4+ T cells specific for viral antigens, including S protein, highly expressed IL-1R1. IL-1ß promoted interferon (IFN)-γ expression by S protein-stimulated CD4+ T cells, supporting the functional implication of IL-1R1. Following the 2nd dose of COVID-19 mRNA vaccines, S protein-specific CD4+ T cells with high levels of IL-1R1 increased, likely reflecting repetitive antigenic stimulation. The expression levels of IL-1R1 by such cells correlated with the development of serum anti-S protein IgG antibody. A similar finding of increased expression of IL-1R1 by S protein-specific CD4+ T cells was also observed in patients with PAD following COVID-19 mRNA vaccination although the expression levels of IL-1R1 by such cells did not correlate with the levels of serum anti-S protein IgG antibody. In mice immunized with COVID-19 mRNA vaccine, neutralizing IL-1R1 decreased IFN-γ expression by S protein-specific CD4+ T cells and the development of anti-S protein IgG antibody. INTERPRETATION: Our results demonstrate the significance of IL-1R1 expression in CD4+ T cells for the development of viral antigen-specific CD4+ T cell responses, contributing to humoral immunity. This provides an insight into the regulation of adaptive immune responses to viruses via the IL-1 and IL-1R1 interface. FUNDING: Moderna to HJP, National Institutes of Health (NIH) 1R01AG056728 and R01AG055362 to IK and KL2 TR001862 to JJS, Quest Diagnostics to IK and RB, and the Mathers Foundation to RB.

An altered relationship of influenza vaccine-specific IgG responses with T cell immunity occurs with aging in humans.

Alterations in T cell immunity occur with aging. Influenza causes significant morbidity and mortality in the elderly. We investigated the relationship of serum IgG responses with hemagglutinin inhibition (HI) antibody titers and the frequency of distinct T cell subsets in young and elderly people who received the inactivated influenza vaccine. Influenza vaccine-specific IgG responses correlated with the increase of HI antibody titers and the frequency of CD4(+) T cells producing IFN-γ and IL-17 in young, but not elderly, people. Also, only in young people, such IgG responses correlated with the frequency of memory T cells, especially central memory cells, CD45RA(-) effector memory CD8(+) T cells and IL-7 receptor alpha high effector memory CD8(+) T cells with potent survival and proliferative capacity. These findings suggest that aging alters the association of influenza-vaccine specific IgG responses with HI antibody titers, cytokine-producing capacity and proportions of memory T cells in humans.

Maintenance of CMV-specific CD8+ T cell responses and the relationship of IL-27 to IFN-γ levels with aging.

We investigated whether healthy young (age ≤ 40) and elderly (age ≥ 65) people infected with cytomegalovirus (CMV) had similar levels of CD8(+) T cell cytokine production and proliferation in response to an immunodominant CMV pp65 peptide pool given the role of CD8(+) T cells in controlling viral infection and the association of CMV with immunosenescence. Plus, we determined the effects of aging and CMV-infectious status on plasma levels of IL-27, an innate immune cytokine with pro- and anti-inflammatory properties, as well as on its relationship to IFN-γ in that IL-27 can promote the production of IFN-γ. The results of our study show that young and elderly people had similar levels of CD8(+) T cell proliferation, and IFN-γ and TNF-α production in response to CMV pp65 peptides. Plasma levels of IL-27 were similar between the two groups although CMV-infected young and elderly people had a trend toward increased levels of IL-27. Regardless of aging and CMV-infectious status, plasma levels of IL-27 correlated highly with plasma levels of IFN-γ. These findings suggest the maintenance of CMV pp65-specific CD8(+) T cell proliferation and cytokine production with aging as well as the sustaining of circulatory IL-27 levels and its biological link to IFN-γ in young and elderly people irrespective of CMV infection.

Changes in the Hospital Standardized Mortality Ratio Before and During the COVID-19 Pandemic: A Disaggregated Analysis by Region and Hospital Type in Korea.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has led to a global shortage of medical resources; therefore, we investigated whether COVID-19 impacted the quality of non-COVID-19 hospital care in Korea by comparing hospital standardized mortality rates (HSMRs) before and during the pandemic. METHODS: This retrospective cohort study analyzed Korean National Health Insurance discharge claim data obtained from January to June in 2017, 2018, 2019, and 2020. Patients' in-hospital deaths were classified according to the most responsible diagnosis categories. The HSMR is calculated as the ratio of expected deaths to actual deaths. The time trend in the overall HSMR was analyzed by region and hospital type. RESULTS: The final analysis included 2 252 824 patients. In 2020, the HSMR increased nationwide (HSMR, 99.3; 95% confidence interval [CI], 97.7 to 101.0) in comparison to 2019 (HSMR, 97.3; 95% CI, 95.8 to 98.8). In the COVID-19 pandemic zone, the HSMR increased significantly in 2020 (HSMR, 112.7; 95% CI, 107.0 to 118.7) compared to 2019 (HSMR, 101.7; 95% CI, 96.9 to 106.6). The HSMR in all general hospitals increased significantly in 2020 (HSMR, 106.4; 95% CI, 104.3 to 108.5) compared to 2019 (HSMR, 100.3; 95% CI, 98.4 to 102.2). Hospitals participating in the COVID-19 response had a lower HSMR (HSMR, 95.6; 95% CI, 93.9 to 97.4) than hospitals not participating in the COVID-19 response (HSMR, 124.3; 95% CI, 119.3 to 129.4). CONCLUSIONS: This study suggests that the COVID-19 pandemic may have negatively impacted the quality of care in hospitals, especially general hospitals with relatively few beds. In light of the COVID-19 pandemic, it is necessary to prevent excessive workloads in hospitals and to properly employ and coordinate the workforce.

Aging gene signature of IL-7 receptor alpha low effector memory CD8+ T cells is associated with neurocognitive functioning in Alzheimer's disease.

CD45RA+ effector memory (EM) CD8+ T cell expansion was reported in Alzheimer's disease (AD). Such cells are IL-7 receptor alpha (IL-7Rα)low EM CD8+ T cells, which expand with age and have a unique aging gene signature (i.e., IL-7Rαlow aging genes). Here we investigated whether IL-7Rαlow aging genes and previously reported AD and memory (ADM) genes overlapped with clinical significance in AD patients. RT-qPCR analysis of 40 genes, including 29 ADM, 9 top IL-7Ralow aging and 2 control genes, showed 8 differentially expressed genes between AD and cognitively normal groups; five (62.5%) of which were top IL-7Rαlow aging genes. Over-representation analysis revealed that these genes were highly present in molecular and biological pathways associated with AD. Distinct expression levels of these genes were associated with neuropsychological testing performance in 3 subgroups of dementia participants. Our findings support the possible implication of the IL-7Rαlow aging gene signature with AD.