PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, but Functional in Patients with COVID-19.

Memory T cell responses have been demonstrated in COVID-19 convalescents, but ex vivo phenotypes of SARS-CoV-2-specific T cells have been unclear. We detected SARS-CoV-2-specific CD8+ T cells by MHC class I multimer staining and examined their phenotypes and functions in acute and convalescent COVID-19. Multimer+ cells exhibited early differentiated effector-memory phenotypes in the early convalescent phase. The frequency of stem-like memory cells was increased among multimer+ cells in the late convalescent phase. Cytokine secretion assays combined with MHC class I multimer staining revealed that the proportion of interferon-γ (IFN-γ)-producing cells was significantly lower among SARS-CoV-2-specific CD8+ T cells than those specific to influenza A virus. Importantly, the proportion of IFN-γ-producing cells was higher in PD-1+ cells than PD-1- cells among multimer+ cells, indicating that PD-1-expressing, SARS-CoV-2-specific CD8+ T cells are not exhausted, but functional. Our current findings provide information for understanding of SARS-CoV-2-specific CD8+ T cells elicited by infection or vaccination.

Sex differences in the relationship between platelet count and type 2 diabetes risk in community-dwelling adults: Longitudinal findings over 14 years.

AIMS: Emerging evidence suggests that platelet count predicts the development of type 2 diabetes; however, there is conflicting evidence concerning the relationship in men and women. This study aimed to assess the longitudinal association between platelet count and the incidence risk of type 2 diabetes. MATERIALS AND METHODS: Among 10,030 participants, 7325 participants (3439 men and 3886 women) without diabetes were selected from the Korean Genome and Epidemiology Study. Platelet count quartiles were divided as follows: Q1 ≤219, Q2, 220-254, Q3, 255-296 and Q4 ≥297 (x103 /ml) for men and ≤232, 233-266, 267-305 and ≥306 (x103 /µL) for women. The hazard ratios (HRs) with 95% confidential intervals (CIs) for incident type 2 diabetes were calculated using multiple Cox proportional hazards regression models according to sex-specific platelet count quartiles. RESULTS: During the biennial follow-up period from 2001 to 2002 to 2013-2014, 750 male participants (21.8%, 750/3439) and 730 female participants (18.8%, 730/3886) had newly developed type 2 diabetes. For women, compared to the reference first quartile, the HRs for incident type 2 diabetes in the second, third, and fourth platelet count quartiles were 1.20 (0.96-1.50), 1.21(0.97-1.51), and 1.47 (1.18-1.82) after adjusting for age, body mass index, smoking status, alcohol intake, physical activity, mean arterial blood pressure, family history of diabetes, and HOMA-IR. However, these positive relationships were not observed in men after adjusting for the same co-variables. CONCLUSIONS: Platelet count was independently associated with an increased risk of incident type 2 diabetes only in women.

Fatty liver index as a predictor for incident type 2 diabetes in community-dwelling adults: longitudinal findings over 12 years.

BACKGROUND: Diagnosing fatty liver and identifying disease status are important for fatty liver related-diseases prevention. The fatty liver index (FLI), which can be easily available in clinical practice, can be very useful for managing fatty liver and preventing related diseases. No large-scale and long-term follow-up prospective studies have investigated the relationship between FLI and incident type 2 diabetes (T2DM) independent of baseline insulin resistance status. Therefore, this study aimed to evaluate the association between FLI and incident T2DM and to determine whether FLI could be used as an indicator of T2DM using a large-sample, community-based Korean cohort over 12 years. METHODS: Among the 10,030 total participants, 7,777 (3,676 men and 4,101 women) without diabetes were selected from the Korean Genome and Epidemiology Study (KoGES). FLI grade, which ranged from 0 to 100, was categorized into three groups: low, FLI (< 30); intermediate, FLI (30-59); and high, FLI (≥ 60). The hazard ratios (HRs) with 95% confidence intervals (CIs) for incident T2DM were calculated using multivariate Cox proportional hazards regression models after adjusting for potentially confounding variables. RESULTS: In total, 1,490 individuals (19.2%) developed T2DM during follow-up. Compared to the reference FLI (< 30), the HRs of incident T2DM for the FLI (30-59), and FLI (≥ 60) increased after adjusting for potentially confounding variables, including the HOMA-IR marker. CONCLUSIONS: FLI grade at baseline could be a future indicator of T2DM even when prior glucose or insulin (HOMA-IR) levels are normal.

Long-Term Adverse Effects of Cigarette Smoking on the Incidence Risk of Metabolic Syndrome With a Dose-Response Relationship: Longitudinal Findings of the Korean Genome and Epidemiology Study Over 12 Years.

OBJECTIVE: To investigate the association between the intensity and cumulative dose of cigarette smoking and incidence risk of metabolic syndrome (MetS) in a longitudinal prospective study over 12 years of follow-up. METHODS: This study included 3151 men aged 40 to 69 years from the Korean Genome and Epidemiology Study. MetS was defined as proposed by the Joint Interim Statement of the Circulation 2009 report. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incidence risk of MetS were calculated from 2 separate perspectives: (1) number of cigarettes smoked per day (intensity) and (2) total number of cigarettes smoked over a person's lifetime (cumulative dose) using multiple logistic regression analyses. RESULTS: In comparison with never smokers, the HRs (95% CIs) were 0.97 (0.78-1.21) for former smokers and 1.50 (1.07-2.01) with 0 to 9 cigarettes per day, 1.66 (1.34-2.06) with 10 to 19 cigarettes per day, and 1.75 (1.34-2.29) with ≥20 cigarettes per day for current smokers after adjusting for confounding variables. Similar positive dose-response relationships were also observed when the cumulative dose of cigarette smoking was categorized into former and current smokers, with subcategories of <20 and >20 pack-years (PYs). The HRs (95% CIs) were 0.99 (0.77-1.23) for <20 PYs and 0.99 (0.77-1.28) for ≥20 PYs for former smokers and 1.63 (1.32-2.02) for <20 PYs and 1.67 (1.30-2.14) for ≥20 PYs for current smokers after adjusting for the same covariables. CONCLUSION: Cigarette smoking intensity and cumulative dose were both found to be positively associated with the incidence risk of MetS in men.

Serum γ-glutamyltransferase level and incidence risk of metabolic syndrome in community dwelling adults: longitudinal findings over 12 years.

PURPOSE: Although a recent meta-analysis demonstrated a positive association between serum γ-glutamyltransferase (GGT) and metabolic syndrome (MetS), sex differences in the relationship between GGT levels and MetS risk were not fully considered. We prospectively examined the relationship between serum GGT levels and incidence risk of MetS. METHODS: Data were collected from the Korean Genome and Epidemiology Study (KoGES) enrolled in 2001-2002. Among 10,030 total participants, 5960 adults (3130 men and 2830 women) aged 40-69 without MetS were included and divided according to sex-specific quartiles of baseline serum GGT levels and followed up biennially until 2014. The hazard ratios (HRs) with 95% confidence intervals (CIs) for incident MetS were prospectively analyzed using multiple Cox proportional hazards regression analysis models. RESULTS: Among 5960 participants, 1215 males (38.8%) and 1263 females (44.6%) developed MetS during 12-year follow up. Higher quartiles of GGT showed significantly higher cumulative incidence of MetS in both sexes (log-rank test P < 0.001). The HRs (95% CIs) for incident type 2 diabetes for the highest quartile versus referent lowest quartile for serum GGT levels were 3.01 (2.35-3.76) for men and 1.83 (1.30-2.57) for women after adjusting for age, smoking status, daily alcohol intake (g/day), regular exercise, family history of diabetes, and log-transformed LDL-cholesterol, creatinine, and aminotransferase levels. CONCLUSION: In conclusion, high levels of GGT were found to be associated with increased risk of Mets in both men and women and the positive associations were stronger in men than in women.

KIR+CD8+ and NKG2A+CD8+ T cells are distinct innate-like populations in humans.

Subsets of the human CD8+ T cell population express inhibitory NK cell receptors, such as killer immunoglobulin-like receptors (KIRs) and NKG2A. In the present study, we examine the phenotypic and functional characteristics of KIR+CD8+ T cells and NKG2A+CD8+ T cells. KIRs and NKG2A tend to be expressed by human CD8+ T cells in a mutually exclusive manner. In addition, TCR clonotypes of KIR+CD8+ T cells barely overlap with those of NKG2A+CD8+ T cells, and KIR+CD8+ T cells are more terminally differentiated and replicative senescent than NKG2A+CD8+ T cells. Among cytokine receptors, IL12Rß1, IL12Rß2, and IL18Rß are highly expressed by NKG2A+CD8+ T cells, whereas IL2Rß is expressed by KIR+CD8+ T cells. IL-12/IL-18-induced production of IFN-γ is prominent in NKG2A+CD8+ T cells, whereas IL-15-induced NK-like cytotoxicity is prominent in KIR+CD8+ T cells. These findings suggest that KIR+CD8+ and NKG2A+CD8+ T cells are distinct innate-like populations with different cytokine responsiveness.

Usefulness of Complete Blood Count (CBC) to Assess Cardiovascular and Metabolic Diseases in Clinical Settings: A Comprehensive Literature Review.

Complete blood count (CBC) is one of the most common blood tests requested by clinicians and evaluates the total numbers and characteristics of cell components in the blood. Recently, many investigations have suggested that the risk of cancer, cardiovascular disease (CVD), arteriosclerosis, type 2 diabetes (T2DM), and metabolic syndrome can be predicted using CBC components. This review introduces that white blood cell (WBC), neutrophil-to-lymphocyte ratio (NLR), hemoglobin (Hb), mean corpuscular volume (MCV), red cell distribution width (RDW), platelet count, mean platelet volume (MPV), and platelet-to-lymphocyte ratio (PLR) are useful markers to predict CVD and metabolic diseases. Furthermore, we would like to support various uses of CBC by organizing pathophysiology that can explain the relationship between CBC components and diseases.

Non-HDL cholesterol as a predictor for incident type 2 diabetes in community-dwelling adults: longitudinal findings over 12 years.

Non-HDL cholesterol is a simple measure to analyze the total amount of proatherogenic lipoproteins in the blood and to predict development of cardiovascular disease. However, it is unclear whether non-HDL cholesterol has a relationship with incident type 2 diabetes. This study aimed to evaluate the association between non-HDL cholesterol and incident type 2 diabetes with a large-sample, community-based Korean cohort over a 12-year period. Among the 10,038 total participants, 7608 (3662 men and 3946 women) without diabetes were selected from the Korean Genome and Epidemiology Study (KoGES). Their non-HDL cholesterol level was divided into quartiles. The hazard ratios (HRs) with 95% confidence intervals (CIs) for incident type 2 diabetes were calculated using multivariate Cox proportional hazards regression models after adjusting for potentially confounding variables. In total, 1442 individuals (18.9%: 1442 of 7608) developed type 2 diabetes during the 12-year follow up period, with an incident rate of 3.0-5.0. Compared to the reference first quartile, the HRs (95% CIs) of incident type 2 diabetes for the second, third, and fourth quartiles increased in a dose-response manner after adjusting for potentially confounding variables, including the HOMA-IR marker. Non-HDL cholesterol level at baseline could be a future predictor of type 2 diabetes even when prior glucose or insulin (HOMA-IR) levels are normal.

Increase of Vδ2+ T Cells That Robustly Produce IL-17A in Advanced Abdominal Aortic Aneurysm Tissues.

Abdominal aortic aneurysm (AAA) is a chronic dilation of the aorta with a tendency to enlarge and eventually rupture, which constitutes a major cause of cardiovascular mortality. Although T-cell infiltrates have been observed in AAA, the cellular, phenotypic, and functional characteristics of these tissue-infiltrating T cells are not fully understood. Here, we investigated the proportional changes of T-cell subsets-including CD4+ T cells, CD8+ T cells, and γδ T cells-and their effector functions in AAAs. We found that Vδ2+ T cells were presented at a higher frequency in aortic aneurysmal tissue compared to normal aortic tissue and PBMCs from patients with AAA. In contrast, no differences were observed in the frequencies of CD4+, CD8+, and Vδ1+ T cells. Moreover, we observed that the Vδ2+ T cells from AAA tissue displayed immunophenotypes indicative of CCR5+ non-exhausted effector memory cells, with a decreased proportion of CD16+ cells. Finally, we found that these Vδ2+ T cells were the main source of IL-17A in abdominal aortic aneurysmal tissue. In conclusion, our results suggest that increased Vδ2+ T cells that robustly produce IL-17A in aortic aneurysmal tissue may contribute to AAA pathogenesis and progression.

IL-15 enhances CCR5-mediated migration of memory CD8+ T cells by upregulating CCR5 expression in the absence of TCR stimulation.

During microbial infection, bystander CD8+ T cells that are not specific to infecting pathogens can be activated by interleukin (IL)-15. However, the tissue-homing properties of bystander-activated CD8+ T cells have not been elucidated. Here, we examine the effects of IL-15 on the expression of chemokine receptors on CD8+ T cells and their migration. IL-15 upregulates CCR5 in memory CD8+ T cells in the absence of T cell receptor (TCR) stimulation and enhances CCR5-dependent migration. IL-15-induced CCR5 upregulation is abrogated by TCR stimulation, indicating that CCR5 is upregulated in bystander-activated CD8+ T cells. Moreover, CCR5 signals increase proliferation and cytotoxic protein expression in IL-15-treated memory CD8+ T cells, although the increase has a small extent. CCR5 upregulation in bystander-activated CD8+ T cells is associated with severe liver injury in patients with acute hepatitis A. Altogether, the results indicate that CCR5 upregulation by IL-15 mediates the migration of bystander-activated CD8+ T cells.

Dynamic changes in circulating PD-1+CD8+ T lymphocytes for predicting treatment response to PD-1 blockade in patients with non-small-cell lung cancer.

BACKGROUND: The predictive value of immune monitoring with circulating CD8+ T lymphocytes for treatment response to programmed cell death protein 1 (PD-1) inhibitors has not been explored in non-small-cell lung cancer (NSCLC), prompting us to investigate whether dynamic changes in PD-1+CD8+ T lymphocytes have predictive value for durable clinical benefit (DCB) and survival after PD-1 blockade. METHODS: Patients with recurrent and/or metastatic NSCLC treated with PD-1 inhibitors were enrolled (discovery cohort; n = 94). Peripheral blood was obtained immediately before and after one cycle of treatment with PD-1 blockade. Phenotyping of circulating CD8+ T lymphocytes was conducted using multi-colour flow cytometry. Predictive values of dynamic changes in circulating PD-1+CD8+ T lymphocytes during the first cycle were validated in an independent cohort (validation cohort; n = 54) of a prospective trial with a PD-1 inhibitor (NCT03486119). RESULTS: Circulating PD-1+CD8+ T lymphocytes were enriched with effector/memory populations with elevated expression of activation- and exhaustion-related markers. Reduction in the frequency of PD-1+ cells among CD8+ T lymphocytes after one cycle of treatment was associated with a higher probability of DCB and superior survival outcomes in the discovery cohort. Similar results were obtained in the analysis of tumour antigen NY-ESO-1-specific CD8+ T lymphocytes and the validation cohort. Mechanistically, PD-1 molecule expression on CD8+ T lymphocytes suppresses the effector functions of tumour antigen-specific CD8+ T lymphocytes. CONCLUSIONS: Dynamic changes in circulating PD-1+CD8+ T lymphocytes predict clinical, and survival benefit from PD-1 blockade treatment in NSCLC, providing a useful tool to identify patient subgroups who will optimally benefit from PD-1 inhibitors.

PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFß Inhibitors.

PURPOSE: Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, anti-programmed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma. EXPERIMENTAL DESIGN: Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8+ T cells and their functional restoration by ex vivo treatment with anti-PD-1 and TGFß inhibitors. RESULTS: We confirmed the upregulation of PD-1 and PD-L1 expression in CD8+ T cells and myeloma cells, respectively, from the BM of multiple myeloma patients. PD-1-expressing CD8+ T cells from the BM of multiple myeloma patients coexpressed other checkpoint inhibitory receptors and exhibited a terminally differentiated phenotype. These results were also observed in BM CD8+ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM CD8+ T cells from multiple myeloma patients exhibited reduced proliferation and cytokine production upon T-cell receptor stimulation. However, anti-PD-1 did not increase the proliferation of BM CD8+ T cells from multiple myeloma patients, indicating that T-cell exhaustion in multiple myeloma is hardly reversed by PD-1 blockade alone. Intriguingly, anti-PD-1 significantly increased the proliferation of BM CD8+ T cells from multiple myeloma patients in the presence of inhibitors of TGFß, which was overexpressed by myeloma cells. CONCLUSIONS: Our findings indicate that combined blockade of PD-1 and TGFß may be useful for the treatment of multiple myeloma.

Inverse Relationship between Hepatic Steatosis and Alanine Aminotransferase with Sex Hormone-Binding Globulin in Men.

PURPOSE: Sex hormone-binding globulin (SHBG) is a serum glycoprotein produced predominantly in hepatocytes. As such, the synthesis of SHBG could be associated with liver function and metabolic syndrome. Alanine aminotransferase (ALT) levels could reflect hepatocellular injury and insulin resistance; however, the relationship between hepatic steatosis and ALT with SHBG has not been investigated in humans. The objective of this study was to investigate the associations between SHBG and hepatocyte damage among Korean male patients with hepatic steatosis enrolled in a health examination program. MATERIALS AND METHODS: We performed a retrospective cross-sectional study with 922 participants who underwent routine health examinations. A total of 922 men with or without hepatic steatosis were divided into three groups. We analyzed the risk of lower serum SHBG levels with or without elevated serum ALT levels using odds ratios with 95% confidence intervals (CIs). RESULTS: A significantly increased risk of lower serum SHBG level was observed in the group with hepatic steatosis and ALT elevation (95% CI 1.591-4.681). CONCLUSION: In men with hepatic steatosis, we found that elevated serum ALT levels were associated with lower serum SHBG levels. This finding suggests that subjects with both hepatic steatosis and increased ALT should be considered to have low levels of SHBG.