Human CD8+ T-Cell Populations That Express Natural Killer Receptors

CD8+ T cells are activated by TCRs that recognize specific cognate Ags, while NK-cell activation is regulated by a balance between signals from germline-encoded activating and inhibitory NK receptors. Through these different processes of Ag recognition, CD8+ T cells and NK cells play distinct roles as adaptive and innate immune cells, respectively. However, some human CD8+ T cells have been found to express activating or inhibitory NK receptors. CD8+ T-cell populations expressing NK receptors straddle the innate-adaptive boundary with their innate-like features. Recent breakthrough technical advances in multi-omics analysis have enabled elucidation of the unique immunologic characteristics of these populations. However, studies have not yet fully clarified the heterogeneity and immunological characteristics of each CD8+ T-cell population expressing NK receptors. Here we aimed to review the current knowledge of various CD8+ T-cell populations expressing NK receptors, and to pave the way for delineating the landscape and identifying the various roles of these T-cell populations.

COVID-19 Vaccination Alters NK CellDynamics and Transiently Reduces HBsAg Titers Among Patients With Chronic Hepatitis B

Coronavirus disease 2019 (COVID-19) vaccination may non-specifically alter the host immune system. This study aimed to evaluate the effect of COVID-19 vaccination on hepatitis B surface Ag (HBsAg) titer and host immunity in chronic hepatitis B (CHB) patients. Consecutive 2,797 CHB patients who had serial HBsAg measurements during antiviral treatment were included in this study. Changes in the HBsAg levels after COVID-19 vaccination were analyzed. The dynamics of NK cells following COVID-19 vaccination were also examined using serial blood samples collected prospectively from 25 healthy volunteers. Vaccinated CHB patients (n=2,329) had significantly lower HBsAg levels 1–30 days post-vaccination compared to baseline (median, −21.4 IU/ml from baseline), but the levels reverted to baseline by 91–180 days (median, −3.8 IU/ml). The velocity of the HBsAg decline was transiently accelerated within 30 days after vaccination (median velocity: −0.06, −0.39, and −0.04 log 10 IU/ml/year in pre-vaccination period, days 1–30, and days 31–90, respectively). In contrast, unvaccinated patients (n=468) had no change in HBsAg levels. Flow cytometric analysis showed that the frequency of NK cells expressing NKG2A, an NK inhibitory receptor, significantly decreased within 7 days after the first dose of COVID-19 vaccine (median, −13.1% from baseline; p<0.001). The decrease in the frequency of NKG2A + NK cells was observed in the CD56dimCD16+ NK cell population regardless of type of COVID-19 vaccine. COVID-19 vaccination leads to a rapid, transient decline in HBsAg titer and a decrease in the frequency of NKG2A + NK cells.

Single-cell Transcriptome of Bronchoalveolar Lavage Fluid Reveals Dynamic Change of Macrophages During SARS-CoV-2 Infection in Ferrets

Although the profile of immune cells changes during the natural course of SARS-CoV-2 inflection in human patients, few studies have used a longitudinal approach to reveal their dynamic features. Here, we performed single-cell RNA sequencing of bronchoalveolar lavage fluid cells longitudinally obtained from SARS-CoV-2-infected ferrets. Landscape analysis of the lung immune microenvironment showed dynamic changes in cell proportions and characteristics in uninfected control, at 2 days post-infection (dpi) (early stage of SARS-CoV-2 infection with peak viral titer), and 5 dpi (resolution phase). NK cells and CD8+ T cells exhibited activated subclusters with interferon-stimulated features, which were peaked at 2 dpi. Intriguingly, macrophages were classified into 10 distinct subpopulations, and their relative proportions changed over the time. We observed prominent transcriptome changes among monocyte-derived infiltrating macrophages and differentiated M1/M2 macrophages, especially at 2 dpi. Moreover, trajectory analysis revealed gene expression changes from monocyte-derived infiltrating macrophages toward M1 or M2 macrophages and identified the distinct macrophage subpopulation that had rapidly undergone SARS-CoV-2-mediated activation of inflammatory responses. Finally, we found that different spectrums of M1 or M2 macrophages showed distinct patterns of gene modules downregulated by immune-modulatory drugs. Overall, these results elucidate fundamental aspects of the immune response dynamics provoked by SARS-CoV-2 infection.

Immunological Characteristics of Hyperprogressive Disease in Patients with Non-small Cell Lung Cancer Treated with Anti-PD-1/PD-L1 Abs

Hyperprogressive disease (HPD) is a distinct pattern of progression characterized by acceleration of tumor growth after treatment with anti-PD-1/PD-L1 Abs. However, the immunological characteristics have not been fully elucidated in patients with HPD. We prospectively recruited patients with metastatic non-small cell lung cancer treated with anti-PD-1/PD-L1 Abs between April 2015 and April 2018, and collected peripheral blood before treatment and 7-days post-treatment. HPD was defined as ≥2-fold increase in both tumor growth kinetics and tumor growth rate between pre-treatment and post-treatment.Peripheral blood mononuclear cells were analyzed by multi-color flow cytometry to phenotype the immune cells. Of 115 patients, 19 (16.5%) developed HPD, 52 experienced durable clinical benefit (DCB; partial response or stable disease ≥6 months), and 44 experienced non-hyperprogressive progression (NHPD). Patients with HPD had significantly lower progression-free survival (p<0.001) and overall survival (p<0.001). When peripheral blood immune cells were examined, the pre-treatment frequency of CD39+ cells among CD8+T cells was significantly higher in patients with HPD compared to those with NHPD, although it showed borderline significance to predict HPD. Other parameters regarding regulatory T cells or myeloid derived suppressor cells did not significantly differ among patient groups. Our findings suggest high pre-treatment frequency of CD39+ CD8+ T cells might be a characteristic of HPD. Further investigations in a larger cohort are needed to confirm our results and better delineate the immune landscape of HPD.

Immunological Characteristics of Hyperprogressive Disease in Patients with Non-small Cell Lung Cancer Treated with Anti-PD-1/PD-L1 Abs

Hyperprogressive disease (HPD) is a distinct pattern of progression characterized by acceleration of tumor growth after treatment with anti-PD-1/PD-L1 Abs. However, the immunological characteristics have not been fully elucidated in patients with HPD. We prospectively recruited patients with metastatic non-small cell lung cancer treated with anti-PD-1/PD-L1 Abs between April 2015 and April 2018, and collected peripheral blood before treatment and 7-days post-treatment. HPD was defined as ≥2-fold increase in both tumor growth kinetics and tumor growth rate between pre-treatment and post-treatment.Peripheral blood mononuclear cells were analyzed by multi-color flow cytometry to phenotype the immune cells. Of 115 patients, 19 (16.5%) developed HPD, 52 experienced durable clinical benefit (DCB; partial response or stable disease ≥6 months), and 44 experienced non-hyperprogressive progression (NHPD). Patients with HPD had significantly lower progression-free survival (p<0.001) and overall survival (p<0.001). When peripheral blood immune cells were examined, the pre-treatment frequency of CD39+ cells among CD8+T cells was significantly higher in patients with HPD compared to those with NHPD, although it showed borderline significance to predict HPD. Other parameters regarding regulatory T cells or myeloid derived suppressor cells did not significantly differ among patient groups. Our findings suggest high pre-treatment frequency of CD39+ CD8+ T cells might be a characteristic of HPD. Further investigations in a larger cohort are needed to confirm our results and better delineate the immune landscape of HPD.

A Retrospective Analysis of Characteristics of Probiotics Associated with Invasive Bacterial Infections in Children

PURPOSE: The purpose of this study was to analyze the clinical features and risk factors of invasive infections caused by Lactobacillus spp. and Saccharomyces spp., components of commercially available probiotics. METHODS: We analyzed demographic and clinical data from children ≤18 years of age with an invasive infection caused by Lactobacillus spp. or Saccharomyces spp. at the Asan Medical Center Children's Hospital from January 1998 to June 2016. Probiotic consumption data were also analyzed. RESULTS: During the study period, a total of 24 episodes of invasive infections were caused by Lactobacillus spp. (n=16) and Saccharomyces cerevisiae (n=8). Along with the increase of probiotic use (755,594 [days/1,000 patient-admission days] in 2001 to 2005, 1,444,066 in 2006 to 2010, and 6,904,736 in 2011 to 2016), the incidence of probiotic-associated invasive infection increased (R2=0.70). The median age of the patients was 1.8 years (range, 2 months to 17 years), and most of them had underlying medical conditions. The 30-day mortality rate was 20.8% (5/24), and 11 (45.8%) of these patients resulted from a severe invasive infection. We determined the risk factors for invasive infection to be: previous intensive care unit stay (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.5 to 6.1] and the presence of a central venous catheter (OR, 2.2; 95% CI, 1.2 to 4.3). CONCLUSIONS: Although the probiotic-associated invasive infections rarely occurred in children, the incidence has increased along with probiotic pressure. Judicious use of probiotics is mandatory, especially in young children with underlying medical conditions and continuous surveillance will be needed to minimize the safety concerns.

A Retrospective Analysis of Characteristics of Probiotics Associated with Invasive Bacterial Infections in Children

PURPOSE: The purpose of this study was to analyze the clinical features and risk factors of invasive infections caused by Lactobacillus spp. and Saccharomyces spp., components of commercially available probiotics. METHODS: We analyzed demographic and clinical data from children ≤18 years of age with an invasive infection caused by Lactobacillus spp. or Saccharomyces spp. at the Asan Medical Center Children's Hospital from January 1998 to June 2016. Probiotic consumption data were also analyzed. RESULTS: During the study period, a total of 24 episodes of invasive infections were caused by Lactobacillus spp. (n=16) and Saccharomyces cerevisiae (n=8). Along with the increase of probiotic use (755,594 [days/1,000 patient-admission days] in 2001 to 2005, 1,444,066 in 2006 to 2010, and 6,904,736 in 2011 to 2016), the incidence of probiotic-associated invasive infection increased (R2=0.70). The median age of the patients was 1.8 years (range, 2 months to 17 years), and most of them had underlying medical conditions. The 30-day mortality rate was 20.8% (5/24), and 11 (45.8%) of these patients resulted from a severe invasive infection. We determined the risk factors for invasive infection to be: previous intensive care unit stay (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.5 to 6.1] and the presence of a central venous catheter (OR, 2.2; 95% CI, 1.2 to 4.3). CONCLUSIONS: Although the probiotic-associated invasive infections rarely occurred in children, the incidence has increased along with probiotic pressure. Judicious use of probiotics is mandatory, especially in young children with underlying medical conditions and continuous surveillance will be needed to minimize the safety concerns.