PDGF-D−PDGFRβ signaling enhances IL-15–mediated human natural killer cell survival

The axis of platelet-derived growth factor (PDGF) and PDGF receptor-beta (PDGFRβ) plays prominent roles in cell growth and motility. In addition, PDGF-D enhances human natural killer (NK) cell effector functions when binding to the NKp44 receptor. Here, we report an additional but previously unknown role of PDGF-D, whereby it mediates interleukin-15 (IL-15)–induced human NK cell survival but not effector functions via its binding to PDGFRβ but independent of its binding to NKp44. Resting NK cells express no PDGFRβ and only a low level of PDGF-D, but both are significantly up-regulated by IL-15, via the nuclear factor κB signaling pathway, to promote cell survival in an autocrine manner. Both ectopic and IL-15–induced expression of PDGFRβ improves NK cell survival in response to treatment with PDGF-D. Our results suggest that the PDGF-D−PDGFRβ signaling pathway is a mechanism by which IL-15 selectively regulates the survival of human NK cells without modulating their effector functions.

Expression of Killer Immunoglobulin Receptor Genes among HIV-Infected Individuals with Non-AIDS Comorbidities

Combined antiretroviral therapy (cART) increased the life expectancy of people living with HIV (PLHIV) and remarkably reduced the morbidity and mortality associated with HIV infection. However, non-AIDS associated comorbidities including diabetes, hypertension, hyperlipidemia, and cardiovascular diseases (CVD) are increasingly reported among PLHIV receiving cART. Killer cell immunoglobulin receptors (KIRs) expressed on the surface of natural killer (NK) cells have been previously implicated in controlling HIV disease progression. The aim of this study is to investigate the role of KIRs in developing non-AIDS associated comorbidities among PLHIV. Demographic and behavioral data were collected from voluntary participants using a standardized questionnaire. Whole blood samples were collected for KIR genotyping. Hypertension (29.5%) and hyperlipidemia (29.5%) followed by diabetes (23.7%) and CVD (9.7%) were mainly reported among our study participants with higher rate of comorbid conditions observed among participants > 40 years old. The observed KIR frequency (OF) was ≥90% for inhibitory KIR2DL1 and KIR3DL1, activating KIR2DS4 and the pseudogene KIR2DP1 among study participants. We detected significant differences in the expression of KIR3DS4 and KIR3DL1 ( p = 0.038 ) between diabetic and nondiabetic and in the expression of KIR2DL3 between hypertensive and normotensive HIV-infected individuals ( p = 0.047 ). Moreover, KIR2DL1 and KIR2DP1 were associated with significantly reduced odds of having CVD (OR 0.08; 95% CI: 0.01-0.69; p = 0.022 ). Our study suggests the potential role of KIR in predisposition to non-AIDS comorbidities among PLHIV and underscores the need for more studies to further elucidate the role of KIRs in this population.

KIR gene content imputation from single-nucleotide polymorphisms in the Finnish population

The killer cell immunoglobulin-like receptor (KIR) gene cluster on chromosome 19 encodes cell surface glycoproteins that bind class I human leukocyte antigen (HLA) molecules as well as some other ligands. Through regulation of natural killer (NK) cell activity KIRs participate in tumour surveillance and clearing viral infections. KIR gene gene copy number variation associates with the outcome of transplantations and susceptibility to immune-mediated diseases. Inferring KIR gene content from genetic variant data is therefore desirable for immunogenetic analysis, particularly in the context of growing biobank genome data collections that rely on genotyping by microarray. Here we describe a stand-alone and freely available gene content imputation for 12 KIR genes. The models were trained using 807 Finnish biobank samples genotyped for 5900 KIR-region SNPs and analysed for KIR gene content with targeted sequencing. Cross-validation results demonstrate a high mean overall accuracy of 98.5% (95% CI [97.0–99.2]%) which compares favourably with previous methods including short-read sequencing based approaches.

Screening and Identification of Key Biomarkers in Lower Grade Glioma via Bioinformatical Analysis

Lower-grade glioma (LGG) is a common type of central nervous system tumor. Due to its complicated pathogenesis, the choice and timing of adjuvant therapy after tumor treatment are controversial. This study explored and identified potential therapeutic targets for lower-grade. The bioinformatics method was employed to identify potential biomarkers and LGG molecular mechanisms. Firstly, we selected and downloaded GSE15824, GSE50161, and GSE86574 from the GEO database, which included 40 LGG tissue and 28 normal brain tissue samples. GEO and VENN software identified of 206 codifference expressed genes (DEGs). Secondly, we applied the DAVID online software to investigate the DEG biological function and KEGG pathway enrichment, as well as to build the protein interaction visualization network through Cytoscape and STRING website. Then, the MCODE plug is used in the analysis of 22 core genes. Thirdly, the 22 core genes were analyzed with UNCLA software, of which 18 genes were associated with a worse prognosis. Fourthly, GEPIA was used to analyze the 18 selected genes, and 14 genes were found to be a significantly different expression between LGGs and normal brain tumor samples. Fifthly, hierarchical gene clustering was used to examine the 14 important gene expression differences in different histologies, as well as analysis of the KEGG pathway. Five of these genes were shown to be abundant in the natural killer cell-mediated cytokines (NKCC) and phagosome pathways. The five key genes that may be affected by the immune microenvironment play a crucial role in LGG development.

Inhibitory KIR2DL2 Receptor and HHV-8 in Classic or Endemic Kaposi Sarcoma

KIR2DL2, an inhibitory Killer cell Immunoglobulin-like Receptor (KIR), has been shown to predispose to the development of several herpesvirus-associated diseases by inhibiting the efficiency of Natural Killer (NK) cells against virus-infected cells. The aim of this observational study was to assess the prevalence of KIR2DL2 and Human Herpes Virus 8 (HHV8) in patients affected with classical and endemic Kaposi sarcoma (KS), as well as in controls. Blood samples collected from 17 Caucasian, HIV-negative, immunocompetent patients affected with classical KS (c-KS), 12 African, HIV-negative patients with endemic KS (e-KS), 83 healthy subjects and 26 psoriatic patients were processed for genotypization by PCR for two KIR alleles, such as KIR2DL2 and KIR2DL3 and analyzed for HHV-8 presence. The totality of both c-KS and e-KS patients presented HHV-8 infection, whereas HHV8 was found in 26.9% of psoriatic subjects and 19.3% of healthy subjects. KIR2DL2 was found in the 76.5% of c-KS subjects, while the receptor was found in 41.7% of the e-KS group, 34.6% of psoriatic patients and 43.4% of healthy controls (p<0.0001). A significantly higher prevalence of KIR2DL2 in c-KS patients than in all the other subjects was also confirmed comparing age-matched groups. Based on these results, the inhibitory KIR2DL2 genotype appears to be a possible cofactor which increases the risk of developing c-KS in HHV8-positive, immunocompetent subjects, while it seems less relevant in e-KS pathogenesis.

Disruption of natural killer cell homing as a biomarker in persons aging with or without HIV

Natural killer (NK) cells are critical modulators of HIV transmission and disease. While recent evidence suggests a loss of NK cell cytotoxicity during aging, a compound analysis of NK cell biology and aging in persons with HIV (PWH) is lacking. We set out to perform one of the first large comprehensive analyses of people aging with and without HIV to determine NK phenotypic changes during aging and how these changes are modulated while aging with HIV. Utilizing high-dimensional polychromatic flow cytometry we analyzed 30 immune-related proteins spanning broad functions such as trafficking, activation/inhibition, NK specific receptors, and memory/checkpoint receptors on peripheral NK cells from health donors, PWH with viral suppression, and viremic PWH. NK cell phenotypes are dynamic across the age span but are significantly altered in HIV and ART and with co-factors such as CMV. Specifically, NK cells in healthy aging show increasing levels of ⍺4β7 and decreasing CCR7 expression during aging, a phenomenon nearly perfectly reversed in PWH. These HIV-associated trafficking changes could be in part due to NK cell recruitment to HIV reservoir formation in lymphoid tissue or failed mucosal signaling in the HIV-infected gut, but regardless appear to be tight biomarkers of age-related NK cell changes.

Dynamic metabolic change of cancer cells induced by natural killer cells at single-cell level studied by label-free mass cytometry

Natural killer cell（NK cell）is an important immune cell which attracts increasing attention in cancer immunotherapy. Due to the heterogeneity of cells, individual cancer cell shows different resistance to NK cytotoxicity,...

Transcriptome Analysis of the Central Nervous System of Sea Slug (Onchidium reevesii) Exposed to Low-Frequency Noise

Low-frequency noise has become a marine pollutant that cannot be ignored, but most studies have focused on the behavioral and physiological effects on marine vertebrates, with few studies in marine mollusks. Therefore, sea slug was used in this study to investigate the effect of low-frequency noise on its physiological aspects. This experiment was designed with different low-frequency noise (0, 100, 300, and 500 Hz) and different stimulation times (0, 6, and 12 h) to measure superoxide dismutase (SOD), malondialdehyde (MDA), and catalase (CAT) activities in hemolymph and transcriptomics in the control (C) and 6 and 12 h groups (L1 and L2) with 500 Hz noise. The results showed a positive correlation between antioxidant enzyme activity and low-frequency noise frequency (P &lt; 0.05) and no correlation with time (P &gt; 0.05). In central nervous system (CNS) transcriptomics, 2,460 and 3,268 genes had upregulated expression and 2,765 and 2,783 genes had downregulated expression in the L1 and L2 groups, respectively, compared to the C group. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, low-frequency noise mainly affects signaling pathways such as cytokine-cytokine receptor interaction, the FoxO signaling pathway, natural killer cell-mediated cytotoxicity, apoptosis immune-related pathways, and energy metabolic pathways such as glycolysis, the TCA cycle, and glycerophospholipid metabolism, as well as neurological pathways such as GABAergic synapses, the synaptic vesicle cycle, amyotrophic lateral sclerosis (ALS) and other neurological pathways. This study would provide valuable reference information on the potential response of mollusks to low-frequency noise stress.