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PubMed2026

Identification of elements determining KIR gene demethylation at the CD56-bright stage of NK cell development.

The variegated expression of the KIR family of class I MHC receptors generates specialized natural killer (NK) cells capable of allele-specific HLA recognition. Understanding the mechanism of KIR gene activation will lead to improved methods for the generation of fully functional NK cells. A central RUNX-binding site in the KIR proximal promoter is required for gene activation. RUNX proteins recruit ten-eleven translocation (TET) proteins that generate 5-hydroxymethylcytosine (5hmC) and drive DNA demethylation. Assessment of 5-methylcytosine (5mC) and 5hmC residues at four stages of NK cell development reveals deposition of 5hmC primarily in a CREB site next to the RUNX site at the CD56Bright stage but not the subsequent CD56Dim stage representing fully mature NK cells. KIR promoter demethylation is delayed relative to other lineage-associated genes, indicating a high threshold for KIR gene demethylation in developing NK cells, and a window of opportunity for RUNX/TET-dependent KIR gene activation in CD56Bright NK cells.

6-base sequencing↗
PubMed2026

Dynamic effects of short-term storage temperature and duration on the transcriptome and functional pathways of umbilical cord blood-derived NK cells.

OBJECTIVE: This study aims to elucidate the dynamic impact of different storage conditions (temperature and time) on the function of natural killer (NK) cells derived from umbilical cord blood (UCB) at the transcriptome level, providing a theoretical basis for optimizing the standardized post-collection processing protocol of UCB in clinical settings. METHODS: Four healthy full-term UCB samples were collected and assigned to a fresh control group (0H) and experimental groups stored at 4 °C (4C) or 25 °C (RT) for 24 h (24H) and 72 h (72H). Umbilical cord blood mononuclear cells (CBMCs) were isolated and expanded in vitro to derive NK cells. Using RNA sequencing (RNA-seq) technology, combined with principal component analysis (PCA), screening of differentially expressed genes (DEGs), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, the effects of storage conditions on the transcriptome of NK cells were comprehensively analyzed. RESULTS: The results indicated that storage time was the primary factor causing transcriptomic differences. Compared to the 0H group, storage for 24 h induced a limited number of Differentially Expressed Genes (DEGs) (only 11 in the 24H-RT group), indicating overall transcriptome stability. In contrast, storage for 72 h triggered profound transcriptomic reprogramming, with DEGs significantly enriched in immune activation-related pathways. Specifically, at the 72-h time point, storage at 4 °C compared to 25 °C prevented the downregulation of key metabolic pathways such as 'response to decreased oxygen levels' and 'regulation of leukocyte cell-cell adhesion'. CONCLUSION: CBMC-derived NK cells can tolerate up to 24 h of ex vivo storage while maintaining transcriptome and core functional stability. However, extending the ex vivo storage period to 72 h leads to significant reprogramming in the expression of immune and metabolism-related genes. Notably, the degree of metabolic suppression under refrigerated conditions at 4 °C was less pronounced than that at 25 °C room temperature storage. This study recommends that the ex vivo storage time of UCB should ideally be limited to within 24 h, with room temperature storage being a viable option. If prolonged storage is necessary, refrigeration at 4 °C is advised.

Humans↗
PubMed1978

Characterization of the human natural killer (NK) cell in blood and lymphoid organs.

The human natural killer (NK) cell in peripheral blood is a non-thymus-dependent, (Fc+ C3-), Ig-bearing lymphocyte and is probably identical to the human K cell, although not requiring the Fc receptor, in contrast to the K cell, for the lytic process. The human NK cell in tonsil and lymph node, on the other hand, is a non-Ig- bearing T lymphocyte, lacking both Fc and C3 receptors.

Cell Migration Inhibition↗
PubMed1978

Mouse natural killer (NK) cell activity against human cell lines is not influenced by superinfection of the target cell with xenotropic murine C-type virus.

Mouse natural killer (NK) cells can lyse a variety of syngeneic, allogeneic and xenogeneic target cells in short-term 51Cr release assays. The target specificity of NK cells is not known, but endogenous C-type viral antigens have been suggested as possible target structures. To test this hypothesis, human lymphoid lines were superinfected with xenotropic mouse C-type virus either by repeated dosage through nude mice or by in vitro superinfection with the supernatants of nude-mouse-passaged lines. The appearance of surface-associated MuLV antigens after superinfection was confirmed in a complement-dependent cytotoxicity test. Subsequently, the NK sensitivity of each infected line was compared with its non-infected counterpart in direct cytolytic and competition assays. None of these two assay systems showed a consistent difference in NK sensitivity of infected and non-infected cell lines. These findings do not lend support to the concept tht murine C-type viral antigens are responsible for NK sensitivity.

Animals↗
PubMed1979

Cytotoxicity against the K562 erythroleukemia cell line by human natural killer (NK) cells which do not bear free Fc receptors for IgG.

When Fc receptors (FcR) on normal human peripheral blood lymphocytes were induced to modulate by overnight (18 h) incubation in the presence of soluble or particulate immune complexes, the natural killer (NK) activity of the effector lymphocyte suspension, as measured against the K562 erythroleukemia cell line, was significantly, but only partially, inhibited. The NK activity which remained was always strong, and was not significantly inhibited by inclusion of antigen-antibody complexes in the cytotoxicity assay, nor was it further depleted by adsorbing the modulated cells on plastic surfaces coated with immobilized antigen-antibody complexes. Antibody-dependent cell-mediated cytotoxicity (ADCC) against rabbit antibody-sensitized Chang liver cells was totally abrogated following the modulation process, and could not be restored by exposure of modulated effector cells to trypsin, indicating that the FcR had actually been shed and were not merely being blocked with immune complexes. Although freshly isolated peripheral blood lymphocytes active in natural (or "spontaneous") cytotoxicity have been shown to bear FcR, our data indicate that NK activity against the K562 cell line can be effectively mediated by NK cells which have lost their FcR. This supports the concept that NK activity against K562 is independent of FcR, and, therefore, of IgG.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1979

Macrophage-dependent, NK-cell-independent "natural" surveillance of tumors in syngeneic mice.

The present study, which was designed to further characterize the "natural" T-independent rejection of syngenetic tumours (Greenberg and Greene, 1976), has revealed the following points: (1) no detectable DBA/2 NK cell activity was demonstrated against the syngeneic tumour lines studied, and these tumours were indensitive to NK cells from high-activity strains; (2) in addition the tumour frequencies in old and young mice receiving small tumour inocula were identical, in contrast with the reported decline in NK cell activity with age, suggesting that the surveillance of small inocula of these tumours was NK-cell-independent; (3) injection of silica intraperitoneally enhanced the frequency of tumours in normal and immunodeficient AT x BM mice, suggesting that the rejection mechanism was macrophage-dependent; (4) the effects of silica injection were maximal if administered 3 days prior to tumour injection, indicating that the period of time in which the rejection mechanism must act was very limited; (5) silica markedly decreased the survival of AKR mice dying of spontaneous tumours, providing evidence that the effect of this agent was not limited to model systems but would influence the appearance of spontaneous tumours; (6) reticuloendothelial stimulants such as mycobacterium butyricum and proteose peptone decreased the tumour frequency of small tumour inocula, indicating that the effector mechanism can be stimulated; and (7) soluble tumour antigen enhanced the tumour frequency in normal and immunodeficient mice, suggesting that the specific receptor molecule of the surveillance mechanism was not thymus-dependent.

Animals↗
PubMed2026

A novel FLNA p.Pro2469Ser variant is associated with impaired T and NK cell function and immune dysregulation.

FLNA encodes filamin A, a ubiquitously expressed actin-binding cytoskeletal protein that cross-links actin filaments and links them to membrane-associated signaling complexes. Although FLNA has been implicated in T-cell signaling and regulatory T-cell development in murine models, its role in human immune-cell function remains incompletely understood. Here, we investigated the immunological phenotype associated with a novel hemizygous FLNA variant identified in a pediatric patient presenting with recurrent infections and inflammatory manifestations. Whole-exome sequencing revealed a hemizygous c.7405C>T (p.Pro2469Ser) variant in FLNA, which was confirmed by Sanger sequencing. Its potential impact on immune-cell function and cytoskeletal organization was evaluated using confocal microscopy, flow cytometry, and molecular assays. Patient-derived T cells showed impaired activation and proliferation following CD3/CD28 and IL-2 stimulation, accompanied by reduced CD25 and CD69 upregulation. CD4+ T cells also exhibited reduced IFN-γ, TNF-α, and IL-2 production after stimulation. Despite elevated basal phospho-STAT5 levels, IL-2-induced STAT5 phosphorylation and TCR-associated signaling responses, including pZAP70, pLCK, and p38 MAPK activation, were attenuated. Confocal imaging together with image-based quantification demonstrated altered cortical cytoskeletal organization in patient T cells despite preserved FLNA expression. In parallel, NK cells showed impaired activation responses and reduced cytotoxic activity under the assay conditions used. Increased apoptosis was observed in CD4⁺, CD8⁺, and NK-cell populations. Inflammatory cytokines were elevated in plasma and colonic tissue, whereas colonic ZO-1 and FLNA expression were reduced. Collectively, these findings indicate that the FLNA p.Pro2469Ser variant is associated with altered immune-cell signaling, disturbed cortical cytoskeletal organization, and immune dysregulation. This study expands the phenotypic spectrum linked to FLNA variants and supports a role for filamin A in human immune-cell regulation.

Humans↗
PubMed1979

Human natural killer cell activity is augmented by interferon via recruitment of 'pre-NK' cells.

Contact with various cell-line targets increases the natural killer (NK) activity of human lymphocytes. Supernatants of such 20 h co-cultures augment the NK activity of virgin lymphocyte populations, and the augmenting factor penetrates 0.2 micrometer Millipore filters. The supernatants also contain interferon, and partially purified human leucocyte interferon increases NK activity when added to 20 h assays with 51Cr-labelled K-562 target cells. Potent anti-interferon antiserum added to the co-cultures inhibits the target-cell-induced augmentation phenomenon. Both the target-cell contact and interferon-induced augmentation affect a population of human lymphocytes, from which the 'mature' NK cells have been removed by adsorption-elution using fetal fibroblasts as adsorbents. The activity of 'mature' NK cells is not enhanced, and we conclude that the augmentation is mediated by recruitment of 'pre-NK' cells.

Adsorption↗
PubMed1978

Natural cell-mediated cytotoxicity in rats. II. In vivo augmentation of NK-cell activity.

Natural cell-mediated cytotoxicity in rats as well as in mice has been shown to vary consistently with age, with peak levels detectable at 5-10 weeks. The levels of cell-mediated cytotoxicity against tumor cells could be augmented in strains of inbred rats with either high or low levels of natural reactivity, by IP injection of a variety of agents, including C. parvum, LCMV, KRV, and poly I:C. The specificity of the augmented cytotoxicity appeared to be the same as the specificity of natural killer cells which are found in normal rat spleen cells. Similarly, the cells mediating the augmented cellular cytotoxicity were small, non-adherent, esterase-negative lymphocytes with Fc receptors, as are rat NK cells. The kinetics and organ distribution of the augmentation of NK activity by poly I:C and C. parvum were compared and the kinetics were found to differ, with a shorter time course of augmented activity seen after inoculation with poly I:C. These data indicate that interferon may play a central role in the augmentation of NK activity in vivo.

Animals↗
PubMed1979

Characteristics and genetic control of NK-cell-mediated cytotoxicity activated by naturally acquired infection in the mouse.

Most and perhaps all natural-cell-mediated cytotoxicity (NCMC) may be activated by a response to exogenous infections. Specific-pathogen-free (SPF) mice have little or no natural killer (NK) cell activity, but when they are relocated in conventional conditions, they develop strong NCMC within 2 to 3 days. Unlike other SPF animals, hypothymic nude mice display good NCMC which is further augmented upon their entry into a pathogenic environment. The ontogeny, genetic control and other features of pathogen-activated NCMC resemble those previously described for NK cells. An H2-D region NCMC regulatory gene is active in either a homozygous or heterozygous state, but to be operative seems to require the presence of an additional complementing locus, which maps outside the H-2 complex. It is proposed that H-2 influences NCMC levels by affecting the expression or immunogenicity of NK cell-activating determinants. Recently activated NK cells were non-adherent and lacked Ia and Thy-1 determinants. NCMC was not affected by treatment with monoclonal high-titer Thy-1.2 antisera and complement. However, an Ly-6.2 antiserum did contain anti-NK cytotoxic activity, which was shown by absorption analysis to be distinct from anti-Ly-6.2 activity. The NK antigen has a strain distribution pattern distinct from Ly-5 and other Ly markers, but may be related or identical to NK-1.

Animals↗
PubMed2026

ZBTB16-associated NK cell alterations reveal shared immunometabolic signatures linking primary Sjögren's syndrome and type 1 diabetes mellitus.

BACKGROUND: Primary Sjögren's syndrome (pSS) and type 1 diabetes mellitus (T1DM) share immune-inflammatory features, yet conserved pathogenic signatures linking these autoimmune disorders remain incompletely understood. The present research sought to uncover common molecular markers and dissect the underlying immune-metabolic cross-talk underlying pSS and T1DM. METHODS: Gene expression profiles of patients with pSS and T1DM were retrieved from the Gene Expression Omnibus database, normalized, and corrected for batch effects prior to downstream analyses. Overlapping potential biomarkers were screened by integrating differential expression analysis, weighted gene co-expression network analysis and least absolute shrinkage and selection operator regression. Functional enrichment based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases was implemented to interpret gene biological properties, and a protein-protein interaction network was further established afterwards. Diagnostic performance was evaluated using receiver operating characteristic analysis. Experimental validation was conducted in non-obese diabetic (NOD) mice using quantitative PCR, immunohistochemistry, and flow cytometry. The CIBERSORT algorithm was adopted to quantify immune cell infiltration levels. RESULTS: ZBTB16 was identified as a shared hub biomarker in both pSS and T1DM and exhibited favorable diagnostic performance. Experimental validation confirmed significantly reduced ZBTB16 expression in peripheral blood mononuclear cells, salivary gland tissues, and pancreatic tissues of NOD mice. Gene Set Enrichment Analysis indicated that ZBTB16-associated signatures were enriched in mitochondrial-related processes, neuroactive ligand-receptor interactions, and ribosome-related pathways. Immune infiltration analysis revealed that resting natural killer (NK) cells were positively correlated with ZBTB16 expression in both diseases. Flow cytometric analysis further confirmed a reduced proportion of resting NK cells in peripheral blood of NOD mice, consistent with the CIBERSORT-based prediction. CONCLUSION: This study identifies ZBTB16 as a shared biomarker linking pSS and T1DM. Reduced resting NK-cell abundance was consistently observed in both computational and experimental analyses, and bioinformatic correlation analysis suggested a positive association with ZBTB16 expression. These findings provide evidence for shared molecular and immunological signatures underlying the two autoimmune disorders and support further investigation of the biological role and diagnostic value of ZBTB16 in pSS and T1DM.

Sjogren's Syndrome↗
PubMed1979

In vitro stimulation of natural killer (NK) cells by soluble factor(s) generated in antigen-stimulated rhesus monkey peripheral blood lymphocyte cultures.

Peripheral blood lymphocytes from rhesus monkeys (Macaca mulatta) sensitized to keyhole limpet hemocyanin (KLH), when stimulated in vitro with KLH, developed natural killer (NK) cell activity that was assayed with Rous Sarcoma virus-transformed marmoset fibroblasts as targets in a 4-hr 51Cr-release assay. The supernatant fluids from 24- to 25-hr KLH-activated cultures were capable of stimulating NK development in nonsensitive lymphocyte cultures. The effector cells were neither macrophages nor B cells (plastic and nylon-wool nonadherent) and did not form E-rosettes with neuraminidase-treated sheep red blood cells. Cultures depleted of EA-rosetting cells, i.e., Fc-receptor-bearing lymphocytes, were incapable of generating NK activity when stimulated in vitro. Kinetic studies showed that peak DNA synthesis, as measured by 3H-T incorporation, preceded maximum cytotoxicity. Elimination of dividing cells by 5-bromo-2'deoxyuridine (BrdU) and light treatment during the interval from day 1 to day 4 inhibited the development of cytotoxicity on day 7. Cell replication was required for the induction of NK cells with KLH as well as with antigen-activated culture supernatant fluids. When cultures were left unstimulated for 4 days, NK activity could not be developed subsequently either by adding antigen, mitogen (PHA), or supernatant fluids from activated cultures.

Animals↗
PubMed1978

Stimulation of human NK-cell activity by cultured cells. I. Response of normals.

Natural cell-mediated cytotoxicity, observed on co-cultivation of peripheral blood lymphocytes (PBL) with malignant melanoma tumor cells (M4), is described. The activity was inhibited when PBL were cultured in autologous serum. Studies using competitive inhibition with cold targets and stimulation of PBL with other tumor cell lines failed to detect specificity.

Cell Line↗
PubMed2026

Tripterygium Glycosides Alleviates Hemophagocytic Lymphohistiocytosis Accompanied With Aggressive NK Cell Leukemia and Epstein-Barr Virus Infection.

Hemophagocytic lymphohistiocytosis (HLH) is a group of hyperinflammatory disorders with a mortality rate exceeding 50%. We report a case of a female Asian patient who developed secondary HLH accompanied by aggressive natural killer cell leukemia and Epstein-Barr virus (EBV) infection, and was treated with tripterygium glycosides (TG), a Chinese patent medicine. Within 3 weeks of oral administration, the patient's recurrent high fever resolved, abdominal distension and splenomegaly improved, ascites diminished, serum soluble CD25 levels decreased, and hematopoietic and coagulation functions recovered. Triptolide, a major component of TG, exhibited cytotoxicity against the patient's ascitic cells and induced apoptosis in a dose-dependent manner ex vivo. Whole-genome and transcriptome sequencing of the patient's tumor cells revealed that TG regulated EBV-associated mutated genes such as PSMD7 and modulated inflammation-related pathways. Molecular docking further suggested direct targeting of PSMD7 by triptolide. Tripterygium glycosides quickly mitigated cytokine storm, alleviated symptoms of HLH, and showed no observed adverse effects with a good cost-benefit profile, thereby offering a potential bridge for follow-up hematopoietic stem cell transplantation.

Humans↗