Natural Killer Cells In Type Research Articles

Metabolic Impairment of Natural Killer Cells in Type 2 Diabetes (T2D) Individuals: A Double-Edged Sword Elevating Susceptibility to Infections and Cancer

Metabolic Impairment of Natural Killer Cells in Type 2 Diabetes (T2D) Individuals: A Double-Edged Sword Elevating Susceptibility to Infections and Cancer

Identification of Immune Gene Signature Associated with T Cells and Natural Killer Cells in Type 1 Diabetes.

This study aimed to investigate the abnormal infiltration of immune cells in type 1 diabetes mellitus (T1D) and elucidate their regulatory mechanisms. Public T1D-related gene expression data were obtained from the Gene Expression Omnibus database.The GSE123658 dataset analyzed whole blood RNA-seq data from type 1 diabetic patients and healthy volunteers. The GSE110914 dataset analyzed neutrophils purified from peripheral blood of patients with symptomatic and pre-symptomatic type 1 diabetes (T1D), at risk of T1D, and healthy controls. Immune cell infiltration analysis was performed to identify abnormally infiltrating immune cells. Differentially expressed immune genes (DEIGs) in T1D samples were identified, followed by the construction of an immune gene signature (IGS) using a protein-protein interaction (PPI) network and Least absolute shrinkage and selection operator Cox regression analyses (LASSO Cox regression analyses). The regulatory mechanisms underlying IGS were explored using gene set enrichment analysis. Furthermore, expression validation, diagnostic efficacy evaluation, and upstream miRNA prediction of hub signature genes were performed. We verified the miRNA expression of the key gene colony stimulating factor 1 (CSF1) and microRNA-326 (miR-326) by reverse transcription-quantitative PCR (RT‒qPCR). The proportion of infiltrating T and natural killer (NK) cells differed between the T1D and control samples, and 207 immune genes (IGs) related to these immune cells were extracted. After differential expression, PPI, and LASSO Cox regression analyses, four signature DEIGs were identified for IGS construction: notch receptor 1 (NOTCH1), Janus kinase 3 (JAK3), tumor necrosis factor receptor superfamily member 4(TNFRSF4), and CSF1. Key pathways such as the Toll-like receptor signaling pathway were significantly activated in the high-risk group. Moreover, the upregulation of CSF1 in T1D samples was confirmed using a validation dataset, and CSF1 showed high diagnostic efficacy for T1D. Furthermore, CSF1 was targeted by miR-326.We used validated key genes in T1D patients, several of which were confirmed by RT‒qPCR. In conclusion, the identified key IGs may play an important role in T1D. CSF1 can be developed as a novel diagnostic biomarker for T1D.

T lymphocyte and monocyte subsets are dysregulated in type 1 diabetes patients with peripheral neuropathic pain

Diabetic neuropathic pain is a common and devastating complication of type 1 diabetes, but the mechanism by which it develops and persists is yet to be fully elucidated. This study utilised high-dimensional suspension mass cytometry in a pilot cohort to investigate differences in peripheral blood immunophenotypes between type 1 diabetes patients with (n ​= ​9) and without (n ​= ​9) peripheral neuropathic pain. The abundance and activation of several leukocyte subsets were investigated with unsupervised clustering approaches FlowSOM and SPADE, as well as by manual gating. Major findings included a proportional increase in CD4+ central memory T cells and an absolute increase in classical monocytes, non-classical monocytes, and mature natural killer cells in type 1 diabetes patients with pain compared to those without pain. The expression of CD27, CD127, and CD39 was upregulated on select T cell populations, and the phosphorylated form of pro-inflammatory transcription factor MK2 was upregulated across most populations. These results provide evidence that distinct immunological signatures are associated with painful neuropathy in type 1 diabetes patients. Further research may link these changes to mechanisms by which pain in type 1 diabetes is initiated and maintained, paving the way for much needed targeted treatments.

The Four-Way Stop Sign: Viruses, 12-Lipoxygenase, Islets, and Natural Killer Cells in Type 1 Diabetes Progression.

Natural killer (NK) cells represent an important effector arm against viral infection, and mounting evidence suggests that viral infection plays a role in the development of type 1 diabetes (T1D) in at least a portion of patients. NK cells recognize their target cells through a delicate balance of inhibitory and stimulatory receptors on their surface. If unbalanced, NK cells have great potential to wreak havoc in the pancreas due to the beta cell expression of the as-yet-defined NKp46 ligand through interactions with the activating NKp46 receptor found on the surface of most NK cells. Blocking interactions between NKp46 and its ligand protects mice from STZ-induced diabetes, but differential expression non-diabetic and diabetic donor samples have not been tested. Additional studies have shown that peripheral blood NK cells from human T1D patients have altered phenotypes that reduce the lytic and functional ability of the NK cells. Investigations of humanT1D pancreas tissues have indicated that the presence of NK cells may be beneficial despite their infrequent detection. In non-obese diabetic (NOD) mice, we have noted that NK cells express high levels of the proinflammatory mediator 12/15-lipoxygenase (12/15-LO), and decreased levels of stimulatory receptors. Conversely, NK cells of 12/15-LO deficient NOD mice, which are protected from diabetes development, express significantly higher levels of stimulatory receptors. Furthermore, the human NK92 cell line expresses the ALOX12 protein [human 12-lipoxygenase (12-LO), related to mouse 12/15-LO] via Western blotting. Human 12-LO is upregulated in the pancreas of both T1D and T2D human donors with insulin-containing islets, showing a link between 12-LO expression and diabetes progression. Therefore, our hypothesis is that NK cells in those susceptible to developing T1D are unable to function properly during viral infections of pancreatic beta cells due to increased 12-LO expression and activation, which contributes to increased interferon-gamma production and an imbalance in activating and inhibitory NK cell receptors, and may contribute to downstream autoimmune T cell responses. The work presented here outlines evidence from our lab, as well as published literature, supporting our hypothesis, including novel data.

The Expanding Role of Natural Killer Cells in Type 1 Diabetes and Immunotherapy.

Treatments for autoimmune diseases including type 1 diabetes (T1D) are aimed at resetting the immune system, especially its adaptive arm. The innate immune system is often ignored in the design of novel immune-based therapies. There is increasing evidence for multiple natural killer (NK) subpopulations, but their role is poorly understood in autoimmunity and likely is contributing to the controversial role reported for NKs. In this review, we will summarize NK subsets and their roles in tolerance, autoimmune diabetes, and immunotherapy.

Functional characterization of natural killer cells in type I leukocyte adhesion deficiency

AbstractIn this study, we analyzed IL-2–activated polyclonal natural killer (NK) cells derived from 2 patients affected by leukocyte adhesion deficiency type I (LAD1), an immunodeficiency characterized by mutations of the gene coding for CD18, the β subunit shared by major leukocyte integrins. We show that LAD1 NK cells express normal levels of various triggering NK receptors (and coreceptors) and that mAb-mediated engagement of these receptors results in the enhancement of both NK cytolytic activity and cytokine production. Moreover, these activating NK receptors were capable of recognizing their specific ligands on target cells. Thus, LAD1 NK cells, similarly to normal NK cells, were capable of killing most human tumor cells analyzed and produced high amounts of IFN-γ when cocultured in presence of target cells. Murine target cells represented a common exception, as they were poorly susceptible to LAD1 NK cells. Finally, LAD1 NK cells could efficiently kill or induce maturation of monocyte-derived immature dendritic cells (DCs). Altogether our present study indicates that in LAD1 patients, 3 important functions of NK cells (eg, cytotoxicity, IFN-γ production, and DC editing) are only marginally affected and provides new insight on the cooperation between activating receptors and LFA-1 in the induction of NK cell activation and function.

Altered Natural Killer Cells in Type 1 Diabetic Patients

Evidence from animal models suggests that natural killer (NK) cells can be important players in the development of type 1 diabetes, although data in humans are still sparse. We studied the frequency and activation state of blood NK cells at different stages of human type 1 diabetes, and whether genetic or phenotypic NK cell peculiarities could be associated with an early onset of diabetes. The onset period is marked by a slight reduction in blood NK cells, but these are unusually activated in some patients (gamma-interferon expression). This activation status does not correlate, however, with a particularly young age at onset. In contrast, NK cells in patients with long-standing type 1 diabetes had a markedly lower expression of p30/p46 NK-activating receptor molecules compared with those of control subjects. A slightly decreased expression of NKG2D in all type 1 diabetic patients relative to control subjects was observed, independent of the duration of disease, parallel to prior observations in the NOD mouse. Finally, type 1 diabetic patients had an increased frequency of KIR gene haplotypes that include the activating KIR2DS3 gene, with a genetic interaction between the KIR and HLA complexes. The reduced activation of NK cells in individuals with long-standing type 1 diabetes would seem to be a consequence rather than a cause, but other peculiarities may relate to type 1 diabetes pathogenesis.

Evidence that the reduced number of natural killer cells in type 1 (insulin-dependent) diabetes may be genetically determined.

Viruses may cause Type 1 (insulin-dependent) diabetes. We wondered whether the number and function of natural killer cells, which are important in anti-viral defense, are disturbed in diabetic patients. We studied 16 recently diagnosed Type 1 diabetic patients, 18 Type 1 diabetic patients diagnosed more than 15 years previously, 18 Type 2 (non-insulin-dependent) diabetic patients and 23 control subjects. We determined the number of natural killer cells (expressed as log10%) using anti-Leu 11 monoclonal antibody and the function (in log10 lytic units) concurrently using a 51Cr release assay with K562 as target cells. We found that the number of natural killer cells was reduced in Type 1 diabetes (1.01 +/- 0.04) as compared with Type 2 diabetic patients (1.16 +/- 0.04, p = 0.004) and normal control subjects (1.16 +/- 0.04, p = 0.006). To establish whether the reduced natural killer cell number is genetically determined we studied 19 identical twin pairs discordant for Type 1 diabetes; we found that even the non-diabetic co-twins had a reduced natural killer cell number (0.93 +/- 0.05, p = 0.0006) as compared with normal control subjects. Natural killer cell function was similar in all groups while natural killer activity per cell was significantly increased in the recently diagnosed diabetic patients (1.63 +/- 0.07) as compared with long-standing diabetic patients (1.26 +/- 0.26, p = 0.03) and controls subjects (1.36 +/- 0.07, p = 0.006). In conclusion the reduced number of natural killer cells in Type 1 diabetes appears to be genetically determined while their activity at diagnosis is increased.