scholarly journals T cell regulation of natural killer cells

2013 ◽  
Vol 210 (6) ◽  
pp. 1065-1068 ◽  
Author(s):  
Yann Kerdiles ◽  
Sophie Ugolini ◽  
Eric Vivier
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Cell Activity ◽  
Adaptive Immune System ◽  
Nk Cell Activity ◽  
Promising Target

In light of their role in the immune response against tumors and viruses, natural killer (NK) cells represent a promising target for immunotherapy. Before this target is reached, the various mechanisms that control NK cell activity must first be identified and understood. In the past decades, studies have identified two critical processes that prevent spontaneous NK cell–mediated autoimmune activation while maximizing the efficiency of these cells during an immune response. First is the education process, whereby NK cells adapt to their environment by sensing ligands for inhibitory and activating receptors. Second is the priming phase of NK cell activation, which arms NK cells with appropriate cytotoxic molecules during inflammation. New studies now indicate that NK cell proliferation, accumulation, and activation are also under the control of regulatory T cells that restrict availability of IL-2 released by activated CD4+ T cells. Together with other recent studies, these data highlight the importance of the adaptive immune system in the regulation of NK cell activity.

scholarly journals miR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yan Feng ◽  
Yan Li ◽  
Ying Zhang ◽  
Bo-Hao Zhang ◽  
Hui Zhao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Nk Cells ◽  
Natural Killer ◽  
Brain Ischemia ◽  
Cell Activation ◽  
Nk Cell ◽  
Cell Activity ◽  
Passive Transfer ◽  
Immune Defense ◽  
Nk Cell Activity

Abstract Background Brain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate NK cell activation and cytotoxicity after ischemic stroke. Methods Using a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia. Results We observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice. Conclusions These findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain.

Adrenal tumors provide insight into the role of cortisol in NK cell activity

2021 ◽  
Author(s):  
Andrew E. Greenstein ◽  
Mouhammed Amir Habra ◽  
Subhagya A. Wadekar ◽  
Andreas Grauer
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Phase 1 ◽  
Cell Activity ◽  
The Cancer Genome Atlas ◽  
Adrenal Tumors ◽  
Steroid Synthesis

Elevated glucocorticoid (GC) activity may limit tumor immune response and immune checkpoint inhibitor (ICI) efficacy. Adrenocortical carcinoma (ACC) provides a unique test case to assess correlates of GC activity, as approximately half of ACC patients exhibit excess GC production (GC+). ACC multi-omics were analyzed to identify molecular consequences of GC+ and assess the rationale for combining the glucocorticoid receptor (GR) antagonist relacorilant with an ICI. GC status, mRNA expression, and DNA mutation and methylation data from 71 adrenal tumors were accessed via The Cancer Genome Atlas. Expression of 858 genes differed significantly between GC- and GC+ ACC cases. KEGG pathway analysis showed higher gene expression of 3 pathways involved in steroid synthesis and secretion in GC+ cases. Fifteen pathways, most related to NK cells and other immune activity, showed lower expression. Hypomethylation was primarily observed in the steroid synthesis pathways. Tumor-infiltrating CD4+ memory (P=.003), CD8+ memory (P=.001), and NKT-cells (P=.014) were depleted in GC+ cases; tumor-associated neutrophils were enriched (P=.001). Given the pronounced differences between GC+ and GC- ACC, the effects of cortisol on NK cells were assessed in vitro (NK cells from human PBMCs stimulated with IL-2 or IL-12/15). Cortisol suppressed, and relacorilant restored, NK cell activation, proliferation, and direct tumor cell killing. Thus, GR antagonism may increase the abundance and function of NK and other immune cells in the tumor microenvironment, promoting immune response in GC+ ACC and other malignancies with GC+. This hypothesis will be tested in a phase 1 trial of relacorilant + ICI.

Thermal stresses reduce natural killer cell cytotoxicity

1995 ◽  
Vol 79 (3) ◽  
pp. 732-737 ◽  
Author(s):  
S. J. Won ◽  
M. T. Lin
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Target Cell ◽  
Nk Cell ◽  
Cell Activity ◽  
Cortisol Concentration ◽  
Target Cells ◽  
Nk Cell Activity ◽  
Colonic Temperature ◽  
Effector Target

The effects of different ambient temperatures (Ta) on the splenic natural killer (NK) cell activity, effector-target cell conjugation activity, and NK cell numbers were assessed in male inbred C3H/HeNCrj mice (7–10 wk old). The splenic NK cytotoxic activities were examined in a 4-h 51Cr release assay in mouse spleen cells that were obtained 1, 2, 4, 8, or 16 days after exposure to Ta of 22, 4, or 35 degrees C. The percentage of conjugating lymphocytes was calculated by counting the number of single lymphocytes bound to single target cells per 400 effector cells. The numbers of NK cells were expressed by the percentage of 5E6-positive cells. The 5E6 identifies only a subset of NK cells. It was found that the splenic NK cell activity, the effector-target cell conjugation activity, or the NK cell number began to fall 1 day after cold (Ta 4 degrees C) or heat (Ta 35 degrees C) stress. After a 16-day period of either cold or heat exposure, the fall in the splenic NK cell activity, the effector-target cell conjugation activity, or the number of 5E6-positive subsets of NK cells was still evident. Compared with those of the control group (Ta 22 degrees C), the cold-stressed mice had higher adrenal cortisol concentration and lower colonic temperature, whereas the heat-stressed animals had higher adrenal cortisol concentration and higher colonic temperature during a 16-day period of thermal exposure. However, neither cold nor heat stress affected both the body weight gain and the spleen weight in our mice.

Elevated CD54 Expression Renders CD4+ T Cells Susceptible to Natural Killer Cell-Mediated Killing

2019 ◽  
Vol 220 (12) ◽  
pp. 1892-1903 ◽  
Author(s):  
Xi Chen ◽  
Huihui Chen ◽  
Zining Zhang ◽  
Yajing Fu ◽  
Xiaoxu Han ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cd4 T Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Adaptive Immune Response ◽  
Phenotypic Analysis

Abstract Background Natural killer (NK) cells are an important type of effector cell in the innate immune response, and also have a role in regulation of the adaptive immune response. Several studies have indicated that NK cells may influence CD4+ T cells during HIV infection. Methods In total, 51 HIV-infected individuals and 15 healthy controls participated in this study. We performed the flow cytometry assays and real-time PCR for the phenotypic analysis and the functional assays of NK cell-mediated deletion of CD4+ T cells, phosphorylation of nuclear factor-κB (NF-κB/p65) and the intervention of metformin. Results Here we detected high CD54 expression on CD4+ T cells in HIV-infected individuals, and demonstrate that upregulated CD54 is associated with disease progression in individuals infected with HIV. We also show that CD54 expression leads to the deletion of CD4+ T cells by NK cells in vitro, and that this is modulated by NF-κB/p65 signaling. Further, we demonstrate that metformin can suppress CD54 expression on CD4+ T cells by inhibiting NF-κB/p65 phosphorylation. Conclusions Our data suggest that further studies to evaluate the potential role of metformin as adjunctive therapy to reconstitute immune function in HIV-infected individuals are warranted.

scholarly journals Dose of Retroviral Infection Determines Induction of Antiviral NK Cell Responses

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Elisabeth Littwitz-Salomon ◽  
Simone Schimmer ◽  
Ulf Dittmer
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Cell Activity ◽  
High Dose ◽  
Nk Cell Activity ◽  
Retroviral Infection ◽  
Cell Functions ◽  
Virus Dose ◽  
Antiviral Activities

ABSTRACT Natural killer (NK) cells are part of the innate immune system and recognize virus-infected cells as well as tumor cells. Conflicting data about the beneficial or even detrimental role of NK cells in different infectious diseases have been described previously. While the type of pathogen strongly influences NK cell functionality, less is known about how the infection dose influences the quality of a NK cell response against retroviruses. In this study, we used the well-established Friend retrovirus (FV) mouse model to investigate the impact of virus dose on the induction of antiviral NK cell functions. High-dose virus inoculation increased initial virus replication compared to that with medium- or low-dose viral challenge and significantly improved NK cell activation. Antiviral NK cell activity, including in vivo cytotoxicity toward infected target cells, was also enhanced by high-dose virus infection. NK cell activation following high-dose viral challenge was likely mediated by activated dendritic cells (DCs) and macrophages and the NK cell-stimulating cytokines interleukin 15 (IL-15) and IL-18. Neutralization of these cytokines decreased NK cell functions and increased viral loads, whereas IL-15 and IL-18 therapy improved NK cell activity. Here we demonstrate that virus dose positively correlates with antiviral NK cell activity and function, which are at least partly driven by IL-15 and IL-18. Our results suggest that NK cell activity may be therapeutically enhanced by administering IL-15 and IL-18 in virus infections that inadequately activate NK cells. IMPORTANCE In infections with retroviruses, like HIV and FV infection of mice, NK cells clearly mediate antiviral activities, but they are usually not sufficient to prevent severe pathology. Here we show that the initial infection dose impacts the induction of an antiviral NK cell response during an acute retroviral infection, which had not investigated before. High-dose infection resulted in a strong NK cell functionality, whereas no antiviral activities were detected after low- or medium-dose infection. Interestingly, DCs and macrophages were highly activated after high-dose FV challenge, which corresponded with increased levels of NK cell-stimulating cytokines IL-15 and IL-18. IL-15 and IL-18 neutralization decreased NK cell functions, whereas IL-15 and IL-18 therapy improved NK cell activity. Here we show the importance of cytokines for NK cell activation in retroviral infections; our findings suggest that immunotherapy combining the well-tolerated cytokines IL-15 and IL-18 might be an interesting approach for antiretroviral treatment.

scholarly journals Patients with a deficiency of natural killer cell activity lack the VEP13-positive lymphocyte subpopulation

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 65-70 ◽  
Author(s):  
HW Ziegler-Heitbrock ◽  
H Rumpold ◽  
D Kraft ◽  
C Wagenpfeil ◽  
R Munker ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Target Cells ◽  
Nk Cell Activity

Many patients with B-type chronic lymphocytic leukemia (CLL) exhibit a profound defect in their natural killer (NK) cell activity, the basis of which is still obscure. Hence, we analyzed the NK cells from peripheral blood samples from 11 patients with CLL for phenotype and function, after removal of the leukemic cells with a monoclonal antibody (BA-1) plus complement. Phenotypic analysis of these nonleukemic cells with monoclonal antibodies (MoAbs) against NK cells revealed that the CLL patients had higher percentages of HNK-1-positive cells (23.5% compared to controls with 14.7%). In contrast, VEP13- positive cells were absent or low in seven patients (0.8% compared to controls with 11.2%) and normal in four patients (10.5%). When testing NK cell activities against K562 or MOLT 4 target cells, patients with no or minimal numbers of VEP13-positive cells were found to be deficient, while patients with normal percentages of VEP13-positive cells had NK cell activity comparable to controls. Isolation by fluorescence-activated cell sorter of HNK-1-positive cells from patients lacking VEP13-positive cells and NK cell activity indicated that the majority of the HNK-1-positive cells in these patients had the large granular lymphocyte morphology that is characteristic of NK cells. Thus, the deficiency of NK cell activity in CLL patients appears to result from the absence of cells carrying the VEP13 marker.

Effect of eccentric exercise on natural killer cell activity

1995 ◽  
Vol 78 (4) ◽  
pp. 1442-1446 ◽  
Author(s):  
J. Palmo ◽  
S. Asp ◽  
J. R. Daugaard ◽  
E. A. Richter ◽  
M. Klokker ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Eccentric Exercise ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Activity ◽  
Control Group ◽  
Systemic Effects ◽  
Nk Cell Activity ◽  
Blood Samples

The effect of eccentric one-legged exercise on natural killer (NK) cell activity was studied in eight healthy males. To distinguish between local and systemic effects, blood samples were collected from veins in the exercising leg and resting arm. However, the results did not significantly differ between the leg and arm. To eliminate diurnal variations, the results were compared with a control group that did not exercise but had blood samples collected at the same time points. In the exercising group, plasma creatine kinase increased progressively during and up to 4 days after exercise. The percentage of CD16+ NK cells increased during exercise, which was paralleled by an increase in the NK cell activity per fixed number of blood mononuclear cells. The NK cell activity on a per NK cell basis did not change. The percentage of CD3+, CD4+, CD8+, CD19+, and CD14+ cells did not change significantly during exercise. The present study thus showed that eccentric exercise with a relatively small muscle mass (1 quadriceps femoris muscle) causes systemic effects on NK cells. It is suggested that the increase in plasma epinephrine during eccentric exercise is responsible for the observed increase in the percentage of CD16+ cells.

scholarly journals Response of resting human peripheral blood natural killer cells to interleukin 2.

1984 ◽  
Vol 160 (4) ◽  
pp. 1147-1169 ◽  
Author(s):  
G Trinchieri ◽  
M Matsumoto-Kobayashi ◽  
S C Clark ◽  
J Seehra ◽  
L London ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Experimental Conditions ◽  
Ifn Gamma

The present study shows that recombinant interleukin 2 (IL-2) purified to homogeneity induces a rapid and potent enhancement of spontaneous cytotoxicity of human peripheral blood lymphocytes. The cells mediating cytotoxicity after 18-h treatment with IL-2 have surface markers of natural killer (NK) cells and are generated from the peripheral blood subset containing spontaneous cytotoxic cells. A parallel production of gamma interferon (IFN-gamma) is induced by recombinant IL-2 (rIL-2), and NK cells appear to be the major producer cells, whereas T cells are unable to produce IFN-gamma under these experimental conditions. However, the kinetics of the enhancement of cytotoxicity are faster than those of IFN-gamma production, and monoclonal anti-IFN-gamma antibodies do not suppress this effect, making it unlikely that the IFN-gamma produced is responsible for the enhancement. The enhancement of NK cell activity induced by rIL-2 precedes any proliferative response of the lymphocytes, which is instead observed in longer-term cultures of both NK and T cells.

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