scholarly journals Perturbed NK Cell Homeostasis Associated with Disease Severity in Chronic Neutropenia

Blood ◽  
2021 ◽  
Author(s):  
Ebba Sohlberg ◽  
Aline Pfefferle ◽  
Eivind Heggernes Ask ◽  
Astrid Tschan-Plessl ◽  
Benedikt Jacobs ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Severe Disease ◽  
Critical Role ◽  
Ki 67 ◽  
Cell Homeostasis ◽  
Development And Differentiation ◽  
And Gender ◽  
Immune Changes ◽  
Chronic Neutropenia

Neutrophils have been suggested to play a critical role in terminal differentiation of NK cells. Whether this is a direct effect or a consequence of global immune changes with effects on NK cell homeostasis remains unknown. Here, we used high-resolution flow- and mass cytometry to examine NK cell repertoires in 64 patients with neutropenia and 27 healthy age- and gender-matched donors. A subgroup of patients with chronic neutropenia showed severely disrupted NK cell homeostasis manifested as increased frequencies of CD56bright NK cells and a lack of mature CD56dim NK cells. These immature NK cell repertoires were characterized by expression of proliferation/exhaustion markers Ki-67, Tim-3 and TIGIT and displayed blunted tumor target cell responses. Systems-level immune mapping revealed that the changes in immunophenotypes were confined to NK cells, leaving T cell differentiation intact. RNA sequencing of NK cells from these patients showed upregulation of a network of genes, including TNFSF9, CENPF, MKI67 and TOP2A, associated with apoptosis and the cell cycle, different from conventional CD56bright signatures. Profiling of 249 plasma proteins showed a coordinated enrichment of pathways related to apoptosis and cell turnover, which correlated with immature NK cell repertoires. Notably, most of these patients exhibited severe-grade neutropenia, suggesting that the profoundly altered NK cell homeostasis was connected to the severity of their underlying etiology. Hence, although our data suggests that neutrophils are dispensable for NK cell development and differentiation, some patients displayed a specific gap in the NK repertoire, associated with poor cytotoxic function and more severe disease manifestations.

scholarly journals Systems-Level Analysis of the Immune Repertoire in Neutropenia Reveal Arrested NK Cell Differentiation and Exhaustion

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 24-25
Author(s):  
Ebba Sohlberg ◽  
Aline Pfefferle ◽  
Eivind Heggernes Ask ◽  
Astrid Tschan-Plessl ◽  
Benedikt Jacobs ◽  
...  
Keyword(s):  
Nk Cells ◽  
Board Of Directors ◽  
Nk Cell ◽  
Critical Role ◽  
Protein Profiling ◽  
Cytokine Signaling ◽  
Cell Compartment ◽  
Advisory Committees ◽  
Cell Homeostasis ◽  
Neutropenic Patients

Neutrophils are innate cells that have been suggested to play a critical role in terminal differentiation of NK cells. Whether this is a direct effect or a consequence of global immune changes with effects on NK cell homeostasis remains unknown. Here, we used high-resolution flow and mass cytometry to examine NK cell repertoires in 64 neutropenic patients and 27 healthy age- and gender-matched controls. A subgroup of neutropenic patients had lower frequencies and absolute numbers of NK cells, yet increased frequencies of CD56bright among NK cells (Figure 1A-C). Moreover, their CD56dim compartment was characterized by a block in differentiation, with a relative lack of NKG2A-CD57+KIR+ NK cells. In line with the differentiation arrest, no expansion of adaptive NK cells could be detected in CMV-seropositive patients from this subgroup. Furthermore, CD56dim NK cells showed increased frequencies of Ki-67+, Tim-3+ and TIGIT+ cells suggestive of activation and exhaustion (Figure 1D). The systemic imprint in the NK cell repertoire was associated with a blunted tumor target cell response with inefficient killing and a lower proportion of degranulating CD56dim cells (Figure 1E). RNA sequencing of the NK cell compartment further revealed that the differentiation arrest was linked to increased expression of transcription factors and genes involved in proliferation and cytokine signaling (Figure 1F). Serum protein profiling of 264 proteins showed upregulation of pathways related to apoptosis and cell turnover, as well as immune regulation and inflammation including higher levels of IL-10, IL-18 and IL-27 in these patients (Figure 1G-H). Notably, the majority of patients with perturbed NK cell compartment exhibited high-grade neutropenia, overall suggesting that the profoundly altered NK cell homeostasis was tightly connected to the severity of their underlying etiology (Figure 1I). Disclosures Meinke: XNK Therapeutics AB: Consultancy. Palmblad:Roche Sweden Inc: Speakers Bureau; Chieti Canada Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Malmberg:Vycellix: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Consultancy, Patents & Royalties.

scholarly journals Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hee Young Na ◽  
Yujun Park ◽  
Soo Kyung Nam ◽  
Jiwon Koh ◽  
Yoonjin Kwak ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Prognostic Significance

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.

scholarly journals The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF

2019 ◽  
Vol 216 (9) ◽  
pp. 2010-2023 ◽  
Author(s):  
Jessica Vetters ◽  
Mary J. van Helden ◽  
Sigrid Wahlen ◽  
Simon J. Tavernier ◽  
Arne Martens ◽  
...  
Keyword(s):  
Cell Death ◽  
Nk Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Homeostasis ◽  
Life And Death ◽  
Cytotoxic Molecules ◽  
Editing Enzyme ◽  
Mtor Activity

The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20−/− cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20−/− cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.

scholarly journals Hitting More Birds with a Stone: Impact of TGF-β on ILC Activity in Cancer

2020 ◽  
Vol 9 (1) ◽  
pp. 143 ◽  
Author(s):  
Cinzia Fionda ◽  
Helena Stabile ◽  
Cristina Cerboni ◽  
Alessandra Soriani ◽  
Angela Gismondi ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Cancer Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Cell Activity ◽  
Lymphoid Cells ◽  
Receptor Expression ◽  
Nk Cell Activity ◽  
Group I

Transforming growth factor (TGF)-β is a central immunosuppressive cytokine within tumor microenvironment inhibiting the expansion and function of major cellular components of adaptive and innate immune system. Among them, compelling evidence has demonstrated that TGF-β is a key regulator of natural killer (NK) cells, innate lymphoid cells (ILCs) with a critical role in immunosurveillance against different kinds of cancer cells. A TGF-β rich tumor microenvironment blocks NK cell activity at multiple levels. This immunosuppressive factor exerts direct regulatory effects on NK cells including inhibition of cytokine production, alteration of activating/inhibitory receptor expression, and promotion of the conversion into non cytotoxic group I ILC (ILC1). Concomitantly, TGF-β can render tumor cells less susceptible to NK cell-mediated recognition and lysis. Indeed, accumulating evidence suggest that changes in levels of NKG2D ligands, mainly MICA, as well as an increase of immune checkpoint inhibitors (e.g., PD-L1) and other inhibitory ligands on cancer cells significantly contribute to TGF-β-mediated suppression of NK cell activity. Here, we will take into consideration two major mechanisms underlying the negative regulation of ILC function by TGF-β in cancer. First, we will address how TGF-β impacts the balance of signals governing NK cell activity. Second, we will review recent advances on the role of this cytokine in driving ILC plasticity in cancer. Finally, we will discuss how the development of therapeutic approaches blocking TGF-β may reverse the suppression of host immune surveillance and improve anti-tumor NK cell response in the clinic.

Cytokine-activated NK cells inhibit PMN apoptosis and preserve their functional capacity

Blood ◽  
2010 ◽  
Vol 116 (8) ◽  
pp. 1308-1316 ◽  
Author(s):  
Nupur Bhatnagar ◽  
Henoch S. Hong ◽  
Jayendra K. Krishnaswamy ◽  
Arash Haghikia ◽  
Georg M. Behrens ◽  
...  
Keyword(s):  
Nk Cells ◽  
Functional Capacity ◽  
Nk Cell ◽  
Expression Patterns ◽  
Critical Role ◽  
Cell Contact ◽  
Polymorphonuclear Cells ◽  
Soluble Factors ◽  
And Function

Abstract Natural killer (NK) cells and polymorphonuclear cells (PMNs) play a critical role in the first line of defense against microorganisms. Upon host infection, PMNs phagocytose invading pathogens with subsequent killing by oxidative or nonoxidative mechanisms. NK cells are known to have immunoregulatory effects on T cells, B cells, dendritic cells (DCs), and monocytes through secretion of various soluble products and cell-cell contact. However, their impact on PMN survival and function is not well known. We found that soluble factors derived from cytokine-activated NK cells delay PMN apoptosis and preserve their ability to perform phagocytosis and produce reactive oxygen species (ROS). The expression patterns of CD11b and CD62L on PMNs differed according to the cytokine combination used for NK-cell stimulation. Irrespective of the NK-cell treatment, however, PMN survival was prolonged with sustained functional capacity. We found that interferon γ, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor α produced by NK cells upon stimulation with cytokines played a crucial role in NK cell–mediated effects on PMNs. Our study demonstrates that soluble factors derived from cytokine-activated NK cells send survival signals to PMNs, which would promote their accumulation and function at the site of inflammation in vivo.

scholarly journals Interleukin-15 is associated with disease severity in viral bronchiolitis

2015 ◽  
Vol 47 (1) ◽  
pp. 212-222 ◽  
Author(s):  
T. Ronan Leahy ◽  
Ross McManus ◽  
Derek G. Doherty ◽  
Robert Grealy ◽  
Tanya Coulter ◽  
...  
Keyword(s):  
Nk Cells ◽  
Disease Severity ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Severe Disease ◽  
Single Centre ◽  
Peripheral Blood Mononuclear ◽  
Mirna Sequencing ◽  
Interleukin 15 ◽  
Study Participants

Disease severity in viral bronchiolitis in infancy is difficult to predict and has been linked to host innate immunity. The study aimed to investigate the innate cytokine interleukin-15 (IL-15) as a marker of disease severity.A prospective single-centre observational study was conducted in a university-affiliated paediatric teaching hospital, comparing children (0–18 months) hospitalised for viral bronchiolitis, those admitted to the paediatric intensive care unit with severe disease and healthy age-matched controls. IL-15-related parameters were compared between groups. PCR and microRNA (miRNA) sequencing was undertaken on natural killer (NK) cells collected from study participants.Samples from 88 children with viral bronchiolitis and 43 controls enrolled between 2009 and 2012 were analysed. Peripheral blood mononuclear cell (PBMC) IL-15 mRNA expression was significantly higher in those with moderate severity bronchiolitis compared with controls and those with severe disease. Serum IL-15 levels correlated with disease severity. The relative frequency of NK cells in peripheral blood was significantly reduced in participants with bronchiolitis. The NK cell miRNA transcriptome in bronchiolitis was distinct. Targets of de-regulated miRNA were differentially expressed in bronchiolitis, including JAK3, STAT5A and NFKB1 on the IL-15 signalling pathway.IL-15 is associated with disease severity in children hospitalised with viral bronchiolitis.

IL-15 is an essential mediator of peripheral NK-cell homeostasis

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4887-4893 ◽  
Author(s):  
Thomas Ranson ◽  
Christian A. J. Vosshenrich ◽  
Erwan Corcuff ◽  
Odile Richard ◽  
Werner Müller ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Dominant Role ◽  
Population Level ◽  
Host Cells ◽  
Class I ◽  
Cell Homeostasis ◽  
Interleukin 7 ◽  
Mhc Class I Molecules

Abstract Several distinct classes of surface receptors can, on ligand binding, transmit signals that modulate the survival, proliferation, and apoptosis of peripheral B, T, and natural killer (NK) cells. At the population level, dynamic changes in lymphocyte cell numbers are strictly regulated to maintain a steady state, a process referred to as homeostasis. Although several studies have investigated the signals that regulate B- and T-cell homeostasis, little is known about the mechanisms that control the survival and proliferation of peripheral NK cells. Using an adoptive transfer system, we have investigated the role of γc-dependent cytokines, in particular interleukin 7 (IL-7) and IL-15, and major histocompatibility complex (MHC) class I molecules in peripheral NK-cell homeostasis. We observed that IL-15 plays a dominant role in the survival of peripheral NK cells, via maintenance of the antiapoptotic factor Bcl-2. IL-15 availability, however, also plays an important role because endogenous NK cells in the recipient mice influence the behavior of adoptively transferred NK cells. Finally, although NK cells bear functional inhibitory Ly49 receptors for MHC class I molecules, the presence or absence of specific ligands on host cells did not influence the survival or homeostatic expansion of donor NK cells.

scholarly journals Defective cytotoxic lymphocyte degranulation in syntaxin-11–deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 1906-1915 ◽  
Author(s):  
Yenan T. Bryceson ◽  
Eva Rudd ◽  
Chengyun Zheng ◽  
Josefine Edner ◽  
Daoxin Ma ◽  
...  
Keyword(s):  
Nk Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Nk Cell ◽  
Severe Disease ◽  
Target Cells ◽  
Loss Of Function ◽  
Cytotoxic Lymphocyte ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Genes Encoding ◽  
Syntaxin 11

Abstract Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsislike illness with cytopenia, hepatosplenomegaly, and deficient lymphocyte cytotoxicity. Disease-causing mutations have been identified in genes encoding perforin (PRF1/FHL2), Munc13-4 (UNC13D/FHL3), and syntaxin-11 (STX11/FHL4). In contrast to mutations leading to loss of perforin and Munc13-4 function, it is unclear how syntaxin-11 loss-of-function mutations contribute to disease. We show here that freshly isolated, resting natural killer (NK) cells and CD8+ T cells express syntaxin-11. In infants, NK cells are the predominant perforin-containing cell type. NK cells from FHL4 patients fail to degranulate when encountering susceptible target cells. Unexpectedly, IL-2 stimulation partially restores degranulation and cytotoxicity by NK cells, which could explain the less severe disease progression observed in FHL4 patients, compared with FHL2 and FHL3 patients. Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may facilitate diagnosis, and that these new insights may offer novel therapeutic possibilities.

scholarly journals Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells

2017 ◽  
Vol 9 (5) ◽  
pp. 511-525 ◽  
Author(s):  
Sophie M. Poznanski ◽  
Amanda J. Lee ◽  
Tina Nham ◽  
Evan Lusty ◽  
Margaret J. Larché ◽  
...  
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Interleukin 12 ◽  
Tnf Α ◽  
Ifn Γ

The combination of interleukin (IL)-18 and IL-12 (IL-18+IL-12) potently stimulates natural killer (NK) cells, triggering an innate immune response to infections and cancers. Strategies exploiting the effects of IL-18+IL-12 have shown promise for cancer immunotherapy. However, studies have primarily characterized the NK cell response to IL-18+IL-12 in terms of interferon (IFN)-γ production, with little focus on other cytokines produced. IL-8 plays a critical role in activating and recruiting immune cells, but it also has tumor-promoting functions. IL-8 is classically produced by regulatory NK cells; however, cytotoxic NK cells do not typically produce IL-8. In this study, we uncover that stimulation with IL-18+IL-12 induces high levels of IL-8 production by ex vivo expanded and freshly isolated NK cells and NK cells in peripheral blood mononuclear cells. We further report that tumor necrosis factor (TNF)-α, produced by NK cells following IL-18+IL-12 stimulation, regulates IL-8 production. The IL-8 produced is in turn required for maximal IFN-γ and TNF-α production. These findings may have important implications for the immune response to infections and cancer immunotherapies. This study broadens our understanding of NK cell function and IL-18+IL-12 synergy by uncovering an unprecedented ability of IL-18+IL-12-activated peripheral blood NK cells to produce elevated levels of IL-8 and identifying the requirement for intermediates induced by IL-18+IL-12 for maximal cytokine production following stimulation.

scholarly journals Treatment of mice with IL2-complex enhances inflammasome-driven IFN-γ production and prevents lethal toxoplasmosis

2019 ◽  
Author(s):  
Andreas Kupz ◽  
Saparna Pai ◽  
Paul R. Giacomin ◽  
Jennifer A. Whan ◽  
Robert A. Walker ◽  
...  
Keyword(s):  
T Cells ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Severe Disease ◽  
Toxoplasmic Encephalitis ◽  
Parasite Invasion ◽  
Ifn Γ

AbstractToxoplasmic encephalitis is an AIDS-defining condition in HIV+individuals. The decline of IFN-γ-producing CD4+T cells in AIDS is a major contributing factor in reactivation of quiescentToxoplasma gondiito an actively replicating stage of infection. Hence, it is important to identify CD4-independent mechanisms to control acuteT. gondiiinfection. Here we have investigated the targeted expansion and regulation of IFN-γ production by CD8+T cells, DN T cells and NK cells in response toT. gondiiinfection using IL-2 complex (IL2C) pre-treatment in an acutein vivomouse model. Our results show that expansion of CD8+T cells, DN T cells and NK cell by S4B6 IL2C treatment increases survival rates of mice infected withT. gondiiand this increased survival is dependent on both IL-12- and IL-18-driven IFN-γ production. Processing and secretion of IFN-γ-inducing, bioactive IL-18 is dependent on the sensing of active parasite invasion by multiple redundant inflammasome sensors in multiple hematopoietic cell types but independent fromT. gondii-derived dense granule (GRA) proteins. Our results provide evidence for a protective role of IL2C-mediated expansion of CD8+T cells, DN T cells and NK cells in murine toxoplasmosis and may represent a promising adjunct therapy for acute toxoplasmosis.Author SummaryA third of the world’s population is chronically infected with the parasiteToxoplasma gondii. In most cases the infection is asymptomatic, but in individuals suffering from AIDS, reactivation of brain and muscle cysts containingT. gondiiis a significant cause of death. The gradual decline of CD4 T cells, the hallmark of AIDS, is believed to be a major contributing factor in reactivation ofT. gondiiinfection and the development of acute disease. In this study, we show that targeted expansion of non-CD4 immune cell subsets can prevent severe disease and premature death via increased availability of interferon gamma-producing immune cells. We also demonstrate that the upstream signaling molecule interleukin-18 is required for the protective immune response by non-CD4 cells and show that the sensing of active parasite invasion by danger recognition molecules is crucial. Our findings reveal that targeted cell expansion may be a promising therapy in toxoplasmosis and suggests that the development of novel intervention strategies targeting danger recognition pathways may be useful against toxoplasmosis, particularly in the context of AIDS.

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