scholarly journals The Effects of Age and Latent Cytomegalovirus Infection on NK-Cell Phenotype and Exercise Responsiveness in Man

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Austin B. Bigley ◽  
Guillaume Spielmann ◽  
Nadia Agha ◽  
Richard J. Simpson
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
The Body ◽  
Cell Phenotype ◽  
Older Individuals ◽  
Acute Bout ◽  
Age Dependent ◽  
Fight Or Flight Response ◽  
Differentiation Marker ◽  
Exercise Induced

The redeployment of NK-cells in response to an acute bout of exercise is thought to be an integral component of the “fight-or-flight” response, preparing the body for potential injury or infection. We showed previously that CMV seropositivity impairs the redeployment of NK-cells with exercise in the young. In the current study, we examined the effect of aging on the redeployment of NK-cells with exercise in the context of CMV. We show here that CMV blunts the exercise-induced redeployment of NK-cells in both younger (23–39 yrs) and older (50–64 yrs) subjects with olderCMVnegsubjects showing the largest postexercise mobilization and 1 h postexercise egress of NK-cells. The blunted exercise response inCMVposindividuals was associated with a decreased relative redeployment of the CD158a+ and CD57+ NK-cell subsets in younger and older individuals. In addition, we show that aging is associated with a CMV-independent increase in the proportion of NK-cells expressing the terminal differentiation marker CD57, while CMV is associated with an age-dependent decrease in the proportion of NK-cells expressing the inhibitory receptors KLRG1 (in the younger group) and CD158a (in the older group). Collectively, these data suggest that CMV may decrease NK-cell mediated immunosurveillance after exercise in both younger and older individuals.

scholarly journals Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3238-3248 ◽  
Author(s):  
Enrico Lugli ◽  
Carolyn K. Goldman ◽  
Liyanage P. Perera ◽  
Jeremy Smedley ◽  
Rhonda Pung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Effector Memory ◽  
Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

scholarly journals Landscape of innate lymphoid cells in human head and neck cancer reveals divergent NK cell states in the tumor microenvironment

2021 ◽  
Vol 118 (28) ◽  
pp. e2101169118
Author(s):  
Uriel Y. Moreno-Nieves ◽  
Joshua K. Tay ◽  
Saumyaa Saumyaa ◽  
Nina B. Horowitz ◽  
June Ho Shin ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Antitumor Activity ◽  
Nk Cells ◽  
Nk Cell ◽  
Human Head ◽  
Lymphoid Cells ◽  
Cell Phenotype ◽  
Tumor Control ◽  
Novel Therapy

Natural killer (NK) cells comprise one subset of the innate lymphoid cell (ILC) family. Despite reported antitumor functions of NK cells, their tangible contribution to tumor control in humans remains controversial. This is due to incomplete understanding of the NK cell states within the tumor microenvironment (TME). Here, we demonstrate that peripheral circulating NK cells differentiate down two divergent pathways within the TME, resulting in different end states. One resembles intraepithelial ILC1s (ieILC1) and possesses potent in vivo antitumor activity. The other expresses genes associated with immune hyporesponsiveness and has poor antitumor functional capacity. Interleukin-15 (IL-15) and direct contact between the tumor cells and NK cells are required for the differentiation into CD49a+CD103+ cells, resembling ieILC1s. These data explain the similarity between ieILC1s and tissue-resident NK cells, provide insight into the origin of ieILC1s, and identify the ieILC1-like cell state within the TME to be the NK cell phenotype with the greatest antitumor activity. Because the proportions of the different ILC states vary between tumors, these findings provide a resource for the clinical study of innate immune responses against tumors and the design of novel therapy.

scholarly journals FC 129CHANGES IN PERIPHERAL NK CELLS IN KIDNEY TRANSPLANT RECIPIENTS WITH AND WITHOUT HLA DSA

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Laura Llinas ◽  
Dolores Redondo Pachon ◽  
Dàlia Raïch Regué ◽  
Maria Jose Perez-Saez ◽  
Sara Sanz ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Count ◽  
Kidney Transplant ◽  
Graft Survival ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Cell Phenotype ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients

Abstract Background and Aims Antibody-mediated rejection (ABMR) is a frequent cause of renal allograft loss. There is increasing evidence of the role of Natural Killer (NK) cells in the establishment of ABMR damage. Our group described that patients with donor-specific antibodies (DSA) and ABMR present higher proportions of NKG2A+ NK cell subset in peripheral blood than those without HLA DSA or HLA antibodies. Method We selected 177 kidney transplant recipients (KT) with renal biopsies 2011-2017: 77 with ABMR (DSA+: 53, DSA-: 24) and 100 without ABMR (DSA+: 15, DSA-: 85). We assessed graft survival with a median time of follow-up since the renal biopsy of 53 months. In 138 KT we evaluated the peripheral blood NK cell immunophenotyping and its value as a prognostic biomarker. Results Graft survival was worse in ABMR-KT at the end of follow-up (p<0.001) independently of DSA detection (p=0.63). Regarding NK cell immunophenotyping, we observed a lower proportion and absolute NK cell count in ABMR+DSA+-KT and ABMR+DSA--KT compared with ABMR-DSA--KT (p=0.027, p=0.017). ABMR+DSA+-KT showed higher proportion of NKG2A+ NK cells compared with ABMR-DSA--KT (p=0.007). All ABMR+ patients, independently of DSA detection, presented lower absolute NKG2A- NK cell count in comparison with ABMR-DSA--KT (p=0.001, p=0.017). Finally, a proportion of NKG2A- <30% was associated with lower graft survival 36 months after graft biopsy with ABMR (p=0.067) (Figure). Conclusion Graft survival is worse in ABMR+ compared with ABMR- KT independently of DSA detection. Kidney transplant recipients with ABMR show reduced peripheral absolute numbers of NK cells and NKG2A- NK cells regardless of undetectable DSA. This NK cell phenotype associated with a worse medium-term graft survival in cases with ABMR.

scholarly journals Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2187
Author(s):  
Raffaella Meazza ◽  
Michela Falco ◽  
Fabrizio Loiacono ◽  
Paolo Canevali ◽  
Mariella Della Chiesa ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Nk Cells ◽  
Nk Cell ◽  
Functional Characterization ◽  
Cell Subset ◽  
Cell Phenotype ◽  
Cell Repertoire ◽  
Hematopoietic Stem ◽  
Γδt Cells ◽  
Effector Cells

NK cells can exert remarkable graft-versus-leukemia (GvL) effect in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Here, we dissected the NK-cell repertoire of 80 pediatric acute leukemia patients previously reported to have an excellent clinical outcome after αβT/B-depleted haplo-HSCT. This graft manipulation strategy allows the co-infusion of mature immune cells, mainly NK and γδT cells, and hematopoietic stem cells (HSCs). To promote NK-cell based antileukemia activity, 36/80 patients were transplanted with an NK alloreactive donor, defined according to the KIR/KIR-Ligand mismatch in the graft-versus-host direction. The analysis of the reconstituted NK-cell repertoire in these patients showed relatively high proportions of mature and functional KIR+NKG2A−CD57+ NK cells, including the alloreactive NK cell subset, one month after HSCT. Thus, the NK cells adoptively transfused with the graft persist as a mature source of effector cells while new NK cells differentiate from the donor HSCs. Notably, the alloreactive NK cell subset was endowed with the highest anti-leukemia activity and its size in the reconstituted repertoire could be influenced by human cytomegalovirus (HCMV) reactivation. While the phenotypic pattern of donor NK cells did not impact on post-transplant HCMV reactivation, in the recipients, HCMV infection/reactivation fostered a more differentiated NK-cell phenotype. In this cohort, no significant correlation between differentiated NK cells and relapse-free survival was observed.

Abstract 037: A Role for IL-17 to Activate Cytolytic Natural Killer Cells in Response to Placental Ischemia

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Denise C Cornelius ◽  
D'Andrea S Thomas ◽  
Jamil Elfarra ◽  
Taia R McAfee ◽  
Babbette LaMarca
Keyword(s):  
Blood Pressure ◽  
Nk Cells ◽  
Renal Dysfunction ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Blood Pressure Response ◽  
Cell Phenotype ◽  
Uterine Perfusion ◽  
Placental Ischemia

Women with preeclampsia (PE), newly developed hypertension and renal dysfunction during pregnancy, have small-for-gestational-age babies and demonstrate an increase in the inflammatory cytokine IL-17, placental oxidative stress, and cytolytic natural killer (NK) cell activation. The stimulus of the cytolytic NK cell phenotype during PE is currently unknown. Moreover, the specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. The reduced uterine perfusion pressure (RUPP) model of placental ischemia exhibits many of the characteristics of preeclampsia including hypertension, renal dysfunction, chronic inflammation and intrauterine growth restriction (IUGR). In this study, we tested the hypothesis that placental ischemia results in cytolytic activation of NK cells, and examined a role for the increased IL-17, in response to placental ischemia, to activate cytolytic NK cells. In this study, blood pressure (MAP) and pup weight were measured, and PBMCs and placental lymphocytes were examined via flow cytometry for surface makers of cytolytic NK cell activation. MAP significantly increased in response to placental ischemia from 103±4.1 mmHg in NP (n=6) to 129.1±3.1 mmHg (n=8) in RUPP rats (p<0.001). Neutralization of IL-17 with a soluble receptor attenuated the blood pressure response to 106.3±2.3 mmHg in RUPP+IL-17RC rats (n=3). Pup weight is significantly decreased in RUPP rats (2.52±0.18g in NP vs 2.03±0.05g in RUPP (p<0.05)), which increased to 2.54±0.36g in RUPP+IL-17RC. Cytolytic activation of circulating NK cells was not significantly changed among any of the groups (NP: 2.49±1.1%; RUPP: 7.74±3.2%; RUPP+IL-17RC:5.50±2.8%). However, cytolytic activation of placental NK cells increased in response to placental ischemia (NP: 3.4±1.1% vs RUPP 10.0±3.4%), and was completely attenuated after treatment with the soluble IL-17 receptor (RUPP+IL-17RC: 0.33±0.17%). These results suggest a role for placental ischemia and increased IL-17 to stimulate cytolytic NK cells. Furthermore, this study links the IL-17 pathway with cytolytic NK cell activation and IUGR in response to placental ischemia, potentially identifying new therapeutic targets to improve maternal and fetal outcomes of PE.

Anti-CD20 Monoclonal Antibody (mAb) with Enhanced Affinity for CD16 Activates NK Cells at Lower Concentrations and More Effectively Than Rituximab ®.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 348-348 ◽  
Author(s):  
George J. Weiner ◽  
Julie A. Bowles ◽  
Brian K. Link ◽  
Mary A. Campbell ◽  
James E. Wooldridge ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mononuclear Cells ◽  
Nk Cell ◽  
Normal Subjects ◽  
Cell Phenotype ◽  
P Value ◽  
Peripheral Blood Mononuclear ◽  
Anti Cd20 ◽  
Anti Tumor Activity ◽  
Ifng Production

Abstract Growing evidence indicates the affinity of mAb for CD16 (FcgRIII) plays a central role in the ability of the mAb to mediate anti-tumor activity. Both polymorphisms in CD16 and structure of mAb Fc can impact on the affinity between CD16 and mAb. Little is known about how affinity between mAb and CD16 impacts on the ability of mAb to activate NK cells. We evaluated how CD16 polymorphisms, and mAb with modified affinity for CD16, impact on NK cell phenotype and cytokine production. MAb consisted of R, anti-CD20 with enhanced affinity for CD20 (AME-133), and AME-133 with Fc engineered to have enhanced affinity for both CD20 and CD16 (Fc-eng-133). Peripheral blood mononuclear cells were obtained from normal subjects that were homozygous for high affinity CD16 (VV at position 158), homozygous low affinity (FF at 158), and heterozygotes and were mixed with mAb and Raji lymphoma cells at an effector:target ratio of 1:1. Higher concentrations of mAb were needed to induce CD16 modulation, CD54 upregulation, and IFNg production on NK cells from subjects with the lower affinity CD16 polymorphism. The dose of mAb needed to induce NK activation was lower with Fc-eng-133 irrespective of CD16 polymorphism. Measure of activation - % of NK cells CD54 bright: EC50 ng/ml (mean moAb concentration +/− SEM): N=4 per polymorphism R AME-133 Fc-eng-133 p&lt;0.01 - R vs AME-133; R vs Fc-eng-133; AME-133 vs Fc-eng-133 for each polymorphism VV 6.2 +/− 1.0 3.9 +/− 0.5 1.0 +/− 0.3 VF 11.6 +/− 1.7 5.7 +/− 0.6 1.4 +/− 0.4 FF 29.9 +/− 10.6 11.5 +/− 2.5 2.8 +/− 0.3 p value VV vs FF &lt;0.05 &lt;0.05 &lt;0.05 At saturating mAb concentrations, peak NK activation was greater for Fc engineered AME-133 when compared to R mAb for all samples studied Ratio of Fc-eng-133 to R % NK cells CD54 bright 1.35 +/− 0.07 IFNg production 2.64 +/− 0.43 These data indicate tumor cells coated with mAb with enhanced affinity for CD16 are more effective at activating NK cells at both low and saturating mAb concentrations irrespective of CD16 polymorphism, and provide further evidence for the clinical development of such mAb with the goal of improving clinical response to mAb.

scholarly journals Enhanced mesenchymal stromal cell recruitment via natural killer cells by incorporation of inflammatory signals in biomaterials

2011 ◽  
Vol 9 (67) ◽  
pp. 261-271 ◽  
Author(s):  
Catarina R. Almeida ◽  
Daniela P. Vasconcelos ◽  
Raquel M. Gonçalves ◽  
Mário A. Barbosa
Keyword(s):  
Inflammatory Response ◽  
Nk Cells ◽  
Natural Killer ◽  
Tissue Repair ◽  
Bone Repair ◽  
Nk Cell ◽  
Fold Increase ◽  
Cell Recruitment ◽  
Inflammatory Signals ◽  
Differentiation Marker

An exacerbated inflammatory response questions biomaterial biocompatibility, but on the other hand, inflammation has a central role in the regulation of tissue regeneration. Therefore, it may be argued that an ‘ideal’ inflammatory response is crucial to achieve efficient tissue repair/regeneration. Natural killer (NK) cells, being one of the first populations arriving at an injury site, can have an important role in regulating bone repair/regeneration, particularly through interactions with mesenchymal stem/stromal cells (MSCs). Here, we studied how biomaterials designed to incorporate inflammatory signals affected NK cell behaviour and NK cell–MSC interactions. Adsorption of the pro-inflammatory molecule fibrinogen (Fg) to chitosan films led to a 1.5-fold increase in adhesion of peripheral blood human NK cells, without an increase in cytokine secretion. Most importantly, it was found that NK cells are capable of stimulating a threefold increase in human bone marrow MSC invasion, a key event taking place in tissue repair, but did not affect the expression of the differentiation marker alkaline phosphatase (ALP). Of significant importance, this NK cell-mediated MSC recruitment was modulated by Fg adsorption. Designing novel biomaterials leading to rational modulation of the inflammatory response is proposed as an alternative to current bone regeneration strategies.

scholarly journals NK Cells in Mucosal Defense against Infection

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Daria Ivanova ◽  
Ryan Krempels ◽  
Jennyfer Ryfe ◽  
Kaitlyn Weitzman ◽  
David Stephenson ◽  
...  
Keyword(s):  
Nk Cells ◽  
Rational Design ◽  
Nk Cell ◽  
The Body ◽  
Parasitic Infections ◽  
Published Data ◽  
Mucosal Tissue ◽  
Rapid Responses ◽  
Mucosal Infection ◽  
Set Up

Conventional natural killer cells (NK cells) provide continual surveillance for cancer and rapid responses to infection. They develop in the bone marrow, emerge as either NK precursor cells, immature, or mature cells, and disperse throughout the body. In the periphery NK cells provide critical defense against pathogens and cancer and are noted to develop features of adaptive immune responses. In the tightly regulated and dynamic mucosal tissues, they set up residency via unknown mechanisms and from sources that are yet to be defined. Once resident, they appear to have the ability to functionally mature dependent on the mucosal tissue microenvironment. Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγproduction against bacteria, fungi, viruses, and parasitic infections. This review presents what is known about NK cell development and phenotypes of mucosal tissue resident conventional NK cells. The question of how they come to reside in their tissues and published data on their function against pathogens during mucosal infection are discussed. Dissecting major questions highlighted in this review will be important to the further understanding of NK cell homing and functional diversity and improve rational design of NK cell based therapies against mucosal infection.

scholarly journals Age-dependent susceptibility to a viral disease due to decreased natural killer cell numbers and trafficking

2010 ◽  
Vol 207 (11) ◽  
pp. 2369-2381 ◽  
Author(s):  
Min Fang ◽  
Felicia Roscoe ◽  
Luis J. Sigal
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Viral Disease ◽  
Viral Diseases ◽  
Cell Responses ◽  
Loss Of Resistance ◽  
Age Dependent

Although it is well known that aged hosts are generally more susceptible to viral diseases than the young, specific dysfunctions of the immune system directly responsible for this increased susceptibility have yet to be identified. We show that mice genetically resistant to mousepox (the mouse parallel of human smallpox) lose resistance at mid-age. Surprisingly, this loss of resistance is not a result of intrinsically defective T cell responses. Instead, the primary reason for the loss of resistance results from a decreased number of total and mature natural killer (NK) cells in the blood and an intrinsic impairment in their ability to migrate to the lymph node draining the site of infection, which is essential to curb systemic virus spread. Hence, our work links the age-dependent increase in susceptibility to a viral disease to a specific defect of NK cells, opening the possibility of exploring treatments to improve NK cell function in the aged with the goal of enhancing their resistance to viral diseases.

scholarly journals Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 226
Author(s):  
Tatiana Pazina ◽  
Alexander W. MacFarlane ◽  
Luca Bernabei ◽  
Essel Dulaimi ◽  
Rebecca Kotcher ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Nk Cell ◽  
Therapeutic Targets ◽  
Progression Free Survival ◽  
Cell Phenotype ◽  
Healthy Controls ◽  
Activating Receptors ◽  
And Function ◽  
Patient Subgroups

Accumulating evidence demonstrates important roles for natural killer (NK) cells in controlling multiple myeloma (MM). A prospective flow cytometry-based analysis of NK cells in the blood and bone marrow (BM) of MM patient subgroups was performed (smoldering (SMM), newly diagnosed (ND), relapsed/refractory, (RR) and post-stem cell transplantation (pSCT)). Assessments included the biomarker expression and function of NK cells, correlations between the expression of receptors on NK cells with their ligands on myeloma cells, and comparisons between MM patient subgroups and healthy controls. The most striking differences from healthy controls were found in RR and pSCT patients, in which NK cells were less mature and expressed reduced levels of the activating receptors DNAM-1, NKG2D, and CD16. These differences were more pronounced in the BM than in blood, including upregulation of the therapeutic targets TIM3, TIGIT, ICOS, and GITR. Their expression suggests NK cells became exhausted upon chronic encounters with the tumor. A high expression of SLAMF7 on blood NK cells correlated with shorter progression-free survival. This correlation was particularly evident in ND patients, including on mature CD56dim NK cells in the BM. Thus, our NK cell analysis identified possible therapeutic targets in MM and a biomarker with prognostic potential for disease progression.

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