scholarly journals Subordinate effect of −21M HLA-B dimorphism on NK cell repertoire diversity and function in HIV-1 infected individuals of African origin

2019 ◽  
Author(s):  
Elia Moreno Cubero ◽  
Ane Ogbe ◽  
Myron S. Cohen ◽  
Barton F. Haynes ◽  
Persephone Borrow ◽  
...  
Keyword(s):  
Nk Cells ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Receptor ◽  
Therapeutic Interventions ◽  
Cell Repertoire ◽  
Healthy Human ◽  
Chronic Viral Infections ◽  
Binding Peptides ◽  
Hiv 1

AbstractNatural Killer (NK) cells play an important role in antiviral defence and their potent effector function identifies them as key candidates for immunotherapeutic interventions in chronic viral infections. Their remarkable functional agility is achieved by virtue of a wide array of germline encoded inhibitory and activating receptors ensuring a self-tolerant and tunable repertoire. NK cell diversity is generated by a combination of factors including genetic determinants and infections/environmental factors, which together shape the NK cell pool and functional potential. Recently a genetic polymorphism at position −21 of HLA-B, which influences the supply of HLA-E binding peptides and availability of HLA-E for recognition by the inhibitory NK cell receptor NKG2A, was shown to have a marked influence on NK cell functionality in healthy human cytomegalovirus (HCMV) seronegative Caucasian individuals. In this study, −21 methionine (M)-expressing alleles supplying HLA-E binding peptides were largely poor ligands for inhibitory killer immunoglobulin-like receptors (KIRs), and a bias to NKG2A-mediated education of functionally-potent NK cells was observed. Here, we investigated the effect of this polymorphism on the phenotype and functional capacity of NK cells in a cohort of African individuals with human immunodeficiency virus type 1 (HIV-1)/HCMV co-infection. A similarly profound influence of dimorphism at position −21 of HLA-B on NK cells was not evident in these subjects. They predominantly expressed African specific HLA-B and −C alleles that contribute a distinct supply of NKG2A and KIR ligands, and these genetic differences were compounded by the marked effect of HIV/HCMV coinfection on NK cell differentiation. Together, these factors resulted in a lack of correlation of the HLA-B −21 polymorphism with surface abundance of HLA-E and loss of the NK cell functional advantage in subjects with −21M HLA-B alleles. Instead our data suggest that during HIV/HCMV co-infection exposure of NK cells to an environment that displays altered HLA-E ligands drives adaptive NKG2C+ NK cell expansions influencing effector responses. Increased efforts to understand how NK cells are functionally calibrated to self-HLA during chronic viral infections will pave the way to developing targeted therapeutic interventions to overcome the current barriers to enhancing immune-based antiviral control.

scholarly journals Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response

2009 ◽  
Vol 206 (3) ◽  
pp. 515-523 ◽  
Author(s):  
Agnieszka Kielczewska ◽  
Michal Pyzik ◽  
Tianhe Sun ◽  
Astrid Krmpotic ◽  
Melissa B. Lodoen ◽  
...  
Keyword(s):  
Nk Cells ◽  
Deletion Mutant ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Receptor ◽  
Major Histocompatability Complex ◽  
Wild Type ◽  
Mcmv Infection ◽  
Host Protection ◽  
Infected Cells

Natural killer (NK) cells are crucial in resistance to certain viral infections, but the mechanisms used to recognize infected cells remain largely unknown. Here, we show that the activating Ly49P receptor recognizes cells infected with mouse cytomegalovirus (MCMV) by a process that requires the presence of H2-Dk and the MCMV m04 protein. Using H2 chimeras between H2-Db and -Dk, we demonstrate that the H2-Dk peptide-binding platform is required for Ly49P recognition. We identified m04 as a viral component necessary for recognition using a panel of MCMV-deletion mutant viruses and complementation of m04-deletion mutant (Δm04) virus infection. MA/My mice, which express Ly49P and H2-Dk, are resistant to MCMV; however, infection with Δm04 MCMV abrogates resistance. Depletion of NK cells in MA/My mice abrogates their resistance to wild-type MCMV infection, but does not significantly affect viral titers in mice infected with Δm04 virus, implicating NK cells in host protection through m04-dependent recognition. These findings reveal a novel mechanism of major histocompatability complex class I–restricted recognition of virally infected cells by an activating NK cell receptor.

scholarly journals Allotype-specific processing of the CD16a N45-glycan from primary human natural killer cells and monocytes

Glycobiology ◽  
2020 ◽  
Vol 30 (7) ◽  
pp. 427-432
Author(s):  
Kashyap R Patel ◽  
Jacob T Roberts ◽  
Adam W Barb
Keyword(s):  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Surface Receptor ◽  
Mass Spectrometry Analysis ◽  
Healthy Human ◽  
Killer Cells ◽  
Spectrometry Analysis

Abstract Fc γ receptor IIIa/CD16a is an activating cell surface receptor with a well-defined role in natural killer (NK) cell and monocyte effector function. The extracellular domain is decorated with five asparagine (N)-linked glycans; N-glycans at N162 and N45 directly contribute to high-affinity antibody binding and protein stability. N-glycan structures at N162 showed significant donor-dependent variation in a recent study of CD16a isolated from primary human NK cells, but structures at N45 were relatively homogeneous. In this study, we identified variations in N45 glycan structures associated with a polymorphism coding for histidine instead of leucine at position 48 of CD16a from two heterozygous donors. It is known that H48 homozygous individuals suffer from immunodeficiency and recurrent viral infections. A mass spectrometry analysis of protein isolated from the primary natural killer cells of individuals expressing both CD16a L48 and H48 variants demonstrated clear processing differences at N45. CD16a H48 displayed a greater proportion of complex-type N45 glycans compared to the more common L48 allotype with predominantly hybrid N45-glycoforms. Structures at the four other N-glycosylation sites showed minimal differences from data collected on donors expressing only the predominant L48 variant. CD16a H48 purified from a pool of monocytes similarly displayed increased processing at N45. Here, we provide evidence that CD16a processing is affected by the H48 residue in primary NK cells and monocytes from healthy human donors.

Cytomegalovirus Reactivation Shapes NK Cells Diversity Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4588-4588
Author(s):  
Li Li ◽  
Muharrem Muftuoglu ◽  
Han Chen ◽  
Duncan Mak ◽  
Elif Gokdemir ◽  
...  
Keyword(s):  
Nk Cells ◽  
Viral Infections ◽  
Nk Cell ◽  
Cmv Infection ◽  
Cell Recovery ◽  
Cell Repertoire ◽  
Hematopoietic Stem ◽  
Healthy Donors ◽  
Before And After ◽  
Cell Diversity

Abstract Natural killer (NK) cells are the first lymphocyte population to reconstitute following allogeneic hematopoietic stem cell transplantation (HSCT) and are key players in immune defense against viral infections and malignant transformation. NK cell numbers generally recover within the first month post-transplant, but the acquisition of mature NK cell phenotype and full functional competency can take over 6 months and is influenced by various host and donor factors. Cytomegalovirus (CMV) infection has been shown to modulate NK cell maturation after HSCT. The diversity of the NK cell repertoire is dictated by a variety of combinatorially expressed activating and inhibitory receptors that dictate the NK activation status. Moreover, whereas the expression of inhibitory receptors is primarily genetically determined, environmental factors such as viral infections influence the expression of activating receptors to a great extent.. We propose that assessment of diversity could provide a different perspective for the evaluation of the NK cell compartment after HSCT, since it is a quantitative measure that takes into account both the number and evenness of the different NK subpopulations. To better understand the factors that influence NK cell recovery after cord blood (CB) transplant (CBT) and specifically the influence of cytomegalovirus (CMV) infection on NK cell maturity, we used 40-parameter mass cytometry (CyTOF) to interrogate the NK cell repertoire. A panel including 37 monoclonal antibodies was designed to recognize NK cells lineage markers and receptors as well as intracellular markers such as transcription factors and adaptor proteins. We first evaluated and compared the diversity of NK cells in 10 CB units and peripheral blood (PB) from 20 healthy donors. We then examined the diversity of NK cells before and after CBT in 22 serially collected blood samples from in 10 CBT recipients. NK cell diversity was significantly lower in CB (mean 574, range 417-891) compared to PB samples from healthy donors (mean 3792, range 1284-5079; P=0.001), indicating less diversification within the naive CB NK compartment. After CBT, NK cell diversity was lower at earlier time point (Day30) (mean 1129, range 428-1768) compared to PB from healthy donors; P=0.01. The diversity of NK cells increased gradually over time following CBT (Day 30 mean 1129 range 428-1768; Day 60, mean 1185, range 515-1864; 4 months, mean 1711 range 597-2640). We also compared the diversity of NK cells in the PB of healthy CMV seronegative (n=10) and seropositive adult donors (n=10). The diversity of NK cells was higher in CMV seropositive vs. CMV seronegative healthy donors (3887 vs 2473; P=0.04). This difference in NK diversity was even more pronounced within the KIR positive (mean 1701, range, 981-2152) compared to the KIR negative subset (mean 551, range 456-647; P=0.02), indicating that CMV infection increases the richness of mature NK cells. In keeping with these findings, CMV infection after CBT was associated with a significantly greater diversity of NK cells, especially within the KIR positive compartment (mean 604, range 207-1035) compared to the KIR negative subset (mean 283, 257-457; P=0.025). However, in CMV negative patients, we found no difference in diversity within the KIR positive and negative subsets (mean 1120 vs. 1366; P=0.28). Taken together, these data suggest that NK cell diversity reflects NK cells differentiation and maturation, and that CMV shapes NK cell diversity, especially within the KIR positive compartment. To further understand how CMV influences NK cells diversity, we examined the top 15 NK cell subsets and their distribution at multiple timepoints before and after CMV reactivation post-CBT. CMV infection post-CBT was associated with a significant change in the distribution of NK subsets within the KIR positive population, with the top 15 subsets prior to CMV reactivation being mostly replaced by the emergence of new subsets. In contrast, the top 15 subsets within the KIR negative NK population remained stable. These data suggest that CMV drives NK cell maturation by differentiating KIR positive NK cells. In summary, we used high-dimensional single-cell data to evaluate NK cell reconstitution following HSCT. These data can help us better understand the biology of NK cell recovery after HSCT and discover the functional significance of NK cell diversity in the setting of viral infections. Disclosures Champlin: Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

scholarly journals The Role of Natural Killer (NK) Cells and NK Cell Receptor Polymorphisms in the Assessment of HIV-1 Neutralization

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e29454 ◽  
Author(s):  
Bruce K. Brown ◽  
Lindsay Wieczorek ◽  
Gustavo Kijak ◽  
Kara Lombardi ◽  
Jeffrey Currier ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Receptor ◽  
Nk Cell Receptor ◽  
Hiv 1

Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3366-3369 ◽  
Author(s):  
Galit Alter ◽  
Nickolas Teigen ◽  
Benjamin T. Davis ◽  
Marylyn M. Addo ◽  
Todd J. Suscovich ◽  
...  
Keyword(s):  
Viral Replication ◽  
Nk Cells ◽  
Cell Function ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Subset ◽  
Multiparameter Flow Cytometry ◽  
Cell Compartment ◽  
Acute Hiv ◽  
Hiv 1

AbstractNatural killer (NK) cells are critical in the first-line defense against viral infections. Chronic HIV-1 infection leads to a perturbation in the NK cell compartment, yet the kinetics of this deregulation and the functional consequences are unclear. Here, we characterized changes in the NK cell compartment longitudinally by multiparameter flow cytometry, starting in acute HIV-1 infection. Acute HIV-1 infection was associated with elevated NK cell numbers, with an expansion of CD3negCD56dimCD16pos NK cells and an early depletion of CD3negCD56brightCD16neg NK cells. Ongoing viral replication resulted in a depletion of CD3negCD56dimCD16pos NK cells with a paralleled increase in functionally anergic CD3negCD56negCD16pos NK cells, accompanied by reduced functional activity, as measured by CD107a expression and cytokine secretion. Taken together, these studies demonstrate a sequential impairment of NK cell function with persistent viral replication resulting from a progressive deregulation of NK cell subsets with distinct functional properties.

scholarly journals HIV-1 Tat Triggers TGF-β Production and NK Cell Apoptosis that is Prevented by Pertussis Toxin B

2006 ◽  
Vol 13 (2-4) ◽  
pp. 369-372 ◽  
Author(s):  
Alessandro Poggi ◽  
Maria Raffaella Zocchi
Keyword(s):  
Nk Cells ◽  
Cell Apoptosis ◽  
Nk Cell ◽  
Cell Receptor ◽  
Toxin B ◽  
Akt Phosphorylation ◽  
Mediated Effects ◽  
Healthy Donors ◽  
Induced Apoptosis ◽  
Hiv 1

Herein, we show that PTX-B and its non-toxic mutant PT9K/129G inhibit transcription and secretion of TGF-β elicited by HIV-1 Tat in NK cells. Moreover, Tat strongly activates the cJun component of the multimolecular complex AP-1, while TGF-β triggers cFos and cJun. Treatment of NK cells In turn,with PTX-B or PT9K/129G inhibits Tat and TGF-β-induced activation of AP-1. TGF-β enhances starvation-induced NK cell apoptosis, reduces the transcription of the antiapoptotic protein Bcl-2 and inhibits Akt phosphorylation induced by oligomerization of the triggering NK cell receptor NKG2D. All these TGF-β-mediated effects are prevented by PTX-B or PT9K/129G, through a PI-3K-dependent mechanism. Finally, PTX-B and PT9K/129G upregulate Bcl-xL, the isoform of Bcl-x that protects cells from starvation-induced apoptosis. Of note, in NK cells from patients with HIV-1 infection, mRNA expression of Bcl-2 and Bcl-xLwas consistently lower than that of healthy donors; interestingly, TGF-β and Tat were detected in the sera of these patients. These data suggest that Tat-induced TGF-β production and the consequent NK cell failure, possibly occurring during early HIV-1 infection, may be regulated by PTX-B and PT9K/129G.

scholarly journals Immunosurveillance of Cancer and Viral Infections with Regard to Alterations of Human NK Cells Originating from Lifestyle and Aging

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 557
Author(s):  
Xuewen Deng ◽  
Hiroshi Terunuma ◽  
Mie Nieda
Keyword(s):  
Nk Cells ◽  
Viral Infections ◽  
Nk Cell ◽  
Healthy Lifestyle ◽  
Cell Activity ◽  
Nk Cell Activity ◽  
Effector Cells ◽  
Cell Dysfunction ◽  
Forest Bathing ◽  
Infected Cells

Natural killer (NK) cells are cytotoxic immune cells with an innate capacity for eliminating cancer cells and virus- infected cells. NK cells are critical effector cells in the immunosurveillance of cancer and viral infections. Patients with low NK cell activity or NK cell deficiencies are predisposed to increased risks of cancer and severe viral infections. However, functional alterations of human NK cells are associated with lifestyles and aging. Personal lifestyles, such as cigarette smoking, alcohol consumption, stress, obesity, and aging are correlated with NK cell dysfunction, whereas adequate sleep, moderate exercise, forest bathing, and listening to music are associated with functional healthy NK cells. Therefore, adherence to a healthy lifestyle is essential and will be favorable for immunosurveillance of cancer and viral infections with healthy NK cells.

scholarly journals The Advances and Challenges of NK Cell-Based Cancer Immunotherapy

2021 ◽  
Vol 28 (2) ◽  
pp. 1077-1093
Author(s):  
Synat Kang ◽  
Xuefeng Gao ◽  
Li Zhang ◽  
Erna Yang ◽  
Yonghui Li ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Nk Cell ◽  
Tumor Development ◽  
Human Leukocyte ◽  
Cell Receptor ◽  
Clinical Applications ◽  
Therapeutic Approaches ◽  
Leukocyte Antigens ◽  
Recognition Specificity

Natural killer (NK) cells can be widely applied for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization or human leukocyte antigens-matching. Several NK-based therapeutic approaches have been attempted in clinical practice, but their efficacy is not sufficient to suppress tumor development mainly because of lacking specificity. To this end, the engineering of NK cells with T cell receptor along with CD3 subunits (TCR-NK) has been developed to increase the reactivity and recognition specificity of NK cells toward tumor cells. Here, we review recent advances in redirecting NK cells for cancer immunotherapy and discuss the major challenges and future explorations for their clinical applications.

scholarly journals Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+T Cells

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Abena K. R. Kwaa ◽  
Chloe A. G. Talana ◽  
Joel N. Blankson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Effector Cell ◽  
Cell Function ◽  
Nk Cell ◽  
Suppressive Capacity ◽  
Short Course ◽  
Shock And Kill ◽  
Hiv 1

ABSTRACTCurrent shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+T cell and natural killer (NK) cell responses. In this study, we tested the hypothesis that alpha interferon (IFN-α) could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-α treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors. Furthermore, IFN-α enhanced global CP CD8+T cell cytokine responses and the suppressive capacity of ES CD8+T cells. Our data suggest that IFN-α treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.IMPORTANCEData suggest that HIV+individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest since they complement the function of CD8+T cells. Here, we demonstrate the ability of short-course alpha interferon (IFN-α) treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+T cell function. These results point to the possibility of exploring such short-course IFN-α treatments for the enhancement of effector cell function in HIV+patients in future cure strategies.

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