Increased Expression of Activating Receptors on NK Cells in the Post-Transplant Period.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1249-1249
Author(s):  
Michael Boyiadzis ◽  
Jesse M. Carson ◽  
Sarfraz A. Memon ◽  
Robert Dean ◽  
Kate Castro ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Hematopoietic Stem ◽  
Lectin Receptors ◽  
Cell Receptors ◽  
Post Transplant ◽  
Lectin Receptor ◽  
Receptor Repertoire ◽  
Nk Cell Receptors ◽  
Activating Receptors

Abstract Following allogeneic and autologous hematopoietic stem cell transplantation (HSCT) natural killer (NK) cells are among the first lymphocyte populations to recover, returning to normal levels within one month after HSCT. We previously reported that levels of IL-15, a cytokine critical to NK cell homeostasis, are elevated during the peri-transplant period (ASH, 2003). Modulation of the relative frequency and intensity of expression of the activating NK cell receptors by IL-15 may contribute to NK-mediated cytotoxicity post transplant. We compared the expression of activating NK receptors in the donor apheresis product and in recipient peripheral blood at one and three months following reduced intensity allogeneic HSCT from HLA-matched siblings. NK cells, divided into CD56bright CD16− and CD56dimCD16+ subsets, were assessed for receptors that trigger cytotoxicity: the natural cytotoxicity receptors (NCR) NKp30 and NKp46, and the C-type lectin receptors NKG2D and NKG2C-CD94. During the first post transplant month the NK cell numbers recovered to normal levels, but the CD56brightCD16− subset increased disproportionately (p = .005). By three months the proportions of the NK cell subsets returned to pre-transplant levels. In both NK subsets, the percentage of cells expressing NCR NKp46 or NKp30 doubled by one month and was sustained at three months. The percentage of cells expressing the C-type lectin receptor CD94 similarly increased by 50% in both NK subsets. The heterodimeric activating partner of CD94, NKG2C, was also increased, but the increase in frequency of cells expressing this receptor was less than those pairing CD94 with its inhibitory NKG2A partner. The homodimeric activating receptor NKG2D increased in the NK CD56brightCD16− subset, but did not significantly change in the CD56dim CD16+ NK population. Consistent with responsiveness to elevated IL-15 during the peri-transplant period, expression of both the IL-2/IL-15 beta and common gamma receptors increased at one and three months. Furthermore, when NK cells from normal donors were cultured with IL-15, we observed both a population shift towards CD56brightCD16− and an up-regulation of the NK cell activating receptors, similar to the changes observed during the early post transplant period. These results suggest that IL-15-dependent changes in NK subset distribution and activating NK receptor repertoire occur during the early post-transplant period. Up-regulation of activating NK cell receptors may contribute to NK cell anti-tumor efficacy in the post transplant period.

Up-Regulation of NK Cell Activating Receptors Associated with Elevated IL-15 Levels Post-Transplant.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1417-1417
Author(s):  
Michael Boyiadzis ◽  
Jesse Carson ◽  
Kenton Allen ◽  
Sarfraz A. Memon ◽  
Robert A. Dean ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nk Cells ◽  
Nk Cell ◽  
Receptor Expression ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Lectin Receptors ◽  
Post Transplant ◽  
Activating Receptors ◽  
Cytokine Milieu

Abstract NK cells express diverse activating and inhibitory receptors, which collectively determine the NK cytotoxic response. Because NK cells can be potent anti-tumor effectors in the post transplant period of minimal residual disease, we investigated the receptor expression on NK cells following non-myeloablative, HLA-matched, allogeneic hematopoietic stem cell transplant (HSCT). We focused on activating receptors, comparing the expression of natural cytotoxicity receptors (NCR) and C-type lectin receptors on circulating NK cells at one, three, six and twelve months following HSCT with that of the donor-derived mobilized stem cell apheresis. During the first post-transplant month, the absolute numbers of NK cells recovered to normal levels in the 14 patients studied, but the subpopulation of CD56++(bright) CD16− NK cells increased disproportionately compared to the more common CD56+(dull) CD16+ NK cells. By six months the proportions of the NK cell subsets normalized to pre-transplant levels. At one month post transplant, the median percentage of NK cells expressing the anti-tumor NCR NKp46 increased from 15 to 64% and that expressing NKp30 increased from 23 to 40% as compared to the donor’s NK cells; expression remained elevated during the first year. Expression of NKG2D, the homodimeric activating C-type lectin receptor, similarly increased post-transplant. CD94 was also upregulated on NK cells, but the activating heterodimeric partner of CD94, NKG2C, did not change significantly. To investigate these shifts in NK populations and receptor expression, we investigated the effect of cytokine milieu post transplant on these shifts in NK populations and receptor expression. We have determined that plasma levels of IL-15, a cytokine critical in NK differentiation and expansion, increase more than 50-fold in these HSCT patients from pretreatment to the day of transplant and decline in the first weeks post transplant, inversely proportional to NK recovery. When NK cells were cultured with rIL-15, we observed a disproportionate expansion of CD56++ NK cells and a rapid up-regulation of the NCR and NKG2D receptors, similar to the changes observed post-transplant. These data suggest that the cytokine milieu of transplant, in particular elevated levels of IL-15, may contribute to anti-tumor efficacy post transplant by affecting the recovery of NK subsets and modulating expression of activating receptors.

Comparative Analysis of NK Receptor and T-Cell Receptor Repertoires in Patients with Chronic Myeloid Leukemia Treated with Different Tyrosine Kinase Inhibitors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5508-5508 ◽  
Author(s):  
Gianni Binotto ◽  
Luca Frison ◽  
Elisa Boscaro ◽  
Renato Zambello ◽  
Federica Lessi ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
T Cell Receptor ◽  
Kinase Inhibitors ◽  
Nk Cell ◽  
Cell Receptor ◽  
Cell Receptors ◽  
Receptor Repertoire ◽  
Nk Cell Receptors ◽  
T Cell Receptor Repertoire

Abstract Introduction: Given the critical role of BCR–ABL kinase activity in chronic myeloid leukemia (CML), tyrosine kinase inhibitors (TKIs) are currently considered the cornerstone of CML treatment. Previous studies have suggested that TKIs may influence anti-tumor immunity through off-target modulation of different immune effectors. Natural killer (NK) cells, as well as T cells in the context of adaptive immunity, are a key component of the innate immune system, providing first-line defense against virally infected cells and tumors. The activity of NK cells is modulated by a finely-tuned balance between signals received from inhibitory and activating cell surface receptors. Aims: We sought to evaluate the impact of first and second generation TKIs on modulating different NK cell receptors patterns; secondly we studied the effect of a TKIs driven NK subpopulations selection on treatment response. Finally, we analyzed the T cells Vβ-TCR repertoire to identify any restrictions. Materials and Methods: Peripheral blood samples from 25, 9 and 8 chronic phase CML patients treated with imatinib frontline, nilotinib and dasatinib as first or second line therapy, respectively, were collected. Patients characteristics are described below (see table 1). After separation of mononuclear cells (PBMC), the expression of several NK cell receptors (Killer Immunoglobulin-like Receptors, KIR: p70, p140, p58/p50; Killer Lectin-like Receptors, KLR: CD94, NKG2A, NKG2C/A, NKG2D; Natural Cytotoxicity Receptors, NCR: NKp30, NKp44, NKp46, NKp80; Co-receptors: 2B4; LIR1/ILT2, GPR56) and Vβ TCR-repertoire were analized by flow cytometry analysis. Treatment response was assessed with standardized real quantitative polymerase chain reaction and cytogenetics according to ELN recommendations. Results: The leukocyte count was not statistically different between groups (WBC = 5.5 x 109 / L vs. 6.8 x 109 / L vs. 5.6 x 109 / L, p = 0.09, respectively); also lymphocytes, considered either in percentage or absolute number, were comparable (32% vs 26% vs 35%, p = 0.08), as well as the percentage and absolute number of NK cells (20%; 0.37 x 109 / L vs. 15%; 0.26 x 109 / L vs. 24%; 0.54 x 109 / L (p = 0.17, p = 0.10).The analysis of NK receptors expression showed that patients treated with Imatinib exhibited a preferential selection of NK cells subpopulations harboring activating receptors (NKp30, NKp46, NKp80 and NKG2D), while in Dasatinib treated patients an increased expression of KIR (KIR2DL1) receptors was observed (figure 1). Interestingly, these effects were documented also in the absence of lymphocytosis. 44.4% (4 of 9 patients) of patients treated with nilotinib showed preferential expression of Vβ chains, compared with 87.5% of patients treated with dasatinib; no TCR-repertoire restriction was documented in the sole TKI primary resistant patient. 8 out of 17 patients showed a preferential expression of more than oneVβ chain (figure 2). No specific NK receptors profiles were found to be associated with different degrees of treatment response. Conclusions: These preliminary data suggest the existence of a different NKRs and T cell receptor repertoire modulation, mediated by Tyrosine-Kinase Inhibitors. Since no significant correlation between response and specific NK receptor profiles has been demonstrated, TKIs immunomodulatory effect seems secondary compared to direct inhibition of BCR-ABL kinase. However, it's conceivable that NK and T cells subpopulations selection, induced by TKIs, may become relevant in the immunological control of leukemic disease at the time of drug discontinuation. These observations are currently being investigated on a larger series of patients. Figure 1 NK cell receptors differentially expressed between imatinib, nilotinib and dasatinib treated patients. Figure 1. NK cell receptors differentially expressed between imatinib, nilotinib and dasatinib treated patients. Figure 2 Figure 2. Figure 3 T cell receptor repertoire in nilotinib (A) and dasatinib (B) treated CML patients Figure 3. T cell receptor repertoire in nilotinib (A) and dasatinib (B) treated CML patients Disclosures No relevant conflicts of interest to declare.

scholarly journals Research Progress on NK Cell Receptors and Their Signaling Pathways

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Yingying Chen ◽  
Dan Lu ◽  
Alexey Churov ◽  
Rong Fu
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Signaling Pathways ◽  
Nk Cell ◽  
Research Progress ◽  
Inhibitory Receptors ◽  
Cell Receptors ◽  
Surface Receptors ◽  
Nk Cell Receptors ◽  
Activating Receptors

Natural killer cells (NK cells) play an important role in innate immunity. NK cells recognize self and nonself depending on the balance of activating receptors and inhibitory receptors. After binding to their ligands, NK cell receptors trigger subsequent signaling conduction and then determine whether NK is activated or inhibited. Furthermore, NK cell response includes cytotoxicity and cytokine release, which is tightly related to the activation of NK cell-activating receptors and the inhibition of inhibitory receptors on the surfaces of NK cells. The expression and function of NK cell surface receptors also alter in virus infection, tumor, and autoimmune diseases and influence the occurrence and development of diseases. So, it is important to understand the mechanism of recognition between NK receptors and their ligands in pathological conditions and the signaling pathways of NK cell receptors. This review mainly summarizes the research progress on NK cell surface receptors and their signal pathways.

Highly functional natural killer (NK) cells as predictive biomarkers associated with long response to castration in newly diagnosed metastatic prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 95-95
Author(s):  
Christine Pasero ◽  
Gwenaelle Gravis ◽  
Mathilde Guerin ◽  
Palma Rocchi ◽  
Jeanne Thomassin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Nk Cells ◽  
Natural Killer ◽  
Metastatic Prostate Cancer ◽  
Nk Cell ◽  
Predictive Biomarkers ◽  
Newly Diagnosed ◽  
Cell Receptors ◽  
Nk Cell Receptors ◽  
Activating Receptors

95 Background: Immunotherapy is now investigated as a promising alternative treatment for patients (pts) with metastatic prostate cancer (PC). Natural killer (NK) cells are powerful effector cells with antitumoral activity and their role have been explored in solid tumors but not yet in prostate cancer. NK cell cytotoxicity is regulated by a balance between activating and inhibitory receptors. Here, we performed a restrospective study to evaluate the link between NK cells and the time of castration response in newly diagnosed PC patients with metastases. Methods: Newly diagnosed metastatic PC pts were divided according the time of castration response, with an 18-months cutoff value: 18 pts with long castration response (LCR, median = 64.6 months), and 14 pts with short castration response ([SCR] median = 11.2 months), with a median overall survival of 97.7 months and 33.8 months respectively. Circulating NK cells from these patients were studied by flow cytometry to evaluate the expression of activating receptors and the NK cell functionality. Results: We observed thatNK cells from LCR pts express higher levels of the maturation marker CD57 (43.3% vs. 23.3% positive cells, p= 0.002), the receptor CD16 involved in cytotoxicity (29,124 vs. 16,806 MFI, p= 0.02), and the activating receptors NKp46 and NKp30 (17.5 vs. 11.4 RMFI, p= 0.0146 , and 10.9 vs. 6.3 RMFI, p = 0.0128 respectively) than NK cells from SCR pts. This suggests that LCR pts have powerful NK cells. Indeed, NK cells from LCR pts are highly efficient in CD107 functional assay than NK cells from SCR pts (28.9% vs. 19.4%, p =0.002). In vitro blocking experiments show that NKp46 is precisely one of the NK cell receptors involved in the NK-mediated recognition of prostate tumor cells, thus higher expression of NKp46 would help to control PC progression. Conclusions: Together our results show for the first time that efficient NK cells are associated to a long response to castration and prolonged survival in newly diagnosed metastatic PC. NK cell receptors might be useful as predictive biomarkers in metastatic PC, to help in stratification of patients and to design NK cell–based immunotherapeutic strategies for PC.

scholarly journals Super-resolution imaging of remodeled synaptic actin reveals different synergies between NK cell receptors and integrins

Blood ◽  
2012 ◽  
Vol 120 (18) ◽  
pp. 3729-3740 ◽  
Author(s):  
Alice C. N. Brown ◽  
Ian M. Dobbie ◽  
Juha-Matti Alakoskela ◽  
Ilan Davis ◽  
Daniel M. Davis
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Three Dimensional ◽  
Super Resolution ◽  
Cortical Actin ◽  
Cell Receptors ◽  
Lytic Granules ◽  
Nk Cell Receptors ◽  
Activating Receptors ◽  
Ifn Γ

Abstract Natural killer (NK) cells secrete lytic granules to directly kill virus-infected or transformed cells and secrete cytokines to communicate with other cells. Three-dimensional super-resolved images of F-actin, lytic granules, and IFN-γ in primary human NK cells stimulated through different activating receptors reveal that both IFN-γ and lytic granules accumulated in domains where the periodicity of the cortical actin mesh at the synapse opened up to be penetrable. Ligation of some activating receptors alone (eg, CD16 or NKG2D) was sufficient to increase the periodicity of the actin mesh, but surprisingly, ligation of others (eg, NKp46 or CD2) was not sufficient to induce cortical actin remodeling unless LFA-1 was coligated. Importantly, influenza virus particles that can be recognized by NK cells similarly did not open the actin mesh but could if LFA-1 was coligated. This leads us to propose that immune cells using germline-encoded receptors to directly recognize foreign proteins can use integrin recognition to differentiate between free pathogens and pathogen-infected cells that will both be present in blood. This distinction would not be required for NK cell receptors, such as NKG2D, which recognize host cell–encoded proteins that can only be found on diseased cells and not pathogens.

Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 1935-1947 ◽  
Author(s):  
Sherif S. Farag ◽  
Todd A. Fehniger ◽  
Loredana Ruggeri ◽  
Andrea Velardi ◽  
Michael A. Caligiuri
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Natural Cytotoxicity ◽  
Receptor Ligand ◽  
Cell Receptors ◽  
Nk Cell Receptors ◽  
Ligand Interactions ◽  
Nk Receptor

AbstractNatural killer (NK) cells have held great promise for the immunotherapy of cancer for more than 3 decades. However, to date only modest clinical success has been achieved manipulating the NK cell compartment in patients with malignant disease. Progress in the field of NK cell receptors has revolutionized our concept of how NK cells selectively recognize and lyse tumor and virally infected cells while sparing normal cells. Major families of cell surface receptors that inhibit and activate NK cells to lyse target cells have been characterized, including killer cell immunoglobulinlike receptors (KIRs), C-type lectins, and natural cytotoxicity receptors (NCRs). Further, identification of NK receptor ligands and their expression on normal and transformed cells completes the information needed to begin development of rational clinical approaches to manipulating receptor/ligand interactions for clinical benefit. Indeed, clinical data suggest that mismatch of NK receptors and ligands during allogeneic bone marrow transplantation may be used to prevent leukemia relapse. Here, we review how NK cell receptors control natural cytotoxicity and novel approaches to manipulating NK receptor-ligand interactions for the potential benefit of patients with cancer.

AFM13 Is the Most Advanced Bispecific NK-Cell Engaging Antibody in Clinical Development Substantially Enhancing NK-Cell Effector Function and Proliferation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1764-1764 ◽  
Author(s):  
Jens Pahl ◽  
Uwe Reusch ◽  
Thorsten Gantke ◽  
Anne Kerber ◽  
Joachim Koch ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Target Cells ◽  
Cell Cytotoxicity ◽  
Cell Receptors ◽  
Cell Responses ◽  
Nk Cell Receptors ◽  
Ifn Γ ◽  
Nk Cell Cytotoxicity

Abstract Introduction: AFM13 is an NK-cell engaging CD30/CD16A bispecific tetravalent TandAb antibody currently in phase 2 clinical development in Hodgkin lymphoma (HL) and other CD30+ malignancies. It engages NK-cells through CD16A with high affinity and specificity and confers significantly stronger NK-cell activation compared to other therapeutic antibodies. We have previously shown synergistic efficacy when NK-cell activation by AFM13 is combined with check-point modulation such as anti-PD-1 treatment, which is known to unleash T cell and NK-cell activity. The goal of this study was to identify further candidates for combination treatments and biomarkers that potentially indicate NK-cell responses to AFM13 treatment. Methods: AFM13-mediated NK-cell cytotoxicity and IFN-γ production after 4-hour interaction with HL cell lines was measured by 51Cr release assays and flow cytometry, respectively. Expression of NK-cell receptors, NK-cell proliferation (CFSE dilution) and expansion (absolute cell counts) was analyzed by flow cytometry. Results: The interaction of NK-cells with AFM13-coated tumor cells up-regulated the expression of NK-cell receptors such as CD25, CD69, CD137/4-1BB as well as molecules that may serve as NK-cell check-points when compared with the unrelated NK-cell binding TandAb AFM12 that does not bind to target cells. Importantly, CD16A engagement by AFM13 enhanced the proliferation and expansion potential of NK-cells when subsequently incubated with IL-15 or with particularly low doses of IL-2. NK-cell cytotoxicity and IFN-γ production was substantially increased towards CD30+ tumor cells in the presence of AFM13. Even target cells resistant to naïve and IL-2/IL-15-activated NK-cells were susceptible to AFM13-induced NK-cell cytotoxicity. AFM13 concentrations of as low as 10-2 µg/mL resulted in maximal activity while AFM13 was significantly more potent than native anti-CD30 IgG1 antibody. NK-cell activation by IL-2 or IL-15 had a synergistic effect on AFM13-mediated cytotoxicity. Conclusion: AFM13 specifically enhances the cytotoxic, proliferative and cytokine-producing potential of NK-cells. Our data indicate that the distinctive modulation of NK-cell receptors can be utilized to monitor NK-cell responses during AFM13 therapy and provides candidates for therapeutic combination strategies. Moreover, the combination with low doses of IL-2 or with IL-15 may expand the quantity of tumor-reactive NK-cells after AFM13 treatment and promote NK-cell functionality in the tumor microenvironment in cancer patients. Disclosures Reusch: Affimed: Employment, Patents & Royalties: Patents. Gantke:Affimed GmbH: Employment. Kerber:Affimed: Employment. Koch:Affimed: Employment. Treder:Affimed: Employment. Cerwenka:Affimed: Research Funding.

Magnesium alterations of graft immune cells (MAGIC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18541-e18541
Author(s):  
Ramy Sedhom ◽  
Andrew Zloza ◽  
Frederick Joseph Kohlhapp ◽  
Daniel Medina ◽  
Roger Strair
Keyword(s):  
Monoclonal Antibodies ◽  
Nk Cells ◽  
Immune Cells ◽  
Nk Cell ◽  
Jurkat Cells ◽  
Nk Activity ◽  
Functional Link ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Nkg2d Expression

e18541 Background: Magnesium plays important roles in cellular processes. Allogeneic hematopoietic stem cell transplantation provides potentially curative therapy to patients with a variety of hematologic malignancies. A common abnormality post transplant is hypomagnesaemia. Recent studies identified magnesium transporter 1 deficiency in association with XMEN syndrome. These patients exhibit low intracellular [Mg++] and low T cell and NK cell NKG2D expression. Therefore, we investigated this potential functional link between magnesium deficiency and immune function in patients post transplant. Methods: A pilot study investigated whether detectable changes in T and NK cells were associated with IV magnesium repletion post hematopoietic transplant. Blood was obtained before and after magnesium transfusions. Immunophenotypic analysis of T and NK cell NKG2D levels using commercially available monoclonal antibodies (CD3, CD16, CD56, CD4, CD8, CD314 [NKG2D]) was performed. Samples from patients demonstrating an increase in NKG2D expression were subsequently analyzed for ex vivo NK activity. Here, NK activity and cytotoxicity of Jurkat cells were assayed using standard laboratory techniques and changes > 2 fold were considered significant. A total of 7 patients were enrolled. Results: NKG2D expression on T and NK cell subsets were determined by flow cytometry using commercially available monoclonal antibodies. NK reactivity and killing of K562 were undertaken using standard cytotoxicity assays. Our findings indicate a significant response in five of the seven enrolled patients. NKG2D expression on CD8+ T cells increased by up to 31%. Conclusions: Our results suggest that magnesium infusions post allogeneic transplant are associated with augmented NKG2D expression on immune cells. Additional studies are needed to clarify the mechanisms by which therapeutic magnesium repletion restores the cytotoxicity of NK cells and T lymphocytes. Although the clinical utility of magnesium supplementation remains to be validated, our data indicate that NKG2D is regulated by magnesium post transplant and magnesium may play a key role in immune regulation.

The Role of NK Cells and NK Cell Receptors inAutoimmune Disease

Autoimmunity ◽  
2004 ◽  
Vol 37 (2) ◽  
pp. 147-153 ◽  
Author(s):  
Hyun-Bae Jie ◽  
Nora Sarvetnick
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Cell Receptors ◽  
Nk Cell Receptors
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