Peripheral Blood (PB) CD56bright and CD56dim Do Not Exhibit Differences in NKR Expression Compared to Their Cord Blood (CB) Counterparts: CB CD56dim May Represent an Intermediary between CB CD56bright and PB CD56dim.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5155-5155
Author(s):  
Evan Shereck ◽  
Prakash Satwani ◽  
Carmella van de Ven ◽  
Janet Ayello ◽  
Ronald J. Wapner ◽  
...  
Keyword(s):  
Nk Cells ◽  
Magnetic Beads ◽  
Ex Vivo ◽  
Killer Cell ◽  
Receptor Expression ◽  
Becton Dickinson ◽  
Lectin Receptors ◽  
Cd16 Expression ◽  
High Concentrations ◽  
And Function

Abstract NK cells are characterized by absent CD3 and expression of CD56. CD56 NK cells are classified into CD56dim (90%) that are primarily cytotoxic, and CD56bright that secrete cytokines (Kaplan et al PNAS 1998; Shankaran et al Nature 2001). NK subsets carry out their respective functions based on their repertoire of NK receptors (NKRs), both activating and inhibiting (Moretta et al Annu Rev Immunol 2001). PB CD56dim cells express high concentrations of killer-cell immunoglobulin receptors (KIR) and C-type lectin receptors. PB CD56bright NK cells have increased expression of C-type lectin receptors, but have low expression of the KIRs (Nagler J. Immunol 1989). CD16 (the Fcγ receptor III or FcγRIII) which is responsible for binding to antibody-coated targets and initiating antibody-dependent cellular cytotoxicity (ADCC) has increased expression in CD56dim vs CD56bright NK cells (Leibson et al Immunity 1997). While the characterization and function of PB NK subsets and NKR expression are well described, there is little information regarding CB NK subsets and NKRs. We previously demonstrated a significant increase in CB NK NKR expression in ex-vivo engineered CB MNC following 48 hours of induction with IL-2, IL-7, IL-12, and Anti-CD3 (Ayello/Cairo et al BBMT 2006). In this study, we compared PB vs. CB NK subsets and NKR expression. PB and CB cells were positively selected for CD56+ using CD56 magnetic beads (Miltenyi, Aubrun, CA). CD56+ cells were sorted into CD3−/CD56bright and CD3−/CD56dim subsets by FACS sorter and NK receptor expression (CD16, CD158a {KIR2DL1} CD158a, h {KIR2DL1 and KIR2DS1}, CD158b {KIR2DL2}, CD161, NKG2A, NKG2C, NKG2D, Nkp44, NKp46, Becton Dickinson, Mountainview, CA,) of each subset was analyzed by flow cytometry. CD56+ selection yielded >89% purity (PB-96%, CB-89%). There was no statistical difference (mean ± SEM) in the receptor expression between the CB CD56bright and PB CD56bright and also between the CB CD56dim and PB CD56dim. However, PB CD56bright vs. PB CD56dim had increased expression of NKG2A (93.28 ± 2.83 vs. 66.64 ±7.74, p< 0.015), NKG2C (62.11 ±11.79 vs. 8.08 ± 2.98, p< 0.12), NKp44 (61.52 ±10.35 vs. 3.79 ± 2.32, p< 0.005) and NKp46 (92.53 ±3.31 vs. 64.66 ± 12.34, p< 0.05). PB CD56dim had increased expression of CD16 (93.30 ± 2.71 vs. 61.15 ± 11.79, p< 0.07) compared to PB CD56bright. The CB CD56dim compared to CB CD56bright has increased CD16 expression (85.06 ± 6.75 vs. 40.91 ± 5.74, p< 0.004) only. The PB CD56bright only differed from the CB CD56dim with respect to NKp44 (p< 0.021). The CB CD56bright differed from the PB CD56dim with respect to KIR2DL1 (p< 0.026), CD161 (p < 0.05), NKG2A (p < 0.025), and NKG2C (p < 0.05). In conclusion, there does appear to be a definite difference in NKR expression in PB CD56bright vs. PB CD56dim. However, PB vs. CB CD56dim and PB vs. CB CD56bright did not have any statistically significant NKR expression differences suggesting that the subsets have similar phenotypes in their respective cell source. Based on these results, we postulate that the CB CD56dim subset might reflect an intermediary step in development transitioning from CB CD56bright to PB CD56dim.

scholarly journals Role and Modulation of NK Cells in Multiple Myeloma

Hemato ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 167-181
Author(s):  
Marie Thérèse Rubio ◽  
Adèle Dhuyser ◽  
Stéphanie Nguyen
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Proteasome Inhibitors ◽  
Disease Evolution ◽  
Cell Functions

Myeloma tumor cells are particularly dependent on their microenvironment and sensitive to cellular antitumor immune response, including natural killer (NK) cells. These later are essential innate lymphocytes implicated in the control of viral infections and cancers. Their cytotoxic activity is regulated by a balance between activating and inhibitory signals resulting from the complex interaction of surface receptors and their respective ligands. Myeloma disease evolution is associated with a progressive alteration of NK cell number, phenotype and cytotoxic functions. We review here the different therapeutic approaches that could restore or enhance NK cell functions in multiple myeloma. First, conventional treatments (immunomodulatory drugs-IMids and proteasome inhibitors) can enhance NK killing of tumor cells by modulating the expression of NK receptors and their corresponding ligands on NK and myeloma cells, respectively. Because of their ability to kill by antibody-dependent cell cytotoxicity, NK cells are important effectors involved in the efficacy of anti-myeloma monoclonal antibodies targeting the tumor antigens CD38, CS1 or BCMA. These complementary mechanisms support the more recent therapeutic combination of IMids or proteasome inhibitors to monoclonal antibodies. We finally discuss the ongoing development of new NK cell-based immunotherapies, such as ex vivo expanded killer cell immunoglobulin-like receptors (KIR)-mismatched NK cells, chimeric antigen receptors (CAR)-NK cells, check point and KIR inhibitors.

scholarly journals gamma-c gene transfer into SCID X1 patients' B-cell lines restores normal high-affinity interleukin-2 receptor expression and function

Blood ◽  
1996 ◽  
Vol 87 (8) ◽  
pp. 3108-3116 ◽  
Author(s):  
H Hacein-Bey ◽  
M Cavazzana-Calvo ◽  
F Le Deist ◽  
A Dautry-Varsat ◽  
C Hivroz ◽  
...  
Keyword(s):  
B Cells ◽  
Gene Transfer ◽  
B Cell ◽  
Cell Lines ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Receptor Expression ◽  
Chain Gene ◽  
High Affinity ◽  
And Function

SCID X1 is characterized by faulty T-cell and natural killer cell differentiation caused by mutation of the gamma-c chain gene encoding a number of multiple cytokine receptors (interleukin-2 [IL-2], IL-4, IL- 7, IL-9, and IL-15 receptors). To assess the feasibility of inducing long-term expression and function of the gamma-c chain, Epstein-Barr virus (EBV)-transformed B-cell lines from two patients with SCID X1 were transduced with a Moloney-derived retroviral vector containing the gamma-c chain cDNA. The viral LTR was used as the promoter. Immediately after two cycles of coculture with the psi-crip clone producing the MFG(B2)-gamma-c cDNA vector, gamma-c expression, assessed by detection of the mRNA and membrane protein expression, was found in 15% to 20% of cells. The degree of membrane expression was similar to that in control EBV-B cells. Expression increased steadily over 6 months, becoming detectable in 100% of cells, and remained stable thereafter for a total of 9 months, reflecting positive selection of transduced cells. A study of provirus integration sites showed multiple integration. The expressed gamma-c was functional, because it restored high-affinity IL- 2 receptor binding, IL-2 endocytosis, and IL-2-triggered phosphorylation of JAK-3 tyrosine kinase. Similar results were obtained with the two B-cell lines. These results show that efficient gamma-c gene transfer into B-cells lacking functional gamma-c is feasible and results in strong and stable expression of a functional gamma-c chain, apparently conferring a selective growth advantage in culture. Further in vitro studies of gamma-c gene transfer into gamma-c- hematopoietic progenitors are being conducted to assess the feasibility of correcting lymphocyte differentiation defects.

scholarly journals Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 926 ◽  
Author(s):  
Stefania Mantovani ◽  
Barbara Oliviero ◽  
Stefania Varchetta ◽  
Dalila Mele ◽  
Mario U. Mondelli
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Escape ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Current Status ◽  
Tumor Immune Escape

Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

A Randomized Phase II Study of Xcellerated T Cells™ with or without Prior Fludarabine Therapy in Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2410-2410
Author(s):  
James R. Berenson ◽  
Ivan M. Borrello ◽  
Ravi Vij ◽  
Asad Bashey ◽  
Thomas Martin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Magnetic Beads ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
New Drugs ◽  
M Protein ◽  
High Dose ◽  
T Cell Therapy

Abstract Background: T cells from myeloma subjects can be activated and expanded ex vivo using the Xcellerate™ Process, in which peripheral blood mononuclear cells are incubated with anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte™-Dynabeads®). In a previous study (Borrello et al., ASCO 2004), Xcellerated T Cells administered to myeloma subjects following high dose chemotherapy and autologous stem cell transplantation led to accelerated lymphocyte recovery and restoration of the T cell receptor repertoire. In the current study, subjects with relapsed or refractory myeloma were randomized to Xcellerated T Cells with or without one cycle of fludarabine prior to Xcellerated T Cells. Fludarabine is being used to assess the influence of lymphoablation on the anti-tumor and immune reconstitution effects of T cell therapy; it has previously been reported to have no significant activty in myeloma (Kraut et al., Invest. New Drugs, 1990). Methods: Approximately 30 subjects are planned to receive treatment. Each receives a single dose of 60–100 x 109 Xcellerated T Cells. Subjects on the fludarabine arm receive a single cycle (5 days at 25 mg/m2), completed 4 days prior to the Xcellerated T Cell infusion. Results: 17 subjects have been enrolled and 13 treated to date, with median last f/u visit of 28 days (range 0–140). Xcellerated T Cells were successfully manufactured in all subjects, with T cell expansion 136 ± 61 fold (mean ± SD), with 79.2 ± 13.8 x 109 cells infused, and final product 98.0 ± 2.0% T cells (n=13). There have been no reported serious adverse events related to Xcellerated T Cells. In the fludarabine arm, lymphocytes decreased from 1,228 ± 290/mm3 (mean ± SEM) to 402 ± 164 following fludarabine, and then increased to 1,772 ± 278 on Day 14 following T cell infusion (n=7). In the non-fludarabine arm, lymphocyte counts increased from 1,186 ± 252 to 3,204 ± 545 on Day 14 (n=4). Lymphocytes were comprised of both CD4+ and CD8+ T cells. Increases were observed in NK cells from 77 ± 26 to 121 ± 25, monocytes from 166 ± 44 to 220 ± 30 and platelets from 218 ± 16 to 235 ± 24 by Day 14 (n=11). In the non-fludarabine arm, neutrophils increased from 3.6 ± 0.9 to 4.8 ± 0.6 on Day 1. On the fludarabine arm, 3 of 6 subjects developed Grade 4 neutropenia and one developed Grade 3 thrombocytopenia. Seven subjects were evaluable for serum M-protein measurements to Day 28. One of three fludarabine treated subjects had an M-protein decrease of 38%. Conclusions: Xcellerated T Cells were well-tolerated and led to increased lymphocytes, including T cells and NK cells. Increases in other hematologic parameters, including neutrophils and platelets were also observed. In this patient population, fludarabine is lymphoablative and also can cause neutropenia and thrombocytopenia. The fludarabine schedule has been decreased from 5 to 3 days. A decrease in M-protein has been observed in one of three fludarabine-treated subjects; data on additional subjects will be presented.

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.

scholarly journals Binding of Excreted and/or Secreted Products of Adult Hookworms to Human NK Cells in Necator americanus-Infected Individuals from Brazil

2008 ◽  
Vol 76 (12) ◽  
pp. 5810-5816 ◽  
Author(s):  
Andréa Teixeira-Carvalho ◽  
Ricardo T. Fujiwara ◽  
Erik J. Stemmy ◽  
Denise Olive ◽  
Jesse M. Damsker ◽  
...  
Keyword(s):  
Nk Cells ◽  
Transforming Growth Factor ◽  
Nk Cell ◽  
Ex Vivo ◽  
Interleukin 10 ◽  
Receptor Expression ◽  
Necator Americanus ◽  
Ifn Γ ◽  
The Impact

ABSTRACT The impact of the interaction between excreted and/or secreted (ES) Necator americanus products and NK cells from Necator-infected individuals was analyzed. We investigated the binding of ES products to NK cells, the expression of NK cell receptors (CD56, CD159a/NKG2A, CD314/NKG2D, CD335/NKp46, and KLRF1/NKp80), the frequency of gamma interferon (IFN-γ)-producing NK cells after whole-blood in vitro stimulation, and the capacity of N. americanus ES products to induce NK cell chemotaxis. In contrast to those from noninfected individuals, NK cells from Necator-infected individuals demonstrated no binding with N. americanus ES products. This phenomenon was not due to alterations in NK cell receptor expression in infected subjects and could not be reproduced with NK cells from uninfected individuals by incubation with immunoregulatory cytokines (interleukin-10/transforming growth factor β). Further, we found that a significantly greater percentage of NK cells from infected subjects than NK cells from uninfected individuals spontaneously produced IFN-γ upon ex vivo culture. Our findings support a model whereby NK cells from Necator-infected individuals may interact with ES products, making these cells refractory to binding with exogenous ES products. During N. americanus infection, human NK cells are attracted to the site of infection by chemotactic ES products produced by adult Necator worms in the gut mucosa. Binding of ES products causes the NK cells to become activated and secrete IFN-γ locally, thereby contributing to the adult hookworm's ability to evade host immune responses.

Soluble HLA-G dampens CD94/NKG2A expression and function and differentially modulates chemotaxis and cytokine and chemokine secretion in CD56bright and CD56dim NK cells

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5840-5850 ◽  
Author(s):  
Fabio Morandi ◽  
Elisa Ferretti ◽  
Roberta Castriconi ◽  
Alessandra Dondero ◽  
Andrea Petretto ◽  
...  
Keyword(s):  
Nk Cells ◽  
Chemokine Receptor ◽  
Nk Cell ◽  
Receptor Expression ◽  
Regulated Secretion ◽  
Cell Functions ◽  
Soluble Hla ◽  
Ifn Γ ◽  
And Function ◽  
Nk Receptor

Abstract Soluble HLA-G (sHLA-G) inhibits natural killer (NK) cell functions. Here, we investigated sHLA-G–mediated modulation of (1) chemokine receptor and NK receptor expression and function and (2) cytokine and chemokine secretion in CD56bright and CD56dim NK cells. sHLA-G-treated or untreated peripheral blood (PB) and tonsil NK cells were analyzed for chemokine receptor and NK receptor expression by flow cytometry. sHLA-G down-modulated (1) CXCR3 on PB and tonsil CD56bright and CD56dim, (2) CCR2 on PB and tonsil CD56bright, (3) CX3CR1 on PB CD56dim, (4) CXCR5 on tonsil CD56dim, and (5) CD94/NKG2A on PB and tonsil CD56bright and CD56dim NK cells. Such sHLA-G–mediated down-modulations were reverted by adding anti–HLA-G or anti–ILT2 mAbs. sHLA-G inhibited chemotaxis of (1) PB NK cells toward CXCL10, CXCL11, and CX3CL1 and (2) PB CD56bright NK cells toward CCL2 and CXCL10. IFN-γ secretion induced by NKp46 engagement was inhibited by NKG2A engagement in untreated but not in sHLA-G–treated NK cells. sHLA-G up-regulated secretion of (1) CCL22 in CD56bright and CD56dim and (2) CCL2, CCL8, and CXCL2-CXCL3 in CD56dim PB NK cells. Signal transduction experiments showed sHLA-G–mediated down-modulation of Stat5 phosphorylation in PB NK cells. In conclusion, our data delineated novel mechanisms of sHLA-G–mediated inhibition of NK-cell functions.

scholarly journals Trib1 regulates eosinophil lineage commitment and identity by restraining the neutrophil program

Blood ◽  
2019 ◽  
Vol 133 (22) ◽  
pp. 2413-2426 ◽  
Author(s):  
Ethan A. Mack ◽  
Sarah J. Stein ◽  
Kelly S. Rome ◽  
Lanwei Xu ◽  
Gerald B. Wertheim ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Receptor Expression ◽  
Lineage Commitment ◽  
Hematopoietic Stem ◽  
Interleukin 5 ◽  
Eosinophil Migration ◽  
Enhancer Binding Protein ◽  
Important Regulator ◽  
And Function

Abstract Eosinophils and neutrophils are critical for host defense, yet gaps in understanding how granulocytes differentiate from hematopoietic stem cells (HSCs) into mature effectors remain. The pseudokinase tribbles homolog 1 (Trib1) is an important regulator of granulocytes; knockout mice lack eosinophils and have increased neutrophils. However, how Trib1 regulates cellular identity and function during eosinophilopoiesis is not understood. Trib1 expression markedly increases with eosinophil-lineage commitment in eosinophil progenitors (EoPs), downstream of the granulocyte/macrophage progenitor (GMP). Using hematopoietic- and eosinophil-lineage–specific Trib1 deletion, we found that Trib1 regulates both granulocyte precursor lineage commitment and mature eosinophil identity. Conditional Trib1 deletion in HSCs reduced the size of the EoP pool and increased neutrophils, whereas deletion following eosinophil lineage commitment blunted the decrease in EoPs without increasing neutrophils. In both modes of deletion, Trib1-deficient mice expanded a stable population of Ly6G+ eosinophils with neutrophilic characteristics and functions, and had increased CCAAT/enhancer binding protein α (C/EBPα) p42. Using an ex vivo differentiation assay, we found that interleukin 5 (IL-5) supports the generation of Ly6G+ eosinophils from Trib1-deficient cells, but is not sufficient to restore normal eosinophil differentiation and development. Furthermore, we demonstrated that Trib1 loss blunted eosinophil migration and altered chemokine receptor expression, both in vivo and ex vivo. Finally, we showed that Trib1 controls eosinophil identity by modulating C/EBPα. Together, our findings provide new insights into early events in myelopoiesis, whereby Trib1 functions at 2 distinct stages to guide eosinophil lineage commitment from the GMP and suppress the neutrophil program, promoting eosinophil terminal identity and maintaining lineage fidelity.

scholarly journals Crucial Role of DNA Methylation in Determination of Clonally Distributed Killer Cell Ig-like Receptor Expression Patterns in NK Cells

2002 ◽  
Vol 169 (8) ◽  
pp. 4253-4261 ◽  
Author(s):  
Simeon Santourlidis ◽  
Hans-Ingo Trompeter ◽  
Sandra Weinhold ◽  
Britta Eisermann ◽  
Klaus L. Meyer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Nk Cells ◽  
Crucial Role ◽  
Expression Patterns ◽  
Killer Cell ◽  
Receptor Expression

scholarly journals Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the FcγRIIIa-158 V/V and V/F polymorphism

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2561-2564 ◽  
Author(s):  
Evdoxia Hatjiharissi ◽  
Lian Xu ◽  
Daniel Ditzel Santos ◽  
Zachary R. Hunter ◽  
Bryan T. Ciccarelli ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Gene Transcript ◽  
Non Hodgkin Lymphoma ◽  
Healthy Donors ◽  
Cd16 Expression ◽  
Cell Expression

The presence of valine (V) at position 158 of FcγRllla (CD16) is known to improve clinical response to rituximab in indolent non-Hodgkin lymphoma (NHL). Little is known about the basic mechanisms for this observation. We examined natural killer (NK) cells from healthy donors representing the FcγRIIIa-158 polymorphic subgroups (V/V, V/F, and F/F) for gene transcript and cell surface CD16 expression, rituximab binding, and rituximab-dependent NK cell-mediated cytotoxicity. We observed higher levels of FcγRIIIa transcripts among individuals with the FcγRIIIa-158 V/V versus V/F or F/F genotype (P < .001); increased cell surface CD16 expression by quantitative flow cytometry on NK cells from individuals expressing at least one valine at FcγRIIIa-158 versus F/F (P = .029); as well as augmented rituximab binding and rituximab-mediated, antibody-dependent cellular cytotoxicity (ADCC). These results suggest that individuals expressing at least one valine at FcγRIIIa-158 might, in part, have better clinical outcomes due to increased CD16 expression, rituximab binding, and rituximab-mediated ADCC.

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