scholarly journals Divergent Traits and Ligand-Binding Properties of the Cytomegalovirus CD48 Gene Family

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 813
Author(s):  
Pablo Martínez-Vicente ◽  
Domènec Farré ◽  
Pablo Engel ◽  
Ana Angulo
Keyword(s):  
Cell Surface ◽  
Cell Function ◽  
Nk Cell ◽  
Receptor Gene ◽  
Costimulatory Molecule ◽  
Gene Families ◽  
Biochemical Properties ◽  
Cell Surface Receptor ◽  
Binding Properties ◽  
Cell Surface Molecule

The genesis of gene families by the capture of host genes and their subsequent duplication is a crucial process in the evolution of large DNA viruses. CD48 is a cell surface molecule that interacts via its N-terminal immunoglobulin (Ig) domain with the cell surface receptor 2B4 (CD244), regulating leukocyte cytotoxicity. We previously reported the presence of five CD48 homologs (vCD48s) in two related cytomegaloviruses, and demonstrated that one of them, A43, binds 2B4 and acts as a soluble CD48 decoy receptor impairing NK cell function. Here, we have characterized the rest of these vCD48s. We show that they are highly glycosylated proteins that display remarkably distinct features: divergent biochemical properties, cellular locations, and temporal expression kinetics. In contrast to A43, none of them interacts with 2B4. Consistent with this, molecular modeling of the N-terminal Ig domains of these vCD48s evidences notable changes as compared to CD48, suggesting that they interact with alternative targets. Accordingly, we demonstrate that one of them, S30, tightly binds CD2, a crucial T- and NK-cell adhesion and costimulatory molecule. Thus, our findings show how a key host immune receptor gene captured by a virus can be subsequently remodeled to evolve new immunoevasins with altered binding properties.

scholarly journals Divergent Traits and Ligand-Binding Features of the Cytomegalovirus CD48 Gene Family

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 23
Author(s):  
Pablo Martinez-Vicente ◽  
Domènec Farré ◽  
Elena Gracia-Latorre ◽  
Pablo Engel ◽  
Ana Angulo
Keyword(s):  
Cell Surface ◽  
Nk Cell ◽  
Viral Evolution ◽  
Costimulatory Molecule ◽  
Surface Protein ◽  
Gene Families ◽  
Biochemical Properties ◽  
Cell Surface Receptor ◽  
Type I ◽  
Independent Functions

The genesis of gene families through the capture of host genes and their subsequent duplication is a crucial process in the evolution of large DNA viruses. CD48 is a cell surface protein with an ectodomain composed of two immunoglobulin (Ig) domains. Via its N-terminal Ig domain, CD48 interacts with the cell surface receptor 2B4, triggering signal transduction events that regulate leukocyte cytotoxicity. We previously reported the presence of five CD48 homologs (vCD48s) in two related cytomegaloviruses, derived from a common host CD48 ancestor gene acquired by retrotranscription. Recently, we examined one member of this family, A43, showing that it acts as a functional viral decoy receptor, binding with high affinity and stability to 2B4 and impairing NK-cell cytotoxicity. Here, we have characterized the rest of the vCD48s. We show that they are highly glycosylated type I transmembrane proteins that display remarkably distinct features: dissimilar structures (e.g., different size stalks and cytoplasmic tails), biochemical properties, locations (cell surface/soluble), and temporal kinetic classes. We found that, in contrast to A43, none of them interacts with 2B4. Consistent with this, the molecular modeling of the N-terminal Ig domains of these vCD48s evidences significant changes in the numbers and lengths of their β-strands and inter-sheet loops that participate in the interaction of CD48 with 2B4. This suggests that these vCD48s have diverged to perform new 2B4-independent functions. Interestingly, we determined that one of them, S30, tightly binds CD2, a T- and NK-cell adhesion and costimulatory molecule whose primary ligand is CD58. Thus, altogether, our results show how a key host immune receptor captured by a virus can be subsequently remodeled during viral evolution to yield new molecules with improved affinities to their cognate receptors or with shifted binding specificities to additional immune targets, expanding the repertoire of viral immunoevasins.

scholarly journals Conjugated Bilirubin Differentially Regulates CD4+ T Effector Cells and T Regulatory Cell Function through Outside-In and Inside-Out Mechanisms: The Effects of HAV Cell Surface Receptor and Intracellular Signaling

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Karla F. Corral-Jara ◽  
Jorge L. Trujillo-Ochoa ◽  
Mauricio Realpe ◽  
Arturo Panduro ◽  
Juan F. Gómez-Leyva ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Surface ◽  
Intracellular Signaling ◽  
Cell Function ◽  
Hepatitis A Virus ◽  
Receptor Gene ◽  
Cell Surface Receptor ◽  
T Effector Cells ◽  
Healthy Donors ◽  
Conjugated Bilirubin

We recently reported an immune-modulatory role of conjugated bilirubin (CB) in hepatitis A virus (HAV) infection. During this infection the immune response relies on CD4+ T lymphocytes (TLs) and it may be affected by the interaction of HAV with its cellular receptor (HAVCR1/TIM-1) on T cell surface. How CB might affect T cell function during HAV infection remains to be elucidated. Herein,in vitrostimulation of CD4+ TLs from healthy donors with CB resulted in a decrease in the degree of intracellular tyrosine phosphorylation and an increase in the activity of T regulatory cells (Tregs) expressing HAVCR1/TIM-1. A comparison between CD4+ TLs from healthy donors and HAV-infected patients revealed changes in the TCR signaling pathway relative to changes in CB levels. The proportion of CD4+CD25+ TLs increased in patients with low CB serum levels and an increase in the percentage of Tregs expressing HAVCR1/TIM-1 was found in HAV-infected patients relative to controls. A low frequency of 157insMTTTVP insertion in the viral receptor geneHAVCR1/TIM-1was found in patients and controls. Our data revealed that, during HAV infection, CB differentially regulates CD4+ TLs and Tregs functions by modulating intracellular pathways and by inducing changes in the proportion of Tregs expressing HAVCR1/TIM-1.

scholarly journals Cancer immune therapy with PD-1-dependent CD137 co-stimulation provides localized tumour killing without systemic toxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yunqian Qiao ◽  
Yangmin Qiu ◽  
Jie Ding ◽  
Nana Luo ◽  
Hao Wang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Liver Toxicity ◽  
Nk Cell ◽  
Immune Therapy ◽  
Clinical Development ◽  
Cell Surface Receptor ◽  
Natural Ligand

AbstractExpression of the cell surface receptor CD137 has been shown to enhance anti-cancer T cell function via engagement with its natural ligand 4-1BBL. CD137 ligation with engineered ligands has emerged as a cancer immunotherapy strategy, yet clinical development of agonists has been hindered by either toxicity or limited efficacy. Here we show that a CD137/PD-1 bispecific antibody, IBI319, is able to overcome these limitations by coupling CD137 activation to PD-1-crosslinking. In CT26 and MC38 syngeneic mouse tumour models, IBI319 restricts T cell co-stimulation to PD-1-rich microenvironments, such as tumours and tumour-draining lymph nodes, hence systemic (liver) toxicity arising from generalised T cell activation is reduced. Besides limiting systemic T cell co-stimulation, the anti-PD-1 arm of IBI319 also exhibits checkpoint blockade functions, with an overall result of T and NK cell infiltration into tumours. Toxicology profiling in non-human primates shows that IBI319 is a well-tolerated molecule with IgG-like pharmacokinetic properties, thus a suitable candidate for further clinical development.

Soluble and Membrane Bound MICA in Myeloma Do Not Adversely Effect Regulation of Natural Killer Cell Function Via NKG2D..

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2462-2462
Author(s):  
Jumei Shi ◽  
Susann Szmania ◽  
Fenghuang Zhan ◽  
John Shaughnessy ◽  
Bart Barlogie ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Elevated Serum ◽  
Serum Levels ◽  
Down Regulation ◽  
Nkg2d Expression ◽  
Mica Gene ◽  
Membrane Bound

Abstract The human MHC class I -related chain gene A (MICA), a highly polymorphic MHC-encoded cell-surface glycoprotein, is a stress-induced and transformation related molecule absent from most normal tissues. Expression of MICA has been reported on a variety of mostly epithelial tumors. MICA can activate Natural Killer (NK) cells via interacting with the immunoreceptor NKG2D. Soluble MICA (sMICA), when shedded from tumor by the action of matrix-metalloproteinases (MMPs), can be detected at high levels in the sera of cancer patients. High levels of sMICA can down-regulate NKG2D expression and lead to functional impairment of NK cells thus providing for a mechanism of tumor escape. Gene array expression profiling of bone marrow biopsies revealed high levels of MMP2 and MMP9 in the bone marrow microenvironment, but not in the purified myeloma cells of the same patients. Since we are developing allogeneic NK cell therapy as a novel treatment for high-risk myeloma we decided to study whether the high activity of MMP2 and MMP9 resulted in 1) elevated sMICA levels in myeloma, and 2) affected NKG2D expression by NK cells. We found by ELISA assays that 28% (13/46) of patients with MM at diagnosis contained elevated serum levels of sMICA (median: 265.2 pg/ml; range: 125.9 – 806.5 pg/ml). sMICA levels were low in 16 control healthy donors tested (median: 0.8 pg/ml; range: 0 – 91 pg/ml). Next, we correlated sMICA levels with indicators of tumor burden and prognosticators of outcome in MM. We observed that sMICA levels in the serum of MM patients was not associated with Ras associated oncogene (RAN) expression, presence of abnormal cytogenetics, elevated CRP, elevated b2-microglobulin or elevated serum M-protein levels. There was also no correlation between MICA gene expression in purified MM cells and increased sMICA levels in the serum. We therefore examined several myeloma cell lines and found that high MICA gene expression does not always correlate with MICA expression at the cell surface as detected by flow cytometry. We hypothesize that the lack of correlation between MICA RNA expression and sMICA may be due to variation in translation of the MICA mRNA or failure to transport the MICA protein to the cell surface. Further, we tested the expression of NKG2D on CD3−/CD56+ cells of 5 MM patients with elevated sMICA serum levels and detected no down-regulation of NKG2D on NK cells compared to controls comprising MM patients with normal sMICA levels (n=3) or normal donors (n=5). Recent studies have suggested that tumor-membrane bound MICA may also play a role in the down-regulation of NKG2D on NK cells. We next incubated normal donor NK cells with a) the high membrane bound MICA expressing MM cell line U266 or b) serum from MM patients containing high MICA levels neither of which resulted in down-regulation of NKG2D. We conclude that despite the high expression of MMP2 and MMP9 both soluble or membrane bound MICA do not down-regulate NKG2D on NK cells and hence do not adversely affect NK cell function in MM. One explanation may be that the sMICA levels we found in myeloma patients were in the order of pg/ml, whilst the levels reported in epithelial tumors are 2–3 logs higher.

Costimulatory molecule profiles and NK cell recovery after autologous hematopoietic cell transplantation (HCT) in multiple myeloma (MM) patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8089-8089
Author(s):  
Myo Htut ◽  
Ghislaine Gallez-Hawkins ◽  
Joycelynne Palmer ◽  
Xueli Liu ◽  
Ricardo Tomas Spielberger ◽  
...  
Keyword(s):  
Nk Cells ◽  
Hematopoietic Cell Transplantation ◽  
Cell Function ◽  
Nk Cell ◽  
Costimulatory Molecule ◽  
Cell Number ◽  
Cell Immune Response ◽  
Cell Recovery ◽  
Start Date ◽  
Autologous Hct

8089 Background: Increased immune responses post autologous HCT may be of benefit in long term disease control. Responses may be mediated by NK cell function and possibly other alternate pathways, including costimulatory molecule pathways. This pilot study assesses the expression of inhibitory (PD-1 and CTLA-4) and stimulatory (OX-40, ICOS, 4-1BB, and CD28) molecules on NK cells after auto-HCT in MM patients and evaluates the effect of lenalidomide treatment on these pathways. Methods: 17 patients with MM undergoing HCT, median age 56.7 years (36 – 67), were included in the study. Peripheral blood samples were taken 3 days prior to HCT and 14, 30, 60, 90, 180 days after HCT. At d180 post-HCT, 13/17 patients were receiving lenalidomide with d91 as median start date. NK cells and their costimulatory molecules were evaluated by flowcytometry using 2 six color panels of antibodies. One way ANOVA test and Kruskal-Wallis test (non-parametric) were applied to analyze the data using the Graphpad Software. Results: See table below. NK cell number was highest (median: 26% of total lymphocytes) at d14 (p: < 0.0001) compared to pre and post HCT levels. At d180, TNF-R OX40 expression was significantly increased in ≤PR group (n=5) (median: 9.5% of NK cells) compared to ≥VGPR (n=12) (0.8%; p=0.0084). In addition, NK cell number was higher in the lenalidomide group (n=13) (median: 15.15 % of total lymphocytes) compared to the no lenalidomide group (n=4) (6.74%; p=0.0108) at d180 post HCT. Significantly lower level of CTLA-4 expression was also found in the lenalidomide group (0.33% vs. 2.54%; p=0.0362). Conclusions: We observed NK cell recovery to baseline values at 60 days after HCT. At d180 post-HCT, OX-40 expression in NK cells was higher in ≤PR group than ≥VGPR group. Lenalidomide treatment was associated with higher NK cells number and decreased expression of CTLA-4. This observation could be a possible marker of enhanced host NK cell immune response against MM. Future clinical trials will explore therapies that increase NK cell responses. [Table: see text]

The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 779-786 ◽  
Author(s):  
Kent S. Boles ◽  
Winfried Barchet ◽  
Tom Diacovo ◽  
Marina Cella ◽  
Marco Colonna
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Suppressor ◽  
Cell Surface ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cell Junctions ◽  
Cell Surface Receptor ◽  
Cytotoxic Lymphocytes

AbstractThe tumor suppressor in lung cancer-1 (TSLC1) gene is frequently silenced in human lung carcinomas, and its expression suppresses tumorigenesis in nude mice. TSLC1 encodes a cell-surface protein called Necl-2 that belongs to the Nectin and Nectin-like (Necl) family of molecules. Necl-2 mediates epithelial cell junctions by homotypic contacts and/or heterotypic interactions with other Nectins and Necls. Thus, it inhibits tumorigenesis by ensuring that epithelial cells grow in organized layers. Here, we demonstrate that natural killer (NK) cells and CD8+ T cells recognize Necl-2 through a receptor known as class I-restricted T-cell–associated molecule (CRTAM), which is expressed only on activated cells. CRTAM–Necl-2 interactions promote cytotoxicity of NK cells and interferon γ (IFN-γ) secretion of CD8+ T cells in vitro as well as NK cell–mediated rejection of tumors expressing Necl-2 in vivo. These results provide evidence for an additional mechanism of tumor suppression mediated by TSLC1 that involves cytotoxic lymphocytes. Furthermore, they reveal Necl-2 as one of the molecular targets that allows the immunosurveillance network to distinguish tumor cells from normal cells.

scholarly journals The Traffic of the NKG2D/Dap10 Receptor Complex during Natural Killer (NK) Cell Activation

2009 ◽  
Vol 284 (24) ◽  
pp. 16463-16472 ◽  
Author(s):  
Pedro Roda-Navarro ◽  
Hugh T. Reyburn
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Receptor Expression ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Receptor Complex ◽  
Secretory Lysosomes

NKG2D is an important activating receptor for triggering the NK cell cytotoxic activity, although chronic engagement of specific ligands by NKG2D is also known to provoke decreased cell surface expression of the receptor and compromised NK cell function. We have studied the dynamics of surface NKG2D expression and how exposure to the specific ligand major histocompatibility complex class I chain-related molecule B (MICB) affects receptor traffic and fate. While in the NKL cell line and “resting” NK cells NKG2D was found principally at the cell surface, in activated primary NK cells an intracellular pool of receptor could also be found recycling to the plasma membrane. Exposure of NK cells to targets expressing MICB resulted in degradation of ∼50% of total NKG2D protein and lysosomal degradation of the DAP10 adaptor molecule. Consistent with these observations, confocal microscopy experiments demonstrated that DAP10 trafficked to secretory lysosomes in both transfected NKL cells and in activated primary NK cells upon interaction with MICB-expressing target cells. Interestingly, polarization to the synapse of secretory lysosomes containing DAP10 was also observed. The implications of the intracellular traffic of the NKG2D/DAP10 receptor complex for NK cell activation are discussed. We propose that the rapid degradation of NKG2D/DAP10 observed coincident with recruitment of the receptor to the cytotoxic immune synapse may explain the loss of NKG2D receptor expression after chronic exposure to NKG2D ligands.

scholarly journals NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17)

Blood ◽  
2013 ◽  
Vol 121 (18) ◽  
pp. 3599-3608 ◽  
Author(s):  
Rizwan Romee ◽  
Bree Foley ◽  
Todd Lenvik ◽  
Yue Wang ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Surface Expression ◽  
Key Points ◽  
And Function

Key Points Activated NK cells loose CD16 (FcRγIII) and CD62L through a metalloprotease called ADAM17. Inhibition of ADAM17 enhances CD16 mediated NK cell function by preserving CD16 on the NK cell surface to enhance ADCC.

scholarly journals Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell–mediated lysis of myeloma

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1309-1317 ◽  
Author(s):  
Jumei Shi ◽  
Guido J. Tricot ◽  
Tarun K. Garg ◽  
Priyangi A. Malaviarachchi ◽  
Susann M. Szmania ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Significant Activity

AbstractHuman leukocyte antigen class I molecules expressed by tumor cells play a central role in the regulation of natural killer (NK) cell–mediated immune responses. The proteasome inhibitor bortezomib has demonstrated significant activity in multiple myeloma (MM). We hypothesized that treatment of MM with bortezomib results in the reduction of cell-surface expression of class I and thereby sensitizes MM to NK cell–mediated lysis. Here we report that bortezomib down-regulates class I in a time- and dose-dependent fashion on all MM cell lines and patient MM cells tested. Downregulation of class I can also be induced in vivo after a single dose of 1.0 mg/m2 bortezomib. Bortezomib significantly enhances the sensitivity of patient myeloma to allogeneic and autologous NK cell–mediated lysis. Further, the level of decrease in class I expression correlates with increased susceptibility to lysis by NK cells. Clinically relevant bortezomib concentrations do not affect NK-cell function. Our findings have clear therapeutic implications for MM and other NK cell–sensitive malignancies in the context of both allogeneic and autologous adoptively transferred NK cells.

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