Editorial: Tailoring NK Cell Receptor-Ligand Interactions: An Art in Evolution.
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ABSTRACT:
SUBMITTER: Koehl U
PROVIDER: S-EPMC5835124 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Editorial: Tailoring NK Cell Receptor-Ligand Interactions: An Art in Evolution.
Koehl Ulrike U Toubert Antoine A Pittari Gianfranco G
Frontiers in immunology 20180227
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Project description: Not available
| S-EPMC5651263 | biostudies-literature
Project description:MotivationIntracellular communication is crucial to many biological processes, such as differentiation, development, homeostasis and inflammation. Single-cell transcriptomics provides an unprecedented opportunity for studying cell-cell communications mediated by ligand-receptor interactions. Although computational methods have been developed to infer cell type-specific ligand-receptor interactions from one single-cell transcriptomics profile, there is lack of approaches considering ligand and receptor simultaneously to identifying dysregulated interactions across conditions from multiple single-cell profiles.ResultsWe developed scLR, a statistical method for examining dysregulated ligand-receptor interactions between two conditions. scLR models the distribution of the product of ligands and receptors expressions and accounts for inter-sample variances and small sample sizes. scLR achieved high sensitivity and specificity in simulation studies. scLR revealed important cytokine signaling between macrophages and proliferating T cells during severe acute COVID-19 infection, and activated TGF-β signaling from alveolar type II cells in the pathogenesis of pulmonary fibrosis.Availability and implementationscLR is freely available at https://github.com/cyhsuTN/scLR.Supplementary informationSupplementary data are available at Bioinformatics online.
| S-EPMC9191214 | biostudies-literature
Project description:Cell surface receptors have been extensively studied because they initiate and regulate signal transduction cascades leading to a variety of functional cellular outcomes. An important class of immune receptors (e.g., T-cell antigen receptors) whose ligands are anchored to the surfaces of other cells remain poorly understood. The mechanism by which ligand binding initiates receptor phosphorylation, a process termed "receptor triggering", remains controversial. Recently, direct measurements of the (two-dimensional) receptor-ligand complex lifetimes at cell-cell interface were found to be smaller than (three-dimensional) lifetimes in solution but the underlying mechanism is unknown. At the cell-cell interface, the receptor-ligand complex spans a short intermembrane distance (15 nm) compared to long surface molecules (LSMs) whose ectodomains span >40 nm and these LSMs include phosphatases (e.g., CD45) that dephosphorylate the receptor. It has been proposed that size-based segregation of LSMs from a receptor-ligand complex is a mechanism of receptor triggering but it is unclear whether the mechanochemistry supports such small-scale segregation. Here we present a nanometer-scale mathematical model that couples membrane elasticity with the compressional stiffness and lateral mobility of LSMs. We find robust supradiffusive segregation of LSMs from a single receptor-ligand complex. The model predicts that LSM redistribution will result in a time-dependent tension on the complex leading to a decreased two-dimensional lifetime. Interestingly, the model predicts a nonlinear relationship between the three- and two-dimensional lifetimes, which can enhance the ability of receptors to discriminate between similar ligands.
| S-EPMC3309404 | biostudies-literature
Project description:To explore how the immune system controls clearance of SARS-CoV-2, we used a single-cell, mass cytometry-based proteomics platform to profile the immune systems of 21 patients who had recovered from SARS-CoV-2 infection without need for admission to an intensive care unit or for mechanical ventilation. We focused on receptors involved in interactions between immune cells and virus-infected cells. We found that the diversity of receptor repertoires on natural killer (NK) cells was negatively correlated with the viral clearance rate. In addition, NK subsets expressing the receptor DNAM1 were increased in patients who more rapidly recovered from infection. Ex vivo functional studies revealed that NK subpopulations with high DNAM1 expression had cytolytic activities in response to target cell stimulation. We also found that SARS-CoV-2 infection induced the expression of CD155 and nectin-4, ligands of DNAM1 and its paired coinhibitory receptor TIGIT, which counterbalanced the cytolytic activities of NK cells. Collectively, our results link the cytolytic immune responses of NK cells to the clearance of SARS-CoV-2 and show that the DNAM1 pathway modulates host-pathogen interactions during SARS-CoV-2 infection.
| S-EPMC8553551 | biostudies-literature
Project description:BackgroundThe effectiveness of killer immunoglobulin-like receptor (KIR) incompatible, alloreactive natural killer (NK) cells has been primarily documented in hematological malignancies following stem-cell transplant. This effect has not been thoroughly evaluated for pediatric solid tumors. In this study, we evaluated KIR receptor-ligand incompatibility of NK cells against osteosarcoma cell lines.ProcedureFollowing the KIR receptor-ligand mismatch model, MHC I cell surface expression and KIR ligand mRNA content of 3 osteosarcoma cell lines was determined by flow cytometry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. NK cells were isolated from healthy volunteer donor peripheral blood mononuclear cells (PBMCs) and KIR surface expression determined by flow cytometry. An Annexin-V based flow cytometric killing assay was used to determine % of dying osteosarcoma target cells by donor NK effector cells.ResultsOne of seven healthy volunteer donors tested lacked phenotypic expression of one KIR. However, variable expression of KIR ligands was observed in 3 osteosarcoma cell lines. The highest rates of dying cells were seen in osteosarcoma cells with the lowest KIR ligand expression. Following down-regulation of KIR ligand expression, an increased susceptibility to NK cell-mediated killing was observed in a previously NK-resistant osteosarcoma cell line.ConclusionsVariable MHC I and KIR ligand expression was observed in osteosarcoma cell lines and this resulted in variable susceptibility to NK cell-mediated killing predicted by the degree of KIR receptor-ligand incompatibility. Collectively, these data provide rationale for the study of KIR incompatible stem-cell transplant for osteosarcoma, although further studies with fresh osteosarcoma samples are necessary.
| S-EPMC3081247 | biostudies-literature
Project description:Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that leads to progressive cyst formation and accelerated loss of pulmonary function. Neoplastic smooth muscle cells from an unknown source metastasize to the lung and drive destructive remodeling. Given the role of NK cells in immune surveillance, we postulated that NK cell activating receptors and their cognate ligands are involved in LAM pathogenesis. We found that ligands for the NKG2D activating receptor UL-16 binding protein 2 (ULBP2) and ULBP3 are localized in cystic LAM lesions and pulmonary nodules. We found elevated soluble serum ULBP2 (mean = 575 pg/ml ± 142) in 50 of 100 subjects and ULBP3 in 30 of 100 (mean = 8,300 pg/ml ± 1,515) subjects. LAM patients had fewer circulating NKG2D+ NK cells and decreased NKG2D surface expression. Lung function decline was associated with soluble NKG2D ligand (sNKG2DL) detection. The greatest rate of decline forced expiratory volume in 1 second (FEV1, -124 ± 30 ml/year) in the 48 months after enrollment (NHLBI LAM Registry) occurred in patients expressing both ULBP2 and ULBP3, whereas patients with undetectable sNKG2DL levels had the lowest rate of FEV1 decline (-32.7 ± 10 ml/year). These data suggest a role for NK cells, sNKG2DL, and the innate immune system in LAM pathogenesis.
| S-EPMC5053147 | biostudies-literature
Project description:Interactions between different cell types are critical for a plethora of biological processes, such as the immune response. We recently developed a novel technology, called LIPSTIC (labeling of immune partnership by SorTagging intercellular contacts), that allows for identifying cells undergoing specific interactions thanks to an enzymatic labeling reaction. Our work demonstrated the use of this technology to monitor interactions between immune cells, both in vitro and in vivo, by the genetic engineering of CD40 and CD40L, an essential costimulatory axis between antigen-presenting cells and T cells. Here we describe protocols to design novel LIPSTIC-engineered ligand and receptor pairs, clone constructs into retroviral expression vector, perform their initial validation, and use them to measure interactions ex vivo. This information will be useful to investigators interested in exploiting the LIPSTIC technology to track their favorite immune interaction. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Design of LIPSTIC-engineered ligand and receptor pairs Basic Protocol 2: Cloning of LIPSTIC-engineered ligand and receptor pairs Basic Protocol 3: Validation of LIPSTIC-engineered ligand and receptor pairs in 293T cells Basic Protocol 4: Measuring interaction with LIPSTIC in immune cells ex vivo.
| S-EPMC7613713 | biostudies-literature
Project description:We introduce three assays for analyzing ligand-receptor interactions based on the specific conjugation of ligands to SNAP-tag fusion proteins. Conjugation of ligands to different SNAP-tag fusions permits the validation of suspected interactions in cell extracts and fixed cells as well as the establishment of high-throughput assays. The different assays allow the analysis of strong and weak interactions. Conversion of ligands into SNAP-tag substrates thus provides access to a powerful toolbox for the analysis of their interactions with proteins.
| S-EPMC3365113 | biostudies-literature
Project description:Background/objectives: The functional activity of a certain tumor determines the effectiveness of primary NK cells and NK-92 cell line-based cancer therapy; their therapeutic effectiveness against different tumors can vary. This work provides a direct simultaneous comparison of the cytotoxic effects of in vitro-activated peripheral NK (pNK) cells and NK-92 cells in spheroid models of BT-474, MCF7 and SKOV-3 carcinomas and uncovers the reasons for the differential effectiveness of NK cells against tumors. Methods: Tumor spheroids of similar size and shape, obtained from agarose molds, were incubated with NK-92 or pNK cells for 24 h. Tumor cell death was detected using flow cytometry or confocal microscopy. Cytokine production, granzyme B levels and NK cell degranulation analyses were performed, along with pNK and target-cell phenotypic characterization. Results: While NK-92 and pNK cells lysed BT-474 spheroids with comparably low efficiency, pNK cells were more capable of eliminating MCF7 and SKOV-3 spheroids than NK-92 cells were. The results of the functional and phenotypic analyses strongly support the participation of the NKG2D-NKG2DL pathway in pNK cell activation induced by the most sensitive cytotoxic attack on SKOV-3 spheroids, whereas the CX3CR1-CX3CL1 axis appears to be involved in the pNK reaction against MCF-7 spheroids. Conclusions: We provide a new approach for the preliminary identification of the most promising NK cell receptors that can alter the effectiveness of cancer therapy depending on the specific tumor type. Using this approach, NK-92 cells or pNK subsets can be selected for further accumulation and/or genetic modification to improve specificity and reactivity.
| S-EPMC11504426 | biostudies-literature
Project description:Described is the development and application of a versatile semisynthetic strategy, based on a combination of sortase-mediated coupling and tetrazine ligation chemistry, which can be exploited for the efficient incorporation of tunable functionality into chimeric recombinant proteins. To demonstrate the scope of the method, the assembly of a set of bivalent ligands, which integrate members of the epidermal growth factor (EGF) ligand family, is described. By using a series of bivalent EGFs with variable intraligand spacing, the differences in structure were correlated with the ability to bias signaling in the ErbB receptor family in a cell motility assay. Biasing away from EGFR-HER2 dimerization with a bivalent EGF was observed to reduce cell motility in an intraligand distance-dependent fashion, thus demonstrating the utility of the approach for acutely perturbing receptor-mediated cell signaling pathways.
| S-EPMC4018821 | biostudies-literature