To see the other types of publications on this topic, follow the link: Cell surface antigen receptors.
Journal articles on the topic 'Cell surface antigen receptors'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Cell surface antigen receptors.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Sachen, Kacey L., Michael J. Strohman, Jonathan Singletary, Ash A. Alizadeh, Nicole H. Kattah, Chen Lossos, Elizabeth D. Mellins, Shoshana Levy, and Ronald Levy. "Self-antigen recognition by follicular lymphoma B-cell receptors." Blood 120, no. 20 (November 15, 2012): 4182–90. http://dx.doi.org/10.1182/blood-2012-05-427534.
Full textAbstract:
Abstract Follicular lymphoma is a monoclonal B-cell malignancy with each patient's tumor expressing a unique cell surface immunoglobulin (Ig), or B-cell receptor (BCR), that can potentially recognize antigens and/or transduce signals into the tumor cell. Here we evaluated the reactivity of tumor derived Igs for human tissue antigens. Self-reactivity was observed in 26% of tumor Igs (25 of 98). For one follicular lymphoma patient, the recognized self-antigen was identified as myoferlin. This patient's tumor cells bound recombinant myoferlin in proportion to their level of BCR expression, and the binding to myoferlin was preserved despite ongoing somatic hypermutation of Ig variable regions. Furthermore, BCR-mediated signaling was induced after culture of tumor cells with myoferlin. These results suggest that antigen stimulation may provide survival signals to tumor cells and that there is a selective pressure to preserve antigen recognition as the tumor evolves.
2
Simon, Bianca, Dennis C. Harrer, Beatrice Schuler-Thurner, Gerold Schuler, and Ugur Uslu. "Arming T Cells with a gp100-Specific TCR and a CSPG4-Specific CAR Using Combined DNA- and RNA-Based Receptor Transfer." Cancers 11, no. 5 (May 20, 2019): 696. http://dx.doi.org/10.3390/cancers11050696.
Full textAbstract:
Tumor cells can develop immune escape mechanisms to bypass T cell recognition, e.g., antigen loss or downregulation of the antigen presenting machinery, which represents a major challenge in adoptive T cell therapy. To counteract these mechanisms, we transferred not only one, but two receptors into the same T cell to generate T cells expressing two additional receptors (TETARs). We generated these TETARs by lentiviral transduction of a gp100-specific T cell receptor (TCR) and subsequent electroporation of mRNA encoding a second-generation CSPG4-specific chimeric antigen receptor (CAR). Following pilot experiments to optimize the combined DNA- and RNA-based receptor transfer, the functionality of TETARs was compared to T cells either transfected with the TCR only or the CAR only. After transfection, TETARs clearly expressed both introduced receptors on their cell surface. When stimulated with tumor cells expressing either one of the antigens or both, TETARs were able to secrete cytokines and showed cytotoxicity. The confirmation that two antigen-specific receptors can be functionally combined using two different methods to introduce each receptor into the same T cell opens new possibilities and opportunities in cancer immunotherapy. For further evaluation, the use of these TETARs in appropriate animal models will be the next step towards a potential clinical use in cancer patients.
3
Kamiya, Takahiro, Desmond Wong, Yi Tian Png, and Dario Campana. "A novel method to generate T-cell receptor–deficient chimeric antigen receptor T cells." Blood Advances 2, no. 5 (March 5, 2018): 517–28. http://dx.doi.org/10.1182/bloodadvances.2017012823.
Full textAbstract:
Key Points Newly designed PEBLs prevent surface expression of T-cell receptor in T cells without affecting their function. Combined with chimeric antigen receptors, PEBLs can rapidly generate powerful antileukemic T cells without alloreactivity.
4
Apostolopoulos, Vasso, Theresia Thalhammer, Andreas G. Tzakos, and Lily Stojanovska. "Targeting Antigens to Dendritic Cell Receptors for Vaccine Development." Journal of Drug Delivery 2013 (October 8, 2013): 1–22. http://dx.doi.org/10.1155/2013/869718.
Full textAbstract:
Dendritic cells (DCs) are highly specialized antigen presenting cells of the immune system which play a key role in regulating immune responses. Depending on the method of antigen delivery, DCs stimulate immune responses or induce tolerance. As a consequence of the dual function of DCs, DCs are studied in the context of immunotherapy for both cancer and autoimmune diseases. In vaccine development, a major aim is to induce strong, specific T-cell responses. This is achieved by targeting antigen to cell surface molecules on DCs that efficiently channel the antigen into endocytic compartments for loading onto MHC molecules and stimulation of T-cell responses. The most attractive cell surface receptors, expressed on DCs used as targets for antigen delivery for cancer and other diseases, are discussed.
5
Wang, Ninghai, Abhay Satoskar, William Faubion, Duncan Howie, Susumu Okamoto, Stefan Feske, Charles Gullo, et al. "The Cell Surface Receptor SLAM Controls T Cell and Macrophage Functions." Journal of Experimental Medicine 199, no. 9 (May 3, 2004): 1255–64. http://dx.doi.org/10.1084/jem.20031835.
Full textAbstract:
Signaling lymphocyte activation molecule (SLAM), a glycoprotein expressed on activated lymphocytes and antigen-presenting cells, has been shown to be a coregulator of antigen-driven T cell responses and is one of the two receptors for measles virus. Here we show that T cell receptor–induced interleukin (IL)-4 secretion by SLAM−/− CD4+ cells is down-regulated, whereas interferon γ production by CD4+ T cells is only slightly up-regulated. Although SLAM controls production of IL-12, tumor necrosis factor, and nitric oxide in response to lipopolysaccharide (LPS) by macrophages, SLAM does not regulate phagocytosis and responses to peptidoglycan or CpG. Thus, SLAM acts as a coreceptor that regulates signals transduced by the major LPS receptor Toll-like receptor 4 on the surface of mouse macrophages. A defective macrophage function resulted in an inability of SLAM−/− C57Bl/6 mice to remove the parasite Leishmania major. We conclude that the coreceptor SLAM plays a central role at the interface of acquired and innate immune responses.
6
Meiliana, Anna, Nurrani Mustika Dewi, and Andi Wijaya. "CAR T Cells: Precision Cancer Immunotherapy." Indonesian Biomedical Journal 10, no. 3 (December 28, 2018): 203–16. http://dx.doi.org/10.18585/inabj.v10i3.635.
Full textAbstract:
BACKGROUND: Current cancer drugs and treatments are aiming at eradicating tumor cells, but often are more toxic then effective, killing also the normal cells and not selectively the tumor cells. There is good personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity, which called adoptive cell therapy (ACT). A review of the unique biology of T cell therapy and of recent clinical experience compels a reassessment of target antigens that traditionally have been viewed from the perspective of weaker immunotherapeutic modalities.CONTENT: Chimeric antigen receptors (CAR) are recombinant receptors which provide both antigen-binding and T cell-activating functions. Many kind of CARs has been reported for the past few years, targeting an array of cell surface tumor antigens. Their biologic functions have extremely changed following the introduction of tripartite receptors comprising a costimulatory domain, termed second-generation CARs. The combination of CARs with costimulatory ligands, chimeric costimulatory receptors, or cytokines can be done to further enhance T cell potency, specificity and safety. CARs reflects a new class of drugs with exciting potential for cancer immunotherapy.SUMMARY: CAR-T cells have been arising as a new modality for cancer immunotherapy because of their potent efficacy against terminal cancers. They are known to exert higher efficacy than monoclonal antibodies and antibodydrug conjugates, and act via mechanisms distinct from T cell receptor-engineered T cells. These cells are constructed by transducing genes encoding fusion proteins of cancer antigen-recognizing single-chain Fv linked to intracellular signaling domains of T cell receptors.KEYWORDS: chimeric antigen receptor, CAR T cells, adoptive cell therapy, ACT, T cell receptor, TCR, cancer, immunotherapy
7
Ketchum, Christina M., Xiaoyu Sun, Alexandra Suberi, John T. Fourkas, Wenxia Song, and Arpita Upadhyaya. "Subcellular topography modulates actin dynamics and signaling in B-cells." Molecular Biology of the Cell 29, no. 14 (July 15, 2018): 1732–42. http://dx.doi.org/10.1091/mbc.e17-06-0422.
Full textAbstract:
B-cell signaling activation is most effectively triggered by the binding of B-cell receptors (BCRs) to membrane-bound antigens. In vivo, B-cells encounter antigen on antigen-presenting cells (APC), which possess complex surfaces with convoluted topographies, a fluid membrane and deformable cell bodies. However, whether and how the physical properties of antigen presentation affect B-cell activation is not well understood. Here we use nanotopographic surfaces that allow systematic variation of geometric parameters to show that surface features on a subcellular scale influence B-cell signaling and actin dynamics. Parallel nanoridges with spacings of 3 microns or greater induce actin intensity oscillations on the ventral cell surface. Nanotopography-induced actin dynamics requires BCR signaling, actin polymerization, and myosin contractility. The topography of the stimulatory surface also modulates the distribution of BCR clusters in activated B-cells. Finally, B-cells stimulated on nanopatterned surfaces exhibit intracellular calcium oscillations with frequencies that depend on topography. Our results point to the importance of physical aspects of ligand presentation, in particular, nanotopography for B-cell activation and antigen gathering.
8
Crowther, Michael D., Inge Marie Svane, and Özcan Met. "T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road." Cells 9, no. 7 (June 30, 2020): 1588. http://dx.doi.org/10.3390/cells9071588.
Full textAbstract:
T-cells have a natural ability to fight cancer cells in the tumour microenvironment. Due to thymic selection and tissue-driven immunomodulation, these cancer-fighting T-cells are generally low in number and exhausted. One way to overcome these issues is to genetically alter T-cells to improve their effectiveness. This process can involve introducing a receptor that has high affinity for a tumour antigen, with two promising candidates known as chimeric-antigen receptors (CARs), or T-cell receptors (TCRs) with high tumour specificity. This review focuses on the editing of immune cells to introduce such novel receptors to improve immune responses to cancer. These new receptors redirect T-cells innate killing abilities to the appropriate target on cancer cells. CARs are modified receptors that recognise whole proteins on the surface of cancer cells. They have been shown to be very effective in haematological malignancies but have limited documented efficacy in solid cancers. TCRs recognise internal antigens and therefore enable targeting of a much wider range of antigens. TCRs require major histocompatibility complex (MHC) restriction but novel TCRs may have broader antigen recognition. Moreover, there are multiple cell types which can be used as targets to improve the “off-the-shelf” capabilities of these genetic engineering methods.
9
Franco, A., M. Paroli, U. Testa, R. Benvenuto, C. Peschle, F. Balsano, and V. Barnaba. "Transferrin receptor mediates uptake and presentation of hepatitis B envelope antigen by T lymphocytes." Journal of Experimental Medicine 175, no. 5 (May 1, 1992): 1195–205. http://dx.doi.org/10.1084/jem.175.5.1195.
Full textAbstract:
Human activated T lymphocytes expressing class II molecules are able to present only complex antigens that bind to their own surface receptors, and thus can be captured, internalized, and processed through the class II major histocompatibility complex processing pathway. We have used the antigen-presenting T cell system to identify the viral receptor used by hepatitis B virus (HBV) to enter cells, as well as the sequence of HB envelope antigen (HBenvAg) involved in this interaction. Results show that both CD4+ and CD8+ T clones can process and present HBenvAg to class II-restricted cytotoxic T lymphocytes and that the CD71 transferrin receptor (TfR) is involved in efficient HBenvAg uptake by T cells. Moreover, we provide evidence that the HBenvAg sequence interacting with the T cell surface is contained within the pre-S2 region. Since TfR is also expressed on hepatocytes, it might represent a portal of cellular entry for HBV infection. This system of antigen presentation by T cells may serve as a model to study both lymphocyte receptors used by lymphocytotropic viruses and viral proteins critical to bind them.
10
Moores, Sheri L., Laura M. Selfors, Jessica Fredericks, Timo Breit, Keiko Fujikawa, Frederick W. Alt, Joan S. Brugge, and Wojciech Swat. "Vav Family Proteins Couple to Diverse Cell Surface Receptors." Molecular and Cellular Biology 20, no. 17 (September 1, 2000): 6364–73. http://dx.doi.org/10.1128/mcb.20.17.6364-6373.2000.
Full textAbstract:
ABSTRACT Vav proteins are guanine nucleotide exchange factors for Rho family GTPases which activate pathways leading to actin cytoskeletal rearrangements and transcriptional alterations. Vav proteins contain several protein binding domains which can link cell surface receptors to downstream signaling proteins. Vav1 is expressed exclusively in hematopoietic cells and tyrosine phosphorylated in response to activation of multiple cell surface receptors. However, it is not known whether the recently identified isoforms Vav2 and Vav3, which are broadly expressed, can couple with similar classes of receptors, nor is it known whether all Vav isoforms possess identical functional activities. We expressed Vav1, Vav2, and Vav3 at equivalent levels to directly compare the responses of the Vav proteins to receptor activation. Although each Vav isoform was tyrosine phosphorylated upon activation of representative receptor tyrosine kinases, integrin, and lymphocyte antigen receptors, we found unique aspects of Vav protein coupling in each receptor pathway. Each Vav protein coprecipitated with activated epidermal growth factor and platelet-derived growth factor (PDGF) receptors, and multiple phosphorylated tyrosine residues on the PDGF receptor were able to mediate Vav2 tyrosine phosphorylation. Integrin-induced tyrosine phosphorylation of Vav proteins was not detected in nonhematopoietic cells unless the protein tyrosine kinase Syk was also expressed, suggesting that integrin activation of Vav proteins may be restricted to cell types that express particular tyrosine kinases. In addition, we found that Vav1, but not Vav2 or Vav3, can efficiently cooperate with T-cell receptor signaling to enhance NFAT-dependent transcription, while Vav1 and Vav3, but not Vav2, can enhance NFκB-dependent transcription. Thus, although each Vav isoform can respond to similar cell surface receptors, there are isoform-specific differences in their activation of downstream signaling pathways.
11
Buhl, Anne Mette, Christopher M. Pleiman, Robert C. Rickert, and John C. Cambier. "Qualitative Regulation of B Cell Antigen Receptor Signaling by CD19: Selective Requirement for PI3-Kinase Activation, Inositol-1,4,5-Trisphosphate Production and Ca2+ Mobilization." Journal of Experimental Medicine 186, no. 11 (December 1, 1997): 1897–910. http://dx.doi.org/10.1084/jem.186.11.1897.
Full textAbstract:
Genetic ablation of the B cell surface glycoprotein CD19 severely impairs the humoral immune response. This requirement is thought to reflect a critical role of CD19 in signal transduction that occurs upon antigen C3dg coligation of antigen receptors with CD19 containing type 2 complement receptors (CR2). Here we show that CD19 plays a key accessory role in B cell antigen receptor signaling independent of CR2 coligation and define molecular circuitry by which this function is mediated. While CD19 is not required for antigen-mediated activation of receptor proximal tyrosines kinases, it is critical for activation of phosphatidylinositol 3-kinase (PI3-kinase). PI3-Kinase activation is dependent on phosphorylation of CD19 Y484 and Y515. Antigen-induced CD19-dependent PI3-kinase activation is required for normal phosphoinositide hydrolysis and Ca2+ mobilization responses. Thus, CD19 functions as a B cell antigen receptor accessory molecule that modifies antigen receptor signaling in a qualitative manner.
12
Palacios, R., M. Kiefer, M. Brockhaus, K. Karjalainen, Z. Dembić, P. Kisielow, and H. von Boehmer. "Molecular, cellular, and functional properties of bone marrow T lymphocyte progenitor clones." Journal of Experimental Medicine 166, no. 1 (July 1, 1987): 12–32. http://dx.doi.org/10.1084/jem.166.1.12.
Full textAbstract:
The continuous proliferating bone marrow clones C4-77, C4-86, and C4-95 express low levels of Thy-1 and Ly-1 surface antigens, but no detectable surface antigens normally present on thymocytes, peripheral mature T lymphocytes, cells of the B lymphocyte or myeloid lineages. They contain the T cell antigen receptor genes alpha, beta, and the T cell-specific gene gamma in the germline configuration, and they express functional receptors for IL-3 and nonfunctional receptors for IL-2. The C4 clones are able to home and undergo differentiation in the thymus of sublethally irradiated mice and give rise in vivo to phenotypically and functionally mature peripheral T lymphocytes displaying several antigen specificities. In vitro 5-Azacytidine induces the C4 clones to express Lyt-2 and L3T4 T cell differentiation antigens, and renders them amenable to be switched from IL-3 to IL-2 dependence. However, the C4 clones seem incapable of giving rise to B lymphocytes either in vivo or in vitro. They self-renew in vitro in the presence of IL-3 every 12-14 h. We conclude that the C4 clones represent cells at the earliest stage of T cell development, i.e., Pro-T lymphocytes.
13
George-Chandy, Annie, Kristina Eriksson, Michael Lebens, Inger Nordström, Emma Schön, and Jan Holmgren. "Cholera Toxin B Subunit as a Carrier Molecule Promotes Antigen Presentation and Increases CD40 and CD86 Expression on Antigen-Presenting Cells." Infection and Immunity 69, no. 9 (September 1, 2001): 5716–25. http://dx.doi.org/10.1128/iai.69.9.5716-5725.2001.
Full textAbstract:
ABSTRACT Cholera toxin B subunit (CTB) is an efficient mucosal carrier molecule for the generation of mucosal antibody responses and/or induction of systemic T-cell tolerance to linked antigens. CTB binds with high affinity to GM1 ganglioside cell surface receptors. In this study, we evaluated how conjugation of a peptide or protein antigen to CTB by chemical coupling or genetic fusion influences the T-cell-activating capacity of different antigen-presenting cell (APC) subsets. Using an in vitro system in which antigen-pulsed APCs were incubated with antigen-specific, T-cell receptor-transgenic T cells, we found that the dose of antigen required for T-cell activation could be decreased >10,000-fold using CTB-conjugated compared to free antigen. In contrast, no beneficial effects were observed when CTB was simply admixed with antigen. CTB conjugation enhanced the antigen-presenting capacity not only of dendritic cells and B cells but also of macrophages, which expressed low levels of cell surface major histocompatibility complex (MHC) class II and were normally poor activators of naive T cells. Enhanced antigen-presenting activity by CTB-linked antigen resulted in both increased T-cell proliferation and increased interleukin-12 and gamma interferon secretion and was associated with up-regulation of CD40 and CD86 on the APC surface. These results imply that conjugation to CTB dramatically lowers the threshold concentration of antigen required for immune cell activation and also permits low-MHC II-expressing APCs to prime for a specific immune response.
14
Shi, Liyun, Kun Luo, Dajing Xia, Taoyong Chen, Guoyou Chen, Yingming Jiang, Nan Li, and Xuetao Cao. "DIgR2, dendritic cell-derived immunoglobulin receptor 2, is one representative of a family of IgSF inhibitory receptors and mediates negative regulation of dendritic cell-initiated antigen-specific T-cell responses." Blood 108, no. 8 (October 15, 2006): 2678–86. http://dx.doi.org/10.1182/blood-2006-04-015404.
Full textAbstract:
AbstractDendritic cells (DCs) are specialized antigen-presenting cells that play crucial roles in the initiation and regulation of immune responses. Maturation and activation of DCs are controlled by a balance of the inhibitory and activating signals transduced through distinct surface receptors. Many inhibitory receptors expressed by DCs have been identified, whereas the new members and their functions need further investigation. In this study, we functionally characterized DC-derived immunoglobulin receptor 2 (DIgR2) as a novel representative of a family of inhibitory receptors belonging to the immunoglobulin superfamily. We show that DIgR2 contains 2 immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within its cytoplasmic region and that DIgR2 associates with Src homology-2 domain-containing protein tyrosine phosphatases-1 (SHP-1). Blockade of DIgR2 on DCs by pretreatment with DIgR2-Ig fusion protein or by silencing with specific small interfering RNA enhances DC-initiated T-cell proliferation and antigen-specific T-cell responses both in vitro and in vivo. Furthermore, immunization of mice with antigen-pulsed, DIgR2-silenced DCs elicits more potent antigen-specific CD4+ and CD8+ T-cell responses, thus protecting the vaccinated mice from tumor challenge more effectively. Our data suggest that DIgR2 is a functionally inhibitory receptor and can mediate negative signaling to regulate DC-initiated antigen-specific T-cell responses.
15
Helsen, Christopher, Vivian Lau, Joanne Hammill, Kenneth Mwawasi, Danielle Hayes, Arya Afsahi, Ksenia Bezverbnaya, Craig Aarts, Galina Denisova, and Jonathan Bramson. "T Cells Engineered with T Cell Antigen Coupler (TAC) Receptors for Haematological Malignancies." Blood 132, Supplement 1 (November 29, 2018): 3267. http://dx.doi.org/10.1182/blood-2018-99-119045.
Full textAbstract:
Abstract Background: We recently described the T cell antigen coupler (TAC) technology (Helsen et. al. Nature Communications) which is a chimeric receptor that targets antigens in an MHC-independent fashion and activates T cells by co-opting the natural TCR receptor. In vitro and in vivo assessments of TAC T cells in solid tumor models have revealed that TACs mediate biological effects that are distinct from conventional chimeric antigen receptors (CARs) and offer safety advantages, including greater target selectivity and reduced off-target toxicity. Here, we present in vitro and in vivo data showing that TAC-engineered T cells directed against CD19 and BCMA demonstrate robust anti-tumor efficacy in haematological malignancies with no detectable side effects. Materials and Methods: T cells from health donors were engineered with TAC receptors directed against CD19 or BCMA using lentivirus vectors. Flow cytometry was employed to measure surface expression of TAC receptors, cytokine production and proliferation of TAC T cells following stimulation with relevant target cells. Antigen-specific toxicity was measured using a luciferase-based killing assay. Anti-tumor activity was measured against acute lymphoblast leukemia for CD19 and multiple myeloma for BCMA xenografts in immunodeficient NRG mice. Results: Engineering T cells with TAC receptors targeted against either CD19 or BCMA revealed antigen-specific activation of cytokine production, cytotoxic function and proliferation. TAC T cells, but not CAR engineered T cells, show significant selectivity towards the context of antigen presentation. This is reflected by the differential proliferative response to a diverse framework of antigen surface arrangement, potentially indicating that TAC T cells are less susceptible to off target activation and the resulting toxicities. Treatment of established NALM-6 xenografts (acute lymphoblastic leukemia) and KMS-11 xenografts (multiple myeloma) with CD19 TAC T cells and BCMA TAC T cells, respectively, resulted in clearance of tumors within a few weeks of T cell infusion. Mice that cleared tumors following TAC T cell treatment were resistant to subsequent challenge with fresh tumor cells demonstrating persistence of TAC T cells. Treatment with control TAC T cells that carry no binding domain had no impact on tumor growth. Monitoring of TAC T cells post-infusion revealed robust expansion that peaked in the peripheral blood 1-2 weeks post-infusion. A clinical manufacturing protocol has been developed for the CD19 TAC T cells in anticipation of human trials. Conclusion: Our pre-clinical evaluation suggests that TAC therapy has the potential to becoming a safer and more effective alternative to conventional CAR therapy. A first in human Phase I/II trial with CD19 TAC T cells is expected to start in the first half of 2019. Disclosures Helsen: Triumvira Immunologics: Employment, Patents & Royalties. Hammill:Triumvira Immunologics: Other: Holding shares, Patents & Royalties. Mwawasi:Triumvira Immunologics: Other: Holding shares, Patents & Royalties. Hayes:Triumvira Immunologics: Employment. Afsahi:Triumvira Immunologics: Patents & Royalties. Denisova:Triumvira Immunologics: Patents & Royalties. Bramson:Triumvira Immunologics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.
16
Tiegs, S. L., D. M. Russell, and D. Nemazee. "Receptor editing in self-reactive bone marrow B cells." Journal of Experimental Medicine 177, no. 4 (April 1, 1993): 1009–20. http://dx.doi.org/10.1084/jem.177.4.1009.
Full textAbstract:
A central paradigm of immunology is clonal selection: lymphocytes displaying clonally distributed antigen receptors are generated and subsequently selected by antigen for growth or elimination. Here we show that in mice transgenic for anti-H-2Kk,b antibody genes, in which a homogeneous clone of developing B cells can be analyzed for the outcome of autoantigen encounter, surface immunoglobulin M+/idiotype+ immature B cells binding to self-antigens in the bone marrow are induced to alter the specificity of their antigen receptors. Transgenic bone marrow B cells encountering membrane-bound Kb or Kk proteins modify their receptors by expressing the V(D)J recombinase activator genes and assembling endogenously encoded immunoglobulin light chain variable genes. This (auto)antigen-directed change in the specificity of newly generated lymphocytes is termed receptor editing.
17
Ishina, Irina A., Ioanna N. Filimonova, Maria Y. Zakharova, Leyla A. Ovchinnikova, Azad E. Mamedov, Yakov A. Lomakin, and Alexey A. Belogurov. "Exhaustive Search of the Receptor Ligands by the CyCLOPS (Cytometry Cell-Labeling Operable Phage Screening) Technique." International Journal of Molecular Sciences 21, no. 17 (August 29, 2020): 6258. http://dx.doi.org/10.3390/ijms21176258.
Full textAbstract:
Effective and versatile screening of the peptide ligands capable of selectively binding to diverse receptors is in high demand for the state-of-the-art technologies in life sciences, including probing of specificity of the cell surface receptors and drug development. Complex microenvironment and structure of the surface receptors significantly reduce the possibility to determine their specificity, especially when in vitro conditions are utilized. Previously, we designed a publicly available platform for the ultra-high-throughput screening (uHTS) of the specificity of surface-exposed receptors of the living eukaryotic cells, which was done by consolidating the phage display and flow cytometry techniques. Here, we significantly improved this methodology and designed the fADL-1e-based phage vectors that do not require a helper hyperphage for the virion assembly. The enhanced screening procedure was tested on soluble human leukocyte antigen (HLA) class II molecules and transgenic antigen-specific B cells that express recombinant lymphoid B-cell receptor (BCR). Our data suggest that the improved vector system may be successfully used for the comprehensive search of the receptor ligands in either cell-based or surface-immobilized assays.
18
Anichini, A., R. Mortarini, and G. Parmiani. "The Role of Cytokines in the Modulation of Cell Surface Antigens of Human Melanoma." International Journal of Biological Markers 8, no. 3 (July 1993): 151–54. http://dx.doi.org/10.1177/172460089300800303.
Full textAbstract:
A number of different cytokines, including IL-1α. and ß, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IFN-α, -ß and γ, TNF-α -ß, and TGF-ß1, can modulate the expression of distinct cell surface antigens of normal and neoplastic cells. Both induction/increase of expression and reduction of expression can be achieved depending on the antigen and on the cytokine. Antigens subjected to the modulating activity of cytokines include distinct families of cell surface structures such as the molecules coded by the major histocompatibility complex (MHC), the superfamily of adhesion receptors that regulate cell-cell and cell-matrix interaction, receptors for cytokines and growth factors and tumor-associated antigens. The modulating activity of cytokines is a consequence of their influence on gene expression, protein synthesis, membrane expression and shedding of antigens from the cell surface. The changes of phenotype due to the action of cytokines can influence the signalling pathways dependent on the expression and function of cell surf ace structures. Therefore, the antigen modulating activity of cytokines can thoroughly affect the biological behavior of normal and neoplastic cells. As described here, most of the modulating effects of cytokines on different cell surface structures and the functional consequences of antigenic modulation can be verified in human malignant melanoma cells.
19
Sutherland, DR, E. Yeo, A. Ryan, GB Mills, D. Bailey, and MA Baker. "Identification of a cell-surface antigen associated with activated T lymphoblasts and activated platelets." Blood 77, no. 1 (January 1, 1991): 84–93. http://dx.doi.org/10.1182/blood.v77.1.84.84.
Full textAbstract:
Abstract We have identified and biochemically characterized an antigen, 8A3, which is expressed on activated T lymphoblasts and activated platelets. Monoclonal antibodies to 8A3 were raised against the primitive lymphoid/myeloid cell line KG1a and additionally bound to the erythroleukemia-derived cell line HEL, whilst exhibiting little or no reactivity with a panel of other hematopoietic cell lines. The 8A3 antigen was expressed on poorly differentiated T-cell leukemias and on phytohemagglutinin-activated T-cells maintained in interleukin-2 (7,000 sites/cell). This antigen, though not detected on resting platelets, was expressed on thrombin-activated platelets (2,000 sites/platelet). Antibodies to 8A3 identified polypeptides of Mr 170,000 and 150,000 in lysates of surface-iodinated KG1a cells, T lymphoblasts, and activated platelets under both reducing and nonreducing conditions. However, peptide mapping and susceptibily to glycosidases indicated that the 8A3 antigen was a monomeric glycoprotein of Mr 170,000 which contained two N-linked endoglycosidase H-sensitive glycans, and that the Mr 150,000 structure was derived from it by proteolytic degradation. The 8A3 antigen was not detectably phosphorylated in KG1a cells in vivo, nor did immune complexes containing it exhibit kinase activity in vitro. Structural and serologic characteristics of the 8A3 antigen indicate that it is different from other previously described leukocyte activation antigens including transferrin receptors, interleukin-2 receptors, members of the integrin family of adhesion molecules, or “restricted” members of the leukocyte-common antigen/CD45 cluster. Furthermore, the 8A3 antigen does not appear to be related to the other previously described activation-specific platelet molecule, GMP140/PADGEM. This antibody may be useful in monitoring T-cell activation status in some clinical situations and in characterizing clinically relevant activation-associated platelet membrane alterations.
20
Sutherland, DR, E. Yeo, A. Ryan, GB Mills, D. Bailey, and MA Baker. "Identification of a cell-surface antigen associated with activated T lymphoblasts and activated platelets." Blood 77, no. 1 (January 1, 1991): 84–93. http://dx.doi.org/10.1182/blood.v77.1.84.bloodjournal77184.
Full textAbstract:
We have identified and biochemically characterized an antigen, 8A3, which is expressed on activated T lymphoblasts and activated platelets. Monoclonal antibodies to 8A3 were raised against the primitive lymphoid/myeloid cell line KG1a and additionally bound to the erythroleukemia-derived cell line HEL, whilst exhibiting little or no reactivity with a panel of other hematopoietic cell lines. The 8A3 antigen was expressed on poorly differentiated T-cell leukemias and on phytohemagglutinin-activated T-cells maintained in interleukin-2 (7,000 sites/cell). This antigen, though not detected on resting platelets, was expressed on thrombin-activated platelets (2,000 sites/platelet). Antibodies to 8A3 identified polypeptides of Mr 170,000 and 150,000 in lysates of surface-iodinated KG1a cells, T lymphoblasts, and activated platelets under both reducing and nonreducing conditions. However, peptide mapping and susceptibily to glycosidases indicated that the 8A3 antigen was a monomeric glycoprotein of Mr 170,000 which contained two N-linked endoglycosidase H-sensitive glycans, and that the Mr 150,000 structure was derived from it by proteolytic degradation. The 8A3 antigen was not detectably phosphorylated in KG1a cells in vivo, nor did immune complexes containing it exhibit kinase activity in vitro. Structural and serologic characteristics of the 8A3 antigen indicate that it is different from other previously described leukocyte activation antigens including transferrin receptors, interleukin-2 receptors, members of the integrin family of adhesion molecules, or “restricted” members of the leukocyte-common antigen/CD45 cluster. Furthermore, the 8A3 antigen does not appear to be related to the other previously described activation-specific platelet molecule, GMP140/PADGEM. This antibody may be useful in monitoring T-cell activation status in some clinical situations and in characterizing clinically relevant activation-associated platelet membrane alterations.
21
Li, Chunrui, Qiuxiang Wang, Hui Zhu, Xia Mao, Ying Wang, Yicheng Zhang, and Jianfeng Zhou. "T Cells Expressing Anti B-Cell Maturation Antigen Chimeric Antigen Receptors for Plasma Cell Malignancies." Blood 132, Supplement 1 (November 29, 2018): 1013. http://dx.doi.org/10.1182/blood-2018-99-116898.
Full textAbstract:
Abstract Introduction: Chimeric antigen receptor (CAR) modified T cells targeting B-cell maturation antigen (BCMA) have shown activity in a case series of patients with relapsed or refractory Multiple Myeloma (MM), but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define the duration of disease, number of treatment lines, treatment course, extramedullary plasma cell tumor, hematopoietic stem cell transplantation, FISH abnormal gene number, risk (combined FISH and second-generation sequencing analysis) ,feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in patients with malignant plasma cell disease treated with BCMA-CAR T cells. This trial is registered with ChiCTR, number ChiCTR-OPC-16009113. Methods: Between March 10, 2017, and March 27, 2018, 28 patients (including 26 patients with relapsed or refractory MM, 1 patient with Plasma cell leukemia and 1 patient with POEMS) were enrolled and infused with BCMA-CAR T cells. The CAR-BCMA chimeric antigen receptor was encoded by the lentiviral vector and contained a murine anti-BCMA single-chain variable fragment, a CD8a hinge, the CD28 transmembrane regions and intracellular domain and CD3-ζ T-cell activation domain. Peripheral blood mononuclear cells were collected from the patient by leukapheresis, and whole peripheral blood mononuclear cells were cultured and transduced. Patients received a target dose of 5.4 ~ 25.0×106 anti-BCMA CAR T cells per kilogram of body weight after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. MM response assessment was conducted according to the International Uniform Response Criteria for MM. Cytokine-release syndrome (CRS) was graded as Lee DW et al. described (Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195.) Results: Twenty-six of 28 treated patients obtained remission. According to the expression rate of BCMA on the surface of plasma cells, all patients were divided into BCMA strong expression group (22 cases, BCMA expression rate ≥ 50%) and BCMA weak expression group (6 cases, BCMA expression rate <50%). The overall response rate for BCMA strong expression group was 87%, with 73% complete response. The overall response rate for the BCMA weak expression group was 100%, with 33% very good partial response or complete response (Figure a-d). The overall survival of the two groups was undefined (a strong group) and 206.5 days (a weak group) respectively (P=0.0468). The median disease-free survival of the two groups was 296 days (strong group, 20 responded cases) and 64 days (weak group,6 cases) respectively (P=0.0069) (Figure e, f). Patients with longer duration have shorter overall survival time. Patients with soft-tissue plasmacytomas have short disease-free survival (155 days vs. 327 days) (Figure g, h). All toxicities were fully reversible, with the most severe being grade 3 cytokine release syndrome that occurred in four of 28 patients. High peak blood CAR+ cell levels were associated with anti-MM responses. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells after infusion. Conclusions: BCMA-CAR T cell therapy is feasible, safe, and mediates potent anti-tumor activity in relapsed/refractory Multiple Myeloma. All toxicities were reversible Our results should encourage additional development of CAR T-cell therapies for other plasma cell malignancies such as plasma cell leukemia and POEMS. Figure Figure. Disclosures No relevant conflicts of interest to declare.
22
Jutila, MA, TK Kishimoto, and EC Butcher. "Regulation and lectin activity of the human neutrophil peripheral lymph node homing receptor." Blood 76, no. 1 (July 1, 1990): 178–83. http://dx.doi.org/10.1182/blood.v76.1.178.178.
Full textAbstract:
Abstract We characterize the nature and regulation of a human neutrophil cell surface antigen recognized by monoclonal antibodies (the DREG series) against a human lymphocyte peripheral lymph node homing receptor. Human neutrophils express high levels of the DREG antigen, whose expression is downregulated after treatment with phorbol myristate acetate, or the chemotactic factors C5a and FMLP. Interestingly, C5a treatment also downregulated the monocyte DREG antigen, but had no effect on expression of the lymphocyte molecule. Within 3 minutes after treatment with C5a, greater than 80% of neutrophil DREG antigen expression is lost, and essentially the molecule is completely removed from the cell surface by 5 minutes. The human neutrophil DREG antigen is 10 Kd larger than the lymphocyte molecule. These features are similar to those of the mouse neutrophil MEL-14 antigen (murine peripheral lymph node homing receptor). The mannose-6-phosphate rich phosphomannan (PPME) binds human lymphocytes via the DREG antigen. PPME also binds neutrophils, but little difference in binding is seen between unactivated and activated cells. We show that PPME binding to unactivated neutrophils is mediated primarily by a cation- and DREG antigen-dependent mechanism, whereas activated neutrophil-PPME binding is DREG antigen- and cation-independent, and may be due to the translocation of lysosomal mannose-6-phosphate receptors to the cell surface. The DREG antibodies offer powerful tools for analyzing the role of homing receptors in human neutrophil-endothelial cell interactions, and also may prove valuable in the clinical assessment of neutrophil activation.
23
Jutila, MA, TK Kishimoto, and EC Butcher. "Regulation and lectin activity of the human neutrophil peripheral lymph node homing receptor." Blood 76, no. 1 (July 1, 1990): 178–83. http://dx.doi.org/10.1182/blood.v76.1.178.bloodjournal761178.
Full textAbstract:
We characterize the nature and regulation of a human neutrophil cell surface antigen recognized by monoclonal antibodies (the DREG series) against a human lymphocyte peripheral lymph node homing receptor. Human neutrophils express high levels of the DREG antigen, whose expression is downregulated after treatment with phorbol myristate acetate, or the chemotactic factors C5a and FMLP. Interestingly, C5a treatment also downregulated the monocyte DREG antigen, but had no effect on expression of the lymphocyte molecule. Within 3 minutes after treatment with C5a, greater than 80% of neutrophil DREG antigen expression is lost, and essentially the molecule is completely removed from the cell surface by 5 minutes. The human neutrophil DREG antigen is 10 Kd larger than the lymphocyte molecule. These features are similar to those of the mouse neutrophil MEL-14 antigen (murine peripheral lymph node homing receptor). The mannose-6-phosphate rich phosphomannan (PPME) binds human lymphocytes via the DREG antigen. PPME also binds neutrophils, but little difference in binding is seen between unactivated and activated cells. We show that PPME binding to unactivated neutrophils is mediated primarily by a cation- and DREG antigen-dependent mechanism, whereas activated neutrophil-PPME binding is DREG antigen- and cation-independent, and may be due to the translocation of lysosomal mannose-6-phosphate receptors to the cell surface. The DREG antibodies offer powerful tools for analyzing the role of homing receptors in human neutrophil-endothelial cell interactions, and also may prove valuable in the clinical assessment of neutrophil activation.
24
Hébert, Eric. "Endogenous Lectins as Cell Surface Transducers." Bioscience Reports 20, no. 4 (August 1, 2000): 213–37. http://dx.doi.org/10.1023/a:1026484722248.
Full textAbstract:
Interactions between cells or between cell and substratum involve specificreceptors and their ligands. Among the various cell surface receptorsidentified during the last decades, the carbohydrate-binding proteins, e.g., lectins are of peculiar interest because glycolipids, glycoproteinsand proteoglycans have been shown to interact with lectins on the surfaceof animal cells. Animal lectins are recognized as molecules playingimportant roles in a variety of biological processes through binding toglycoconjugates and lectin-like receptors such as selectins, sialoadhesins(CD22, CD33), natural killer receptors (NKR-P1, CD69 and CD94/NKG2), hyaluronate receptors (CD44, RHAMM, ICAM-1), B-cell associated antigen(CD23, CD72), γ2 leukocyte integrin (CD11b/CD18) or the well-knownreceptors for mannose, mannose-6-phosphate or asialoglycoprotein havebeen suggested to be able to mediate the transfer of information fromthe outside to the inside of the cell. This review focuses on the mostrecent advances in our understanding of the molecular basis of “outside-in” signaling mediated by lectins. Lectin-likereceptors are involved in signal transduction in a great variety of ways;at the molecular level, they mimic in most of the cases the function ofgrowth factor receptor either coupled to tyrosine kinase activity or toheterotrimeric G protein. They lead to a multiplicity of cellular eventsfollowing their activation depending on factors such as cellular type, species and/or tissue. Nevertheless the potential of surface lectins astransducers is emphasized by the observation that in a few cases lectin-likereceptors induce either novel signal transduction mechanism or newintracellular events with regards to what it has been observed as aconsequence of growth factor receptor activation. This observation bringsthe idea that lectins may offer, as cell surface transducers, an alternativeor additional signaling potential to cell.
25
Sachen, Kacey Layn, Ash A. Alizadeh, Nicole Kattah, Shoshana Levy, and Ron Levy. "Self-Antigen Recognition by the B Cell Receptors of Follicular Lymphoma." Blood 116, no. 21 (November 19, 2010): 4124. http://dx.doi.org/10.1182/blood.v116.21.4124.4124.
Full textAbstract:
Abstract Abstract 4124 There is accumulating evidence that FL is a non-autonomous disease. Firstly, the t(14:18) translocation, which places the bcl-2 proto-oncogene under control of the IgH promotor, is a cytogenetic hallmark of FL, yet it can be detected in B cells from healthy individuals, indicating that this translocation is not sufficient for disease. Phenotypically, follicular lymphoma tumor cells resemble antigen experienced germinal center B cells in that they have highly mutated B cell receptors (BCRs) and are continually undergoing somatic hypermutation (SHM). Despite the high risk of SHM leading to the introduction of nonsense mutations, follicular lymphoma cell continue to express functional BCRs on their surface. These features suggest a selective pressure for the maintenance of BCR expression and indicate the possibility that follicular lymphoma cells may be receiving survival signals through the BCR via antigen recognition. We hypothesize that follicular lymphoma BCRs can recognize self-antigens. To determine the frequency of tumors with self-reactive BCRs, recombinant tumor immunoglobulins were utilized in an indirect immunofluorescence assay with the HEp-2 human cell line. With this assay self-reactivity was detected in 43/99 (43%) of tested tumor immunoglobulins. Within the self-reactive tumor immunoglobulins there was a great diversity of staining patterns, indicating the absence of a unifying antigen that is recognized by all follicular lymphoma BCRs. Autoantigen protein microarrays were utilized to determine the frequency of tumor immunoglobulins reactive for known autoantibody targets associated with autoimmune diseases. Irrespective of HEp-2 reactivity status, none of the tumor immunoglobulins tested (0/50) were reactive against known auto-antigens. These observations indicate that the self-antigens recognized by tumor immunoglobulins might be categorically different from those recognized by the autoantibodies present in patients with autoimmune disease. In an effort to identify specific self-antigens being recognized we utilized the recombinant follicular lymphoma immunoglobulins to immunoprecipitate targets from HEp-2 cell lysates. For one patient's tumor immunoglobulin we identified myoferlin as a recognized self-antigen. The presence of ongoing SHM in follicular lymphoma tumors leads to the existence of multiple tumor clones. To assess how antigen recognition changed as this patient's tumor evolved through SHM we performed a rescue fusion, which immortalizes the tumor cells, halts SHM, and allows for the secretion of the tumor immunoglobulins. Recovered clones differed by a number of silent and replacement mutations, yet all remained HEp-2 reactive. Additionally, all clones maintained their ability to bind myoferlin, though with variable avidity. The observation that ongoing SHM did not break the self-reactivity of the patient's tumor supports the possibility that there is a selective pressure to preserve antigen recognition. Disclosures: No relevant conflicts of interest to declare.
26
Moot, Robert, Sunil Raikar, Lauren C. Fleischer, David McCarty, Melissa Querrey, Christopher B. Doering, and H. Trent Spencer. "Expanding the Ligand Binding Repertoire of Chimeric Antigen Receptors Using Lamprey Variable Lymphocyte Receptors." Blood 126, no. 23 (December 3, 2015): 3244. http://dx.doi.org/10.1182/blood.v126.23.3244.3244.
Full textAbstract:
Abstract Although chimeric antigen receptors (CARs) are yielding promising clinical results, the technology remains limited by the availability of conjugate cancer cell target antigens. As a means to increase both the identification of cancer cell target antigens and simultaneously generate unique single chain binding domain structures we utilized the immune system of jawless vertebrates. Sea lamprey possess an adaptive immune system primarily characterized by variable lymphocyte receptors (VLRs) as membrane bound and soluble immune effectors analogous but not homologous to immunoglobulins (Ig). VLRs have a fundamentally different structure and geometry than Ig-based antibodies while still demonstrating high degrees of specificity and avidity. Additionally, VLRs exist naturally as single chain structures with their variable region consisting of multiple assembled repeating sequences termed leucine rich repeats. These repeats can be directly inserted onto a CAR scaffold by genetic engineering. To test this platform technology, a yeast display method previously described (Tasumi et al., PNAS 2009; Xu et al., Humana press 2011) was used as a means of assaying and selecting appropriate VLRs. VLRs meeting the set criteria are sequenced and cloned into a lentiviral vector (LV) CAR transgene cassette plasmid. We constructed a CAR containing a well characterized VLR specific for the B cell receptor of a murine B cell leukemia (BCL) cell line. The CAR design incorporates the anti-BCL-VLR, Myc tag, CD28 transmembrane domain, and the intracellular CD3ζ signaling domain. SIN VLR-CAR LV was produced at high titer (~1x108) and used to transduce Jurkat cells. Transduced Jurkat cells showed successful CAR protein expression confirmed via Western Blot as well as persistent surface CAR expression for over 2 months with cell viability remaining over 85%. To determine whether the VLR was capable of signaling through the CAR, transduced Jurkat cells were incubated with the BCL cell line expressing the target B cell receptor. Using this assay, we demonstrated potent T cell activation via the VLR-CAR. CAR expressing T-cells demonstrated activation in ~80% of the cells. Furthermore, NK-92 cells expressing the VLR-CAR demonstrated an ability to recognize and kill BCL cells at target to effector ratios as low as 1:1, with 30% target cell killing. Little to no killing was observed with a control B cell line. Additionally, we created a CAR using a published VLR sequence targeting the human surface antigen CD5 (Yu et al., J. Immunol Methods, 2012). CD5 is primarily a T-cell marker, thus an anti-CD5-VLRCAR could be potentially used to target T-cell malignancies. Jurkat cells were transduced with high titer SIN VLR-CAR LV at various MOIs. Since Jurkat cells express CD5 on their surface, we tested the different transduced groups for self-activation at several time points. The corresponding transduced copy number was determined using quantitative PCR. The degree of activation directly correlated with the LV copy number, with highest activation being seen when the MOI approach 50, with >60% highly activated cells. No activation was observed in the GFP control groups. Additionally, we engineered three different CAR constructs consisting of two CD5 VLRs connected by either a helical linker with a 180° rotation, a helical linker with a 360° rotation, or a non-rigid linker allowing for flexibility among the two VLRs. Transduced Jurkat cells expressing the double CD5-VLR CARs indicated, via flow cytometry, that linking two VLRs does not provide any benefit in terms of activation compared to the single CD5-VLR-CAR. Current testing includes the use of NK-92 cells expressing the anti-CD5-VLR-CAR against T cell leukemia cell lines. Collectively, these results show that VLRs can be used to increase the repertoire of CAR binding motifs. Furthermore, these data suggest that VLRs provide both a unique and effective method for activating CAR-T cells and can expand the number and variety of antigens that may be targeted. Disclosures Doering: Expression Therapeutics: Equity Ownership; Bayer Healthcare: Consultancy, Honoraria, Research Funding.
27
Hwang, Inkyu, Jing-Feng Huang, Hidehiro Kishimoto, Anders Brunmark, Per A. Peterson, Michael R. Jackson, Charles D. Surh, Zeling Cai, and Jonathan Sprent. "T Cells Can Use Either T Cell Receptor or Cd28 Receptors to Absorb and Internalize Cell Surface Molecules Derived from Antigen-Presenting Cells." Journal of Experimental Medicine 191, no. 7 (March 27, 2000): 1137–48. http://dx.doi.org/10.1084/jem.191.7.1137.
Full textAbstract:
At the site of contact between T cells and antigen-presenting cells (APCs), T cell receptor (TCR)–peptide–major histocompatibility complex (MHC) interaction is intensified by interactions between other molecules, notably by CD28 and lymphocyte function-associated antigen 1 (LFA-1) on T cells interacting with B7 (B7-1 and B7-2), and intracellular adhesion molecule 1 (ICAM-1), respectively, on APCs. Here, we show that during T cell–APC interaction, T cells rapidly absorb various molecules from APCs onto the cell membrane and then internalize these molecules. This process is dictated by at least two receptors on T cells, namely CD28 and TCR molecules. The biological significance of T cell uptake of molecules from APCs is unclear. One possibility is that this process may allow activated T cells to move freely from one APC to another and eventually gain entry into the circulation.
28
Weitzman, James, Monica Betancur, Laurent Boissel, Arthur P. Rabinowitz, and Hans Klingemann. "Variable Contribution of Different Monocloncal Antibodies to NK Cell-Mediated ADCC Against Primary CLL Cells." Blood 110, no. 11 (November 16, 2007): 4715. http://dx.doi.org/10.1182/blood.v110.11.4715.4715.
Full textAbstract:
Abstract Chronic Lymphocytic Leukemia (CLL) is characterized by the expression of the B-cell antigens CD19, 20 and 22, along with CD5 and CD23. These antigens make the malignant cells an ideal target for monoclonal antibody (mAb) therapy. Although the mechanism of action of mAbs is complex and not fully understood, one well-described action is antibody-dependent cellular cytotoxicity (ADCC). Binding of mAb to its target surface antigen initiates cytotoxicity through the interaction of the Fc portion of the mAb with the Fc receptor (FcR) on natural killer (NK) cells. This triggers release of perforin and granzymes from NK cells, and subsequent killing of the target cells. This study’s objectives were to measure ADCC of 4 different mAbs against primary CLL cells, and determine if cytotoxicity is dependent on antigen density. Methods: Mononuclear cells from 16 patients with untreated CLL were separated by density gradient separation and served as targets. The antigen density for CD20, 22 and 23 of each patient sample was quantified by flow cytometry. Effector cells for ADCC were NK-92 cells that do not express FcR, and a high affinity Fc receptor-expressing NK-92 variant (NK92.26.5) that also expresses inhibitory receptors (i.e. KIR). A fluourochrome-based flow cytometric assay determined ADCC by subtracting NK-92 induced cytotoxicity from NK-92.26.5 induced killing. Monoclonal antibodies tested were Rituximab (anti-CD20, Biogen/IDEC), Veltuzumab (anti-CD20, Immunomedics), Epratuzumab (anti-CD22, Immunomedics), and Lumiliximab (anti-CD23, Biogen/IDEC). Results: Mean ADCC of the four antibodies tested against 16 primary CLL cells were: 46.5% for Rituximab; 43.4% for Veltuzumab; 5.8% for Epratuzumab; 8.8% for Lumiliximab. Cytotoxicity of NK-92 and NK-92.26.5 against CLL cells without antibody ranged from 2–6%. Mean antigen density on the 16 CLL patient specimens were: CD20: 27,900 (range: 10,000–56,100); CD22: 820 (600–1300); CD23: 9870 (2340–14,800). Conclusions: We have developed a reliable in vitro assay to measure ADCC of mAbs against CLL cells. Our results indicate that ADCC contributes to cytotoxcity of CLL in vitro, and suggest that the magnitude of ADCC depends upon the surface antigen targeted. Anti-CD20 antibodies had significantly greater ADCC than the anti-CD22 and CD23 antibodies. This pattern was consistent in all patient cells tested. A similar pattern was observed with the surface antigen density on CLL cells tested, suggesting a correlation between cell surface antigen density and ADCC. Our results also suggest that resistance of primary CLL cells toward NK-mediated killing can be overcome by monoclonal antibodies even in the presence of inhibitory KIR expression on NK cells.
29
Alonso-Camino, Vanesa, David Sánchez-Martín, Marta Compte, Natalia Nuñez-Prado, Rosa M. Diaz, Richard Vile, and Luis Alvarez-Vallina. "CARbodies: Human Antibodies Against Cell Surface Tumor Antigens Selected From Repertoires Displayed on T Cell Chimeric Antigen Receptors." Molecular Therapy - Nucleic Acids 2 (2013): e93. http://dx.doi.org/10.1038/mtna.2013.19.
Full text
30
Oliver, J. M., J. C. Seagrave, J. R. Pfeiffer, M. L. Feibig, and G. G. Deanin. "Surface functions during mitosis in rat basophilic leukemia cells." Journal of Cell Biology 101, no. 6 (December 1, 1985): 2156–66. http://dx.doi.org/10.1083/jcb.101.6.2156.
Full textAbstract:
At the entry into mitosis, cells abruptly lose membrane activities such as phagocytosis, pinocytosis, and capping. The present studies test if mitotic cells also resist functional responses to cell surface ligand-receptor interactions. The IgE receptors of RBL-2H3 rat basophilic leukemia cells were labeled with anti-dinitrophenol IgE (anti-DNP-IgE) and then cross-linked with multivalent ligands (DNP-bovine serum albumin [BSA]; DNP-B-phycoerythrin; DNP-BSA-gold). IgE-receptor cross-linking modulates cell surface organization and function and releases serotonin and other mediators of allergic and asthmatic reactions from interphase cells (Pfeiffer, J. R., JC. Seagrave, B. H. Davis, G. G. Deanin, and J. M. Oliver, 1985, J. Cell Biol., 101:2145-2155). It was found that anti-DNP-IgE-receptor complexes are preserved on the cell surface throughout mitosis; they continue to bind DNP-proteins, and the resulting antigen-IgE-receptor complexes can redistribute to coated pits on the cell surface. Furthermore, there is no loss of [3H]serotonin through mitosis. Nevertheless, antigen-stimulated [3H]-serotonin release is strongly impaired in mitotic-enriched as compared with mixed interphase or G1-enriched cell populations. In addition, antigen binding transforms the surface of interphase cells from a microvillous to a plicated topography and stimulates the uptake of fluorescein isothiocyanate-conjugated dextran by fluid pinocytosis. Mitotic cells maintain a microvillous surface topography after antigen treatment, and fluid pinocytosis virtually ceases from prometaphase to telophase. Phorbol myristate acetate, a tumor promoter that activates protein kinase C, restores surface ruffling activity to mitotic cells. Thus, the mitosis-specific freezing of membrane and secretory responses is most likely due to the failure of transmembrane signaling.
31
Yednock, T. A., E. C. Butcher, L. M. Stoolman, and S. D. Rosen. "Receptors involved in lymphocyte homing: relationship between a carbohydrate-binding receptor and the MEL-14 antigen." Journal of Cell Biology 104, no. 3 (March 1, 1987): 725–31. http://dx.doi.org/10.1083/jcb.104.3.725.
Full textAbstract:
Blood-borne lymphocytes extravasate in large numbers within peripheral lymph nodes (PN) and other secondary lymphoid organs. It has been proposed that the initiation of extravasation is based upon a family of cell adhesion molecules (homing receptors) that mediate lymphocyte attachment to specialized high endothelial venules (HEV) within the lymphoid tissues. A putative homing receptor has been identified by the monoclonal antibody, MEL-14, which recognizes an 80-90-kD glycoprotein on the surface of mouse lymphocytes and blocks the attachment of lymphocytes to PN HEV. In a companion study we characterize a carbohydrate-binding receptor on the surface of mouse lymphocytes that also appears to be involved in the interaction of lymphocytes with PN HEV. This receptor selectively binds to fluorescent beads derivatized with PPME, a polysaccharide rich in mannose-6-phosphate. In this report we examine the relationship between this carbohydrate-binding receptor and the putative homing receptor identified by the MEL-14 antibody. We found that: MEL-14 completely and selectively blocks the activity of the carbohydrate-binding receptor on mouse lymphocytes; the ability of six lymphoma cell lines to bind PPME beads correlates with cell-surface expression of the MEL-14 antigen, as well as PN HEV-binding activity; selection of lymphoma cell line variants for PPME-bead binding by fluorescence-activated cell sorting (FACS) produces highly correlated (r = 0.974, P less than 0.001) and selective changes in MEL-14 antigen expression. These results show that the carbohydrate-binding receptor on lymphocytes and the MEL-14 antigen, which have been independently implicated as receptors involved in PN-specific HEV attachment, are very closely related, if not identical, molecules.
32
Mehta, Kapil, Teresa McQueen, Taghi Manshouri, Michael Andreeff, Steven Collins, and Maher Albitar. "Involvement of Retinoic Acid Receptor-α–Mediated Signaling Pathway in Induction of CD38 Cell-Surface Antigen." Blood 89, no. 10 (May 15, 1997): 3607–14. http://dx.doi.org/10.1182/blood.v89.10.3607.
Full textAbstract:
Abstract Human leukocyte antigen CD38, a 45-kD single-chain, transmembrane glycoprotein, is a bifunctional ectoenzyme that participates in signal transduction pathways involved in the regulation of cell growth and differentiation. In this study, we demonstrate the nature of retinoid receptors involved in retinoic acid–induced expression of CD38 protein in the human myeloblastic leukemia cell line HL-60. We used a variant HL-60 cell line, HL-60R, in which retinoid receptor function has been abrogated by a trans-dominant negative mutation. We introduced the normal retinoic acid receptors (RAR)-α, -β, and -γ or retinoid X receptor (RXR)-α into HL-60R cells by retroviral vector-mediated gene transfer. Based on experiments using these cell lines and receptor-specific synthetic retinoids that preferentially bind to one of the RARs or RXRs, we conclude that RAR-α is involved in retinoid-induced CD38 expression in HL-60 cells. Further evidence included our demonstration that blocking of RAR-α with the antagonist Ro 41-5253 completely suppressed the retinoid-induced expression of CD38 mRNA transcript and the production of CD38 protein in HL-60 cells. Various tissues from transgenic mice that expressed an antisense construct of RAR-α lacked or produced very low levels of CD38. As expected, the tissues from transgenic mice contained 50% to 80% reduced levels of RAR-α. These results suggest that regulation of CD38 expression, both in vitro and in vivo, is under the direct control of RAR-α retinoid receptors.
33
Mehta, Kapil, Teresa McQueen, Taghi Manshouri, Michael Andreeff, Steven Collins, and Maher Albitar. "Involvement of Retinoic Acid Receptor-α–Mediated Signaling Pathway in Induction of CD38 Cell-Surface Antigen." Blood 89, no. 10 (May 15, 1997): 3607–14. http://dx.doi.org/10.1182/blood.v89.10.3607.3607_3607_3614.
Full textAbstract:
Human leukocyte antigen CD38, a 45-kD single-chain, transmembrane glycoprotein, is a bifunctional ectoenzyme that participates in signal transduction pathways involved in the regulation of cell growth and differentiation. In this study, we demonstrate the nature of retinoid receptors involved in retinoic acid–induced expression of CD38 protein in the human myeloblastic leukemia cell line HL-60. We used a variant HL-60 cell line, HL-60R, in which retinoid receptor function has been abrogated by a trans-dominant negative mutation. We introduced the normal retinoic acid receptors (RAR)-α, -β, and -γ or retinoid X receptor (RXR)-α into HL-60R cells by retroviral vector-mediated gene transfer. Based on experiments using these cell lines and receptor-specific synthetic retinoids that preferentially bind to one of the RARs or RXRs, we conclude that RAR-α is involved in retinoid-induced CD38 expression in HL-60 cells. Further evidence included our demonstration that blocking of RAR-α with the antagonist Ro 41-5253 completely suppressed the retinoid-induced expression of CD38 mRNA transcript and the production of CD38 protein in HL-60 cells. Various tissues from transgenic mice that expressed an antisense construct of RAR-α lacked or produced very low levels of CD38. As expected, the tissues from transgenic mice contained 50% to 80% reduced levels of RAR-α. These results suggest that regulation of CD38 expression, both in vitro and in vivo, is under the direct control of RAR-α retinoid receptors.
34
Lee, Jinmin, Prabuddha Sengupta, Joseph Brzostowski, Jennifer Lippincott-Schwartz, and Susan K. Pierce. "The nanoscale spatial organization of B-cell receptors on immunoglobulin M– and G–expressing human B-cells." Molecular Biology of the Cell 28, no. 4 (February 15, 2017): 511–23. http://dx.doi.org/10.1091/mbc.e16-06-0452.
Full textAbstract:
B-cell activation is initiated by the binding of antigen to the B-cell receptor (BCR). Here we used dSTORM superresolution imaging to characterize the nanoscale spatial organization of immunoglobulin M (IgM) and IgG BCRs on the surfaces of resting and antigen-activated human peripheral blood B-cells. We provide insights into both the fundamental process of antigen-driven BCR clustering and differences in the spatial organization of IgM and IgG BCRs that may contribute to the characteristic differences in the responses of naive and memory B-cells to antigen. We provide evidence that although both IgM and IgG BCRs reside in highly heterogeneous protein islands that vary in size and number of BCR single-molecule localizations, both resting and activated B-cells intrinsically maintain a high frequency of single isolated BCR localizations, which likely represent BCR monomers. IgG BCRs are more clustered than IgM BCRs on resting cells and form larger protein islands after antigen activation. Small, dense BCR clusters likely formed via protein–protein interactions are present on the surface of resting cells, and antigen activation induces these to come together to form less dense, larger islands, a process likely governed, at least in part, by protein–lipid interactions.
35
Martínez-Cingolani, Carolina, and Jean Christophe Bories. "Development of chimeric antigen receptors for multiple myeloma." Biochemical Society Transactions 44, no. 2 (April 11, 2016): 397–405. http://dx.doi.org/10.1042/bst20150280.
Full textAbstract:
Multiple myeloma (MM) is a haematologic malignancy characterized by the expansion of monoclonal plasma cells in the bone marrow. It is associated with serum or urine monoclonal protein and organ damage including renal failure, anaemia, hypercalcaemia and bone lesions. Despite recent improvements MM still remains an incurable disease. Previous studies have shown that the adoptive transfer of autologous T-cells modified to express chimeric antigen receptors (CAR) is effective in cases of acute and chronic lymphoid leukaemia. However, the adjustment of CAR-T-cell therapy to MM is hindered by the scarcity of antigens specific to the tumour plasma cells. Most candidate targets are shared by healthy tissues, and entail high risks of toxicity. Therefore several strategies have been proposed to regulate CAR-T-cell function as well as to enhance CAR-T-cell specificity against tumour cells. In this article we summarize the surface markers that have been investigated as targets to eliminate MM plasma cells and the MM-specific CARs that have been developed to date. Then we describe the different CAR-T-cell designs that could be applied in the case of MM to circumvent current problems of toxicity.
36
Kailayangiri, Sareetha, Bianca Altvater, Malena Wiebel, Silke Jamitzky, and Claudia Rossig. "Overcoming Heterogeneity of Antigen Expression for Effective CAR T Cell Targeting of Cancers." Cancers 12, no. 5 (April 26, 2020): 1075. http://dx.doi.org/10.3390/cancers12051075.
Full textAbstract:
Chimeric antigen receptor (CAR) gene-modified T cells (CAR T cells) can eradicate B cell malignancies via recognition of surface-expressed B lineage antigens. Antigen escape remains a major mechanism of relapse and is a key barrier for expanding the use of CAR T cells towards solid cancers with their more diverse surface antigen repertoires. In this review we discuss strategies by which cancers become amenable to effective CAR T cell therapy despite heterogeneous phenotypes. Pharmaceutical approaches have been reported that selectively upregulate individual target antigens on the cancer cell surface to sensitize antigen-negative subclones for recognition by CARs. In addition, advanced T cell engineering strategies now enable CAR T cells to interact with more than a single antigen simultaneously. Still, the choice of adequate targets reliably and selectively expressed on the cell surface of tumor cells but not normal cells, ideally by driving tumor growth, is limited, and even dual or triple antigen targeting is unlikely to cure most solid tumors. Innovative receptor designs and combination strategies now aim to recruit bystander cells and alternative cytolytic mechanisms that broaden the activity of CAR-engineered T cells beyond CAR antigen-dependent tumor cell recognition.
37
Schultz, Liora M., Debra K. Czerwinski, Aihua Fu, Shoshana Levy, and Ronald Levy. "Generating Chimeric Antigen Receptors Utilizing Novel Anti-CD3 Nanobeads." Blood 124, no. 21 (December 6, 2014): 5949. http://dx.doi.org/10.1182/blood.v124.21.5949.5949.
Full textAbstract:
Abstract The processes of ex vivo transduction of T cells to express chimeric antigen receptors (CARs) and of CAR+ T cell expansion influence the phenotype, function and ultimate fate of the final CAR+T cell product infused into patients. CAR constructs, despite expression of endogenous activation signals, require exogenous T cell activation during CAR transduction to allow optimal lenti-viral or retroviral-mediated integration of the CAR gene of interest into T cells. Clinical CAR therapy trials utilize anti-CD3 antibody-mediated activation or combined CD3 and CD28 stimulation using CD3, CD28 specific magnetic beads. We introduce novel magnetic nanoparticle beads generated from iron oxide nanoparticles conjugated to streptavidin and bound to biotinylated T cell activating antibodies for the purpose of CAR transduction. The small size of these nanobeads confers the advantage of decreased steric hindrance and enhanced capability of bead surface antibodies to access T cell surface antigen for binding and stimulation. We achieve efficient CAR transduction using anti-CD3 nanobead-mediated T cell stimulation and demonstrate CD19 specific CAR-mediated cytotoxicity of CD19+ tumor using an annexin V and 7AAD cytotoxicity assay. Evaluation of T cell phenotype following anti-CD3 nanobead-mediated T cell activation demonstrates preferential activation of naïve T cells as compared to central and effector memory cells. Addition of anti-CD28 costimulation is not necessary to achieving or inhibiting this preferential naïve T cell activation. Naïve T cells exhibit greater replicative capacity and anti-tumor function as compared to both effector and central memory T cells for adoptive transfer. We anticipate that preferential generation of naïve T cell derived CAR+ T cells achieved by introducing anti-CD3 nanobead stimulation can further improve the outcomes of clinical trials using CAR therapy. Disclosures Fu: NVIGEN Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
38
Wayner, E. A., and W. G. Carter. "Identification of multiple cell adhesion receptors for collagen and fibronectin in human fibrosarcoma cells possessing unique alpha and common beta subunits." Journal of Cell Biology 105, no. 4 (October 1, 1987): 1873–84. http://dx.doi.org/10.1083/jcb.105.4.1873.
Full textAbstract:
Using monoclonal antibody technology and affinity chromatography we have identified four distinct classes of cell surface receptors for native collagen on a cultured human fibrosarcoma cell line, HT-1080. Two classes of monoclonal antibodies prepared against HT-1080 cells inhibited adhesion to extracellular matrix components. Class I antibodies inhibited cell adhesion to collagen, fibronectin, and laminin. These antibodies immunoprecipitated two noncovalently linked proteins (subunits) with molecular masses of 147 and 125 kD, termed alpha and beta, respectively. Class II antibodies inhibited cell adhesion to native collagen only and not fibronectin or laminin. Class II antibodies immunoprecipitated a single cell surface protein containing two noncovalently linked subunits with molecular masses of 145 and 125 kD, termed alpha and beta, respectively. The two classes of antibodies did not cross-react with the same cell surface protein and recognized epitopes present on the alpha subunits. Pulse-chase labeling studies with [35S]methionine indicated that neither class I nor II antigen was a metabolic precursor of the other. Comparison of the alpha and beta subunits of the class I and II antigens by peptide mapping indicated that the beta subunits were identical while the alpha subunits were distinct. In affinity chromatography experiments HT-1080 cells were extracted with Triton X-100 or octylglucoside detergents and chromatographed on insoluble fibronectin or native type I or VI collagens. A single membrane protein with the biochemical characteristics of the class I antigen was isolated on fibronectin-Sepharose and could be immunoprecipitated with the class I monoclonal antibody. The class I antigen also specifically bound to type I and VI collagens, consistent with the observation that the class I antibodies inhibit cell adhesion to types VI and I collagen and fibronectin. The class II antigen, however, did not bind to collagen (or fibronectin) even though class II monoclonal antibodies completely inhibited adhesion of HT-1080 cells to types I and III-VI collagen. The class I beta and II beta subunits were structurally related to the beta subunit of the fibronectin receptor described by others. However, none of these receptors shared the same alpha subunits. Additional membrane glycoprotein(s) with molecular mass ranges of 80-90 and 35-45 kD, termed the class III and IV receptors, respectively, bound to types I and VI collagen but not to fibronectin. Monoclonal antibodies prepared against the class III receptor had no consistent effect on cell attachment or spreading, suggesting that it is not directly involved in adhesion to collagen-coated substrates.(ABSTRACT TRUNCATED AT 400 WORDS)
39
Lehmann, Christian H. K., Anna Baranska, Gordon F. Heidkamp, Lukas Heger, Kirsten Neubert, Jennifer J. Lühr, Alana Hoffmann, et al. "DC subset–specific induction of T cell responses upon antigen uptake via Fcγ receptors in vivo." Journal of Experimental Medicine 214, no. 5 (April 7, 2017): 1509–28. http://dx.doi.org/10.1084/jem.20160951.
Full textAbstract:
Dendritic cells (DCs) are efficient antigen-presenting cells equipped with various cell surface receptors for the direct or indirect recognition of pathogenic microorganisms. Interestingly, not much is known about the specific expression pattern and function of the individual activating and inhibitory Fcγ receptors (FcγRs) on splenic DC subsets in vivo and how they contribute to the initiation of T cell responses. By targeting antigens to select activating and the inhibitory FcγR in vivo, we show that antigen uptake under steady-state conditions results in a short-term expansion of antigen-specific T cells, whereas under inflammatory conditions especially, the activating FcγRIV is able to induce superior CD4+ and CD8+ T cell responses. Of note, this effect was independent of FcγR intrinsic activating signaling pathways. Moreover, despite the expression of FcγRIV on both conventional splenic DC subsets, the induction of CD8+ T cell responses was largely dependent on CD11c+CD8+ DCs, whereas CD11c+CD8− DCs were critical for priming CD4+ T cell responses.
40
Somanchi, Srinivas S., Anitha Gururajan, Laurence J. N. Cooper, and Dean A. Lee. "NK-Cell Acquisition of Chemokine Receptors From Engineered Antigen Presenting Cells." Blood 116, no. 21 (November 19, 2010): 1744. http://dx.doi.org/10.1182/blood.v116.21.1744.1744.
Full textAbstract:
Abstract Abstract 1744 Natural Killer (NK) cells are able to extract fragments of cell membrane from antigen presenting cells through the immunological synapse, functionally incorporating the membrane receptors contained therein by a process called trogocytosis. Recently it was demonstrated that NK cells can acquire functional CCR7 from dendritic cells through this process and migrate in response to chemokines (CCL19 and CCL21). We investigated whether this process could be used to transiently modify NK cells ex vivo without genetic intervention. In previous work, we developed a K562-based artificial antigen presenting cell (aAPC) expressing membrane-bound IL-21 (K562-cl9-mIL21) which enables robust NK-cell expansion, and determined that NK cells did not express detectable CCR7 during this process. To investigate trogocytosis in this system, we genetically modified K562-cl9-mIL21 to express membrane-bound CCR7 (K562 cl9 mIL21CCR7) using the Sleeping Beauty transposon/transposase system. After 24 hours of co-culture the NK cells cultured with K562-cl9-mIL21CCR7 demonstrated marked surface expression of CCR7 compared to NK cells cultured on K562-cl9-mIL21 (Figure 1a). In kinetic experiments using three independent donors, CCR7 peak uptake occured at 24 hours (Figure 1b), followed by a decline that corresponded with the loss of aAPCs in the cultures due to lysis by NK cells. This demonstrates that NK cells can be transiently modified during in vitro expansion to bear receptors that are otherwise not a normal part of their transcriptional repertoire. We are currently establishing the functionality of trogocytosed receptors in vitro and in vivo, and investigating the kinetics of CCR7 persistence after removal of the aAPCs. However, even transient expression as demonstrated might be sufficient for bestowing novel NK-cell migration ability in vivo in response to chemokine signaling, giving the engineered NK cells ability to reach desired tissue targets. Disclosures: Lee: Altor BioScience Corp: Research Funding; Celgene: Research Funding.
41
Furuno, Tadahide, Reiko Teshima, Seiichi Kitani, Jun-ichi Sawada, and Mamoru Nakanishi. "Surface Expression of CD63 Antigen (AD1 Antigen) in P815 Mastocytoma Cells by Transfected IgE Receptors." Biochemical and Biophysical Research Communications 219, no. 3 (February 1996): 740–44. http://dx.doi.org/10.1006/bbrc.1996.0304.
Full text
42
Hershberg, Robert M. "V. Polarized compartmentalization of antigen processing and Toll-like receptor signaling in intestinal epithelial cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 283, no. 4 (October 1, 2002): G833—G839. http://dx.doi.org/10.1152/ajpgi.00208.2002.
Full textAbstract:
The intestinal epithelial cell (IEC) is exposed at the apical surface to a high concentration of foreign antigen and bacterial products capable of triggering inflammatory responses. Complex intracellular pathways of antigen trafficking and the polarized expression of immunologically active receptors provide additional means to regulate the inflammatory pathways in these cells. In the case of human leukocyte antigen (HLA) class II heterodimers, surface expression is highly restricted to the basolateral surface, and this also appears to be the case for Toll-like receptor 5 (TLR5) on polarized T84 human colon cancer cells. Processing of soluble antigen via HLA class II in IEC can occur following internalization from the apical surface but is highly inefficient. In addition, certain bacteria can facilitate the transport of flagellin (the ligand for TLR5) across an intact epithelium. Disruption of the tight junctions between IECs, allowing direct access of antigen and flagellin to the basolateral surface of the cell, dramatically affects the functional outcome HLA class II and TLR5 pathways.
43
Watanabea, Motoo, Tania H. Watts, Jean Gariepy, and Nobumichi Hozumi. "Function and behavior of surface immunoglobulin receptors in antigen-specific T cell-B cell interaction." Cellular Immunology 112, no. 1 (March 1988): 226–35. http://dx.doi.org/10.1016/0008-8749(88)90291-2.
Full text
44
Davison, Glenda M., Heather L. Hendrickse, and Tandi E. Matsha. "Do Blood Group Antigens and the Red Cell Membrane Influence Human Immunodeficiency Virus Infection?" Cells 9, no. 4 (March 31, 2020): 845. http://dx.doi.org/10.3390/cells9040845.
Full textAbstract:
The expression of blood group antigens varies across human populations and geographical regions due to natural selection and the influence of environment factors and disease. The red cell membrane is host to numerous surface antigens which are able to influence susceptibility to disease, by acting as receptors for pathogens, or by influencing the immune response. Investigations have shown that Human Immunodeficiency Virus (HIV) can bind and gain entry into erythrocytes, and therefore it is hypothesized that blood groups could play a role in this process. The ABO blood group has been well studied. However, its role in HIV susceptibility remains controversial, while other blood group antigens, and the secretor status of individuals, have been implicated. The Duffy antigen is a chemokine receptor that is important in the inflammatory response. Those who lack this antigen, and type as Duffy null, could therefore be susceptible to HIV infection, especially if associated with neutropenia. Other antigens including those in the Rh, Lutheran and OK blood group systems have all been shown to interact with HIV. More recently, experiments show that cells which overexpress the Pk antigen appear to be protected against infection. These reports all demonstrate that red cell antigens interact and influence HIV infection. However, as the red cell membrane is complex and the pathogenesis of HIV multi-factorial, the role of blood group antigens cannot be studied in isolation.
45
Greenblatt, MS, and L. Elias. "The type B receptor for tumor necrosis factor-alpha mediates DNA fragmentation in HL-60 and U937 cells and differentiation in HL-60 cells." Blood 80, no. 5 (September 1, 1992): 1339–46. http://dx.doi.org/10.1182/blood.v80.5.1339.1339.
Full textAbstract:
Abstract Tumor necrosis factor-alpha (TNF) binds to two specific cell surface receptors, types A and B, which are both present on HL-60 and U937 cells, and induces monocytoid differentiation in HL-60 cells and early DNA fragmentation in HL-60 and U937 cells. To further define the receptors' roles, we studied how monoclonal antibodies (MoAbs) against each receptor affected TNF-induced cellular responses. HTR-9, an MoAb against the type B (low affinity, 55 Kd) receptor, reproduced all of these effects in a dose-dependent manner. UTR-1, an MoAb against the type A (high affinity, 75 Kd) receptor, had no effect in saturating doses, but supersaturating doses enhanced DNA fragmentation threefold. TNF and interferon gamma (IFN-gamma) synergistically induced morphologic differentiation and monocytic antigen expression, while the antitype B receptor MoAb was synergistic for morphologic response, but not antigen expression. Our results indicate that (1) the type B receptor mediates some responses to TNF in HL-60 and U937 cells, (2) the type A receptor does not stimulate these responses, (3) the TNF molecule is not necessary for some of these actions, and (4) TNF- induced morphologic changes and surface antigen expression in HL-60 cells may be regulated by separate postreceptor pathways.
46
Greenblatt, MS, and L. Elias. "The type B receptor for tumor necrosis factor-alpha mediates DNA fragmentation in HL-60 and U937 cells and differentiation in HL-60 cells." Blood 80, no. 5 (September 1, 1992): 1339–46. http://dx.doi.org/10.1182/blood.v80.5.1339.bloodjournal8051339.
Full textAbstract:
Tumor necrosis factor-alpha (TNF) binds to two specific cell surface receptors, types A and B, which are both present on HL-60 and U937 cells, and induces monocytoid differentiation in HL-60 cells and early DNA fragmentation in HL-60 and U937 cells. To further define the receptors' roles, we studied how monoclonal antibodies (MoAbs) against each receptor affected TNF-induced cellular responses. HTR-9, an MoAb against the type B (low affinity, 55 Kd) receptor, reproduced all of these effects in a dose-dependent manner. UTR-1, an MoAb against the type A (high affinity, 75 Kd) receptor, had no effect in saturating doses, but supersaturating doses enhanced DNA fragmentation threefold. TNF and interferon gamma (IFN-gamma) synergistically induced morphologic differentiation and monocytic antigen expression, while the antitype B receptor MoAb was synergistic for morphologic response, but not antigen expression. Our results indicate that (1) the type B receptor mediates some responses to TNF in HL-60 and U937 cells, (2) the type A receptor does not stimulate these responses, (3) the TNF molecule is not necessary for some of these actions, and (4) TNF- induced morphologic changes and surface antigen expression in HL-60 cells may be regulated by separate postreceptor pathways.
47
Pullen, Robert H., and Steven M. Abel. "Mechanical feedback enables catch bonds to selectively stabilize scanning microvilli at T-cell surfaces." Molecular Biology of the Cell 30, no. 16 (July 22, 2019): 2087–95. http://dx.doi.org/10.1091/mbc.e19-01-0048.
Full textAbstract:
T-cells use microvilli to search the surfaces of antigen-presenting cells for antigenic ligands. The active motion of scanning microvilli provides a force-generating mechanism that is intriguing in light of single-molecule experiments showing that applied forces increase the lifetimes of stimulatory receptor–ligand bonds (catch-bond behavior). In this work, we introduce a theoretical framework to explore the motion of a microvillar tip above an antigen-presenting surface when receptors on the tip stochastically bind to ligands on the surface and dissociate from them in a force-dependent manner. Forces on receptor-ligand bonds impact the motion of the microvillus, leading to feedback between binding and microvillar motion. We use computer simulations to show that the average microvillar velocity varies in a ligand-dependent manner; that catch bonds generate responses in which some microvilli almost completely stop, while others move with a broad distribution of velocities; and that the frequency of stopping depends on the concentration of stimulatory ligands. Typically, a small number of catch bonds initially immobilize the microvillus, after which additional bonds accumulate and increase the cumulative receptor-engagement time. Our results demonstrate that catch bonds can selectively slow and stabilize scanning microvilli, suggesting a physical mechanism that may contribute to antigen discrimination by T-cells.
48
Foa, C., P. Bongrand, J. R. Galindo, and P. Golstein. "Unexpected cell surface labeling in conjugates between cytotoxic T lymphocytes and target cells." Journal of Histochemistry & Cytochemistry 33, no. 7 (July 1985): 647–54. http://dx.doi.org/10.1177/33.7.2861226.
Full textAbstract:
Specific binding of target cells by cytotoxic T lymphocytes (CTL) is an example of tight interaction between two different cell types. The molecular events that occur at the cell membranes during these interactions are largely unknown. In the present report, we describe an electron microscopic immunostaining study made on CTL-target cell conjugates. Various membrane structures were labeled with monoclonal antibodies specific for structures possibly relevant to cytolysis (Lyt-2, LFA-1, and target cell class I major histocompatibility antigens) or probably unrelated to the cytolytic process (effector cell class I major histocompatibility antigens). Antibodies against Thy-1 were also used. Staining was achieved with immunoperoxidase or immunoferritin. With both techniques nonconjugated cells were either stained or not, depending on whether they bore the antigen corresponding to the antibody used. However, when conjugated to an antigen-bearing cell, a "non-antigen bearing" cell was labeled near the cell interaction area. No increased Fc receptor activity could be detected on bound cells near the interaction area. These data are consistent with the occurrence of limited exchange of membrane macromolecules between bound CTL and target cell.
49
Fernández-Segura, Eduardo, O. Manuel Garcia-Lopez, Antonio Gutierrez, and Antonio Campos. "A quantitative immunoscanning EM analysis of CD16 (FeRIII) antigen on peripheral blood leukocytes." Proceedings, annual meeting, Electron Microscopy Society of America 48, no. 3 (August 12, 1990): 866–67. http://dx.doi.org/10.1017/s0424820100161898.
Full textAbstract:
A common feature of many cell types which mediate major histocompatibility complex (MCH)-unrestricted lysis is the presence of receptors for the Fc region of IgG (FcR) on the surface. Monoclonal antibodies (MAbs) against these receptors have identified three distinct FcR, i.e., FcRI, FcRII, FcRIII. These receptors are expressed on different but overlapping cells populations, the level of FcR expression being a characteristc of each populations. FcRIII (CD16 antigen) is the low-affinity IgG Fc-receptor whLch is predominantly expressed on human natural killer (NK) cells and granulocytes. With the recent application of immunogold labelling for scanning electron microscopy (immuno-SEM) in the backscattered electron imaging (BEI) mode allow us to correlate antigenic expression with cell surface morphology. In this report we analize the expression and distribution of the CD16 (FcRIII) antigen on peripheral blood leukocytes as observed with immuno-SEM.Material and Methods. Mononuclear cells (MC) were isolated from normal peripheral blood using Ficoll-Paque (Pharmacia Fine Chemicals, Uppsala, Sweden).
50
Jarjour, W., L. A. Mizzen, W. J. Welch, S. Denning, M. Shaw, T. Mimura, B. F. Haynes, and J. B. Winfield. "Constitutive expression of a groEL-related protein on the surface of human gamma/delta cells." Journal of Experimental Medicine 172, no. 6 (December 1, 1990): 1857–60. http://dx.doi.org/10.1084/jem.172.6.1857.
Full textAbstract:
Rabbit antibodies to hsp58 (P1), the human homologue of the Escherichia coli stress protein groEL, react specifically in indirect immunofluorescence and complement-dependent microcytoxicity experiments with a cell surface antigen expressed constitutively by T cell lines bearing gamma/delta receptors. This anti-hsp58-reactive antigen is not demonstrable on T cells that express alpha/beta receptors or on various cells that lack T cell receptors. Certain evidence was obtained to suggest that the target antigen on the surface of gamma/delta T cells is a approximately 77-kD protein distinct from intracellular hsp58 and known members of the hsp70 stress protein family. While the exact nature and significance of this anti-hsp58-reactive protein remain to be determined, these data may help to clarify the roles of groEL-related stress proteins and gamma/delta cells that recognize groEL homologous in immunologic defense against infection and in autoimmune disease.