• Similar to T-cell receptors (TCRs), functional genes of immunoglobulins (Igs) are the result of somatic recombination of DNA containing the relatively limited germinal genetic information, using the so-called V(D)J recombination process that occurs between individual genes (also referred to as gene segments) of the variable domains of the H and L chains (or α, β, γ, and δ chains of TCRs). (intechopen.com)
  • In contrast to NKT cells, NK cells do not express T-cell antigen receptors (TCR) or pan T marker CD3 or surface immunoglobulins (Ig) B cell receptors, but they usually express the surface markers CD16 (FcγRIII) and CD56 in humans, NK1.1 or NK1.2 in C57BL/6 mice. (wikipedia.org)
  • Acquisition of anti-CD19 CARs via trogocytosis enhanced NK cell-mediated cytotoxicity against the B-cell acute lymphoblastic leukemia (B-ALL) cell lines and primary B-ALL cells derived from patients. (plos.org)
  • To our knowledge, this is the first report that describes the increased cytotoxicity of NK cells following the acquisition of CARs via trogocytosis. (plos.org)
  • Further, expression of anti-CD19 chimeric antigen receptors (CARs) containing 41BB and CD3ζ signal domains on NK cells enhanced the activating signals originating from CD19 antigen engagement, leading to cytotoxicity specifically against B-cell leukemia . (plos.org)
  • Despite the clinical success of CD20-specific antibody rituximab, malignancies of B-cell origin continue to present a major clinical challenge, in part due to an inability of the antibody to activate antibody-dependent cell-mediated cytotoxicity (ADCC) in some patients, and development of resistance in others. (springer.com)
  • While activity of the retargeted NK-92 against CD20-negative targets remained unchanged, the gene modified NK cells displayed markedly enhanced cytotoxicity toward NK-sensitive CD20 expressing cells. (springer.com)
  • NK-92-scFv(Leu-16)-ζ cells were incubated with 100 μM of the serine protease inhibitor DCI (3,4-dichloroisocoumarin) (Roche, Mannheim, Germany) in X-VIVO 10 medium for 1 h at 37°C, before their cytotoxic activity towards CD20 expressing NIH3T3-CD20 cells was analyzed in a 3 h MTT cytotoxicity assay as described in the methods section (E/T ratio of 10:1). (springer.com)
  • The expression of common acute lymphoblastic leukemia antigen (CALLA) on a human neuroblastoma cell line, SJ-N-CG, was demonstrated by indirect membrane immunofluorescence, complement-dependent cytotoxicity, and quantitative absorption, using two monoclonal antibodies (J-5 and BA-3) directed against CALLA. (aacrjournals.org)
  • Changes in cell surface membrane antigens associated with morphological differentiation were studied by indirect immunofluorescence and complement-dependent cytotoxicity using a panel of seven monoclonal antibodies. (aacrjournals.org)
  • Dsg3 CAAR-T cells exhibit specific cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro and expand, persist, and specifically eliminate Dsg3-specific B cells in vivo. (sciencemag.org)
  • Natural cytotoxicity receptors directly induce apoptosis after binding to Fas ligand that directly indicate infection of a cell. (wikipedia.org)
  • NCR (natural cytotoxicity receptors), a type of type 1 transmembrane proteins of the immunoglobulin superfamily, upon stimulation, mediate NK killing and release of IFNγ. (wikipedia.org)
  • For example, several groups have reported clinical trials with anti-CD19 CART cells in which favorable clinical efficacy resulted from the specific recognition and eradication of CD19-positive tumor cells [ 3 , 4 , 6 ]. (hindawi.com)
  • Furthermore, our data are consistent with the view that the mechanism of recognition of these compounds presented by CD1d to the Vα14 i NKT cell TCR is likely to fit a lock-and-key model. (pnas.org)
  • Overall, these findings emphasize the distinct properties of glycosphingolipid antigen recognition by Vα14 i NKT cells. (pnas.org)
  • Here, using a panel of mice lacking various combinations of adenosine receptors, and mast cells derived from these animals, we show that adenosine receptor agonists provide an effective means of inhibition of mast cell degranulation and induction of cytokine production both in vitro and in vivo. (aspetjournals.org)
  • We also present indirect evidence for spontaneous MHC class I acquisition in vivo, as well as describe an in vitro coculture system with transfected cells in which the same phenomenon occurred. (rupress.org)
  • In vivo requirement for Atg5 in antigen presentation by dendritic cells. (nih.gov)
  • However, the role of autophagic process in antigen presentation in vivo is unclear. (nih.gov)
  • T cells react to extremely small numbers of activating agonist peptides. (pnas.org)
  • Here we have designed an experimental strategy that enables control over the number of agonist peptides per TCR cluster, without altering the total number engaged by the cell. (pnas.org)
  • In contrast, cross-presentation of peptides on MHC I was intact in the absence of Atg5. (nih.gov)
  • Mast cell activation results in the immediate release of proinflammatory mediators prestored in cytoplasmic granules, as well as initiation of lipid mediator production and cytokine synthesis by these resident tissue leukocytes. (aspetjournals.org)
  • Cooperativity among multiple receptors within the TCR-pMHC clusters is also implicated ( 8 ), which may result from conformation-induced clustering ( 9 ), kinetic segregation ( 10 ), or lipid-mediated assembly ( 11 ). (pnas.org)
  • The strategy is based on the hybrid live cell-supported membrane configuration, in which a solid supported lipid bilayer takes the place of the antigen presenting cell ( 12 - 14 ) ( Fig. 1 ). (pnas.org)
  • Video 2 Accumulation of BCRs into the contact area between B cells and antigen-containing planar lipid bilayers is affinity dependent, as observed by imaging Ig α -YFP. (rupress.org)
  • Video 5 BCR microclusters grow with time when encountering antigen-containing lipid bilayers. (rupress.org)
  • A and B) The μ-High and μ-Low J558L cells labeled with Alexa Fluor 568-Fab anti-IgM were placed on planar lipid bilayers lacking antigen (A) or containing NIP1-His12 (B), and single BCR molecule TIRF images were acquired. (rupress.org)
  • A-F) Shown are two-color time-lapse TIRF images of μ-High J558L cells labeled with Alexa Fluor 568-Fab anti-IgM placed on planar lipid bilayers containing antigen NIP1-His12 (A-C) or lacking antigen (D-F) over a time course of 120 s ( Video 5 ). (rupress.org)
  • Ligand acquisition sometimes reached 20% of the MHC class I expression on surrounding cells, involved transfer of the entire MHC class I protein to the NK cell, and was independent of whether or not the NK cell expressed the MHC class I ligand itself. (rupress.org)
  • The A1F4--induced phosphorylations were abolished in cells in which protein kinase C was depleted by prior treatment with phorbol myristate acetate. (jimmunol.org)
  • All of these observations are compatible with the interpretation that the A1F4- phosphorylation is mediated by protein kinase C. Antigen and anti-receptor antibody-induced receptor serine phosphorylation and phophatidylinositol turnover are blocked by raising intracellular levels of cyclic adenosine monophosphate. (jimmunol.org)
  • in contrast, inhibitors of protein synthesis were ineffective. (gallusimmunotech.com)
  • Immunoprecipitation of solubilized 125 I-labeled membrane proteins from SJ-N-CG cells with J-5 antibody revealed a protein with a molecular weight of 100,000 as determined on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. (aacrjournals.org)
  • Chimeric antigen receptor (CAR)-modified T cells targeting CD19, the best-studied CAR T-cell therapy to date, will be discussed, with a focus on clinical trials for ALL demonstrating efficacy as well as toxicity and toxicity management. (bloodjournal.org)
  • A K562 cell line expressing high levels of anti-CD19 CARs was generated as a donor cell to transfer the anti-CD19 CARs onto NK cells via trogocytosis. (plos.org)
  • Anti-CD19 CAR expression was observed in expanded NK cells after these cells were co-cultured for one hour with freeze/thaw-treated donor cells expressing anti-CD19 CARs. (plos.org)
  • Immunofluorescence analysis confirmed the localization of the anti-CD19 CARs on the NK cell surface. (plos.org)
  • CD19 is an ideal target antigen for immunotherapy because it is expressed on nearly all leukemia cells in most patients with B-cell acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL) , . (plos.org)
  • CD19-specific chimeric antigen receptor T cells (CARTs) have achieved impressive results in pivotal clinical trials. (medworm.com)
  • Molecular support for this hypothesis was obtained when Karlhofer and colleagues identified an inhibitory receptor on NK cells that bound an MHC class I molecule ( 4 ). (rupress.org)
  • 22. The nucleic acid molecule of claim 21, wherein said inducible regulatory construct further comprises a binding domain that allows two of said inducible regulatory constructs to dimerize, wherein dimerization initiates a co-stimulatory signal to a cell. (freepatentsonline.com)
  • We identify A 2B as the primary receptor limiting mast cell degranulation, whereas the combined activity of A 2A and A 2B is required for the inhibition of cytokine synthesis. (aspetjournals.org)
  • Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome (CRS), posing a unique challenge for toxicity management. (bloodjournal.org)
  • Vα14 i NKT cells produce large amounts of cytokines rapidly after stimulation ( 4 ), and this cytokine burst may have a widespread influence on immune responses, including protection against autoimmune diseases, the host response to parasites and bacteria, and antitumor responses ( 2 , 3 , 5 - 8 ). (pnas.org)
  • Typically, immune cells detect major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. (wikipedia.org)
  • Spatial organization of T-cell receptors (TCR) and their peptide-major histocompatibility complex (pMHC) ligands into microclusters is correlated with T-cell activation. (pnas.org)
  • Further analysis suggests that triggering thresholds are determined by the number of activating ligands available to individual TCR clusters, not by the total number encountered by the cell. (pnas.org)
  • We report that during interactions with cells in the environment, NK cells acquired MHC class I ligands from surrounding cells in a Ly49-specific fashion and displayed them at the cell surface. (rupress.org)
  • Similarly, T cells captured NKG2D and NKp46 ligands on tumor cells through trogocytosis and promoted NK cell activity . (plos.org)
  • We also show that this phenomenon is not unique to Ly49A, but occurred for several other inhibitory Ly49 receptors. (rupress.org)
  • Interestingly, the one activating Ly49 receptor we tested did not acquire MHC class I from surrounding cells, suggesting that inhibitory and activating MHC class I receptors may behave differently in this respect. (rupress.org)
  • Thus, our study revealed that DCs utilize autophagic machinery to optimally process and present extracellular microbial antigens for MHC II presentation. (nih.gov)
  • The authors describe the first human application of autologous chimeric antigen receptor gene-modified T cells targeting TAG-72 in the treatment of metastatic colorectal cancer in two clinical trials. (springer.com)
  • As the TCR engage antigen pMHC at high antigen densities, clustering ensues until all pMHC within a single corral of the grid-partitioned supported membrane are coalesced into a single cluster with their cognate TCR receptors ( 12 ) ( Fig. 1 D and Fig. S2 ). (pnas.org)
  • Targeting pathways that limit antigen-induced mast cell activation may have greater therapeutic efficacy by inhibiting the synthesis and release of many proinflammatory mediators produced in the mast cell. (aspetjournals.org)
  • Instead, the NK cells use several germ-line encoded receptors, with either activating or inhibitory function, whose activities are balanced to control self tolerance and reactivity ( 2 ). (rupress.org)
  • Natural killer cell activation is determined by the balance of inhibitory and activating receptor stimulation. (wikipedia.org)
  • Mice with dendritic cell (DC)-conditional deletion in Atg5, a key autophagy gene, showed impaired CD4(+) T cell priming after herpes simplex virus infection and succumbed to rapid disease. (nih.gov)
  • B) Three days later, the draining lymph node DCs were purified and cocultured for 72 hr with CD4 + T cells isolated from day 7 ivag WT HSV-1-infected mice. (nih.gov)
  • Invariant Vα14 rearrangement (Vα14 i ) natural killer (NK) T cells constitute the most numerous glycolipid-reactive population identified in mice, and a homologous population of Vα24 i NKT cells is present in humans ( 2 , 3 ). (pnas.org)
  • Using mice bearing the Lewis lung carcinoma (3LL), we asked whether one or more of the enzymatic pathways that metabolize l -Arg were present in the tumor microenvironment and could explain the molecular alterations seen in T cells from patients with cancer. (aacrjournals.org)
  • The NKp46 cell surface marker constitutes, at the moment, another NK cell marker of preference being expressed in both humans, several strains of mice (including BALB/c mice) and in three common monkey species. (wikipedia.org)
  • It was previously shown that the Vα14 i T cell antigen receptor (TCR) has a high affinity for the α-GalCer/CD1d complex, driven by a long half-life ( t 1/2 ). (pnas.org)
  • Although this result could have reflected the unique attributes of α-GalCer, using several related glycolipid compounds, we show here that the threshold for full activation of Vα14 i NKT cells by these glycosphingolipids requires a relatively high-affinity TCR interaction with a long t 1/2 . (pnas.org)
  • We and others have shown previously that the TCR of Vα14 i NKT cells exhibits a high-affinity binding to the α-GalCer/CD1d complex and a long half-life ( t 1/2 ) ( 15 - 18 ). (pnas.org)
  • The organization of immune cells into a social network ( 1 ) underscores the functional complexity inherent in its design to defend against any pathological noxa. (frontiersin.org)
  • We live because our immune cells are able to kill or neutralize these invisible predators. (gatech.edu)
  • What is even more remarkable is that our immune cells evolve repeatedly during our lifetime. (gatech.edu)
  • Moreover, cells infected by these pathogens are recognized by immune cells with the ability to directly kill their targets by releasing perforin and granzymes and inducing programmed cell death ( 3 - 5 ). (frontiersin.org)
  • Trogocytosis is a process in which membrane patches are exchanged between target and immune cells - . (plos.org)
  • During cell-mediated responses, immune cells that can destroy infected host cells become active. (encyclopedia.com)
  • In many species, the immune system can be classified into subsystems, such as the innate immune system versus the adaptive immune system, or humoral immunity versus cell-mediated immunity. (wikipedia.org)
  • In contrast to innate mechanisms that hinder the entrance and initial spread of disease, adaptive immunity is more selective in its activity, and upon repeated exposures to pathogens can often prevent disease. (encyclopedia.com)
  • A major selective force that regulates the phenotype of an infecting microbial pathogen population is the host's immune system, which is also highly adaptive, especially in discriminating self and nonself antigens ( 2 , 4 ). (cdc.gov)
  • The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. (wikipedia.org)
  • NK cells also play a role in the adaptive immune response: numerous experiments have demonstrated their ability to readily adjust to the immediate environment and formulate antigen-specific immunological memory, fundamental for responding to secondary infections with the same antigen. (wikipedia.org)
  • The role of NK cells in both the innate and adaptive immune responses is becoming increasingly important in research using NK cell activity as a potential cancer therapy. (wikipedia.org)
  • Recent studies have highlighted the successes of chimeric antigen receptor-modified T- (CART-) cell-based therapy for B-cell malignancies, and early phase clinical trials have been launched in recent years. (hindawi.com)
  • After two decades of preclinical research and clinical trials, the safety and feasibility of CART-cell-based therapy have been confirmed, and unprecedented clinical results have been obtained in hematological malignancies [ 3 - 5 ]. (hindawi.com)
  • These clinical studies indicate that CART-cell therapy can produce clinical responses in patients with advanced hematological malignancies. (hindawi.com)
  • Current status of clinical trials of chimeric antigen receptor-modified T (CART) cells in malignancies. (hindawi.com)
  • Finally NaF treatment resulted in phosphorylation of the gamma and epsilon chains of the T cell receptor indistinguishable from the effects of phorbol esters. (jimmunol.org)
  • No exogenous viral antigens were added. (nih.gov)
  • However, use of viral transduction methods raises the safety concern of viral integration into the NK cell genome. (plos.org)
  • In this study, we used trogocytosis as a non-viral method to modify NK cells for immunotherapy. (plos.org)
  • NK cells provide rapid responses to viral-infected cells, acting at around 3 days after infection, and respond to tumor formation. (wikipedia.org)
  • Functional studies in the latter model showed that uptake of H-2D d by Ly49A + NK cells was accompanied by a partial inactivation of cytotoxic activity in the NK cell, as tested against H-2D d -negative target cells. (rupress.org)
  • The phenomenon is also known from neurobiology, in which a similar transfer of proteins between cells has been shown to be part of an intercellular communication system, with functional consequences for the cells involved ( 13 ). (rupress.org)
  • Using indirect immunofluorescence procedures two inflammatory markers, class II MHC antigens HLA DR and the receptor to IgE (CD23), were sought in impression cytology specimens obtained from 80 patients. (bmj.com)
  • When stimulated by antigen exposure, B start secreting large amounts of antibody and enormous increase in endoplasmic reticulum and golgi. (coursehero.com)
  • The changes of expression of some antigens on exposure of cells to dibutyryl adenosine 3′-5′-cyclic monophosphoric acid may enable us to have a greater understanding of the differentiation of neuroblastoma to a more mature ganglioneuroblastoma phenotype. (aacrjournals.org)
  • These cells phagocytose or endocytose pathogens or foreign macromolecules, digest them to peptide fragments, and then export these peptide fragments bound to MHC II proteins to the cell surface for inspection by helper T cells. (gatech.edu)
  • Helper T cells are activated when their TCR recognizes the antigen presented by an APC. (gatech.edu)
  • They divide to form both activated helper T cells and long-lived memory helper T cells. (gatech.edu)