NKG2D
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Membrane rafts are microdomains of the plasma membrane that have multiple biological functions. The involvement of these structures in the biology of T cells, namely in signal transduction by the TCR, has been widely studied. However, the role of membrane rafts in immunoreceptor signaling in NK cells is less well known. We studied the distribution of the activating NKG2D receptor in lipid rafts by isolating DRMs in a sucrose density gradient or by raft fractionation by β-OG-selective solubility in the NKL cell line. We found that the NKG2D-DAP10 complex and pVav are recruited into rafts upon receptor stimulation. Qualitative proteomic analysis of these fractions showed that the actin cytoskeleton is involved in this process. In particular, we found that the actin-bundling protein L-plastin plays an important role in the clustering of NKG2D into lipid rafts. Moreover, coengagement of the inhibitory receptor NKG2A partially disrupted NKG2D recruitment into rafts. Furthermore, we demonstrated that L-plastin participates in NKG2D-mediated inhibition of NK cell chemotaxis.
- MeSH
- buněčná membrána účinky léků metabolismus MeSH
- buňky NK cytologie metabolismus MeSH
- centrifugace - gradient hustoty MeSH
- chemotaxe leukocytů fyziologie MeSH
- detergenty farmakologie MeSH
- kultivované buňky MeSH
- lektinové receptory NK-buněk - podrodina C metabolismus MeSH
- lektinové receptory NK-buněk - podrodina K fyziologie MeSH
- lidé MeSH
- malá interferující RNA farmakologie MeSH
- membránové mikrodomény účinky léků fyziologie MeSH
- mikrofilamenta fyziologie MeSH
- mikrofilamentové proteiny antagonisté a inhibitory genetika fyziologie MeSH
- multiproteinové komplexy MeSH
- proteom MeSH
- receptory imunologické metabolismus MeSH
- RNA interference MeSH
- signální transdukce imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Advanced metastatic colorectal cancer (CRC) with deficient DNA mismatch repair (MMR-d), or immune-hot CRCs, show significantly improved clinical outcomes compared to MMR-proficient (MMR-p), or immune-cold CRCs. While the prior represents about 5% of all CRCs, the latter represent 95% and are characterized by low immunogenicity. This study investigates bis-diethyldithiocarbamate (CuET), a novel anticancer compound, and its impact on the colorectal cancer tumor microenvironment (TME). CuET is shown to convert immunologically inactive tumors into hotbeds of antitumor immune responses, marked by increased lymphocyte infiltration, heightened cytotoxicity of natural killer (NK) and T cells, and enhanced non-self recognition by lymphocytes. The potent anticancer cytotoxicity and in vivo safety and efficacy of CuET are established. In summary, CuET transforms the colorectal cancer TME, bolstering NK and T cell cytotoxicity and refining tumor cell recognition through non-classical activation via the NKG2D/NKG2DL axis. This study unveils a novel mechanism of action for CuET: a potent immunomodulator capable of turning cold tumors hot.
- MeSH
- buňky NK imunologie účinky léků metabolismus MeSH
- dithiokarb * farmakologie MeSH
- kolorektální nádory * farmakoterapie imunologie metabolismus patologie MeSH
- lektinové receptory NK-buněk - podrodina K * metabolismus MeSH
- lidé MeSH
- měď MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádorové mikroprostředí * účinky léků imunologie MeSH
- protinádorové látky farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Natural killer cells possess key regulatory function in various malignant diseases, including acute myeloid leukemia. NK cell activity is driven by signals received through ligands binding activating or inhibitory receptors. Their activity towards elimination of transformed or virally infected cells can be mediated through MICA, MICB and ULBP ligands binding the activating receptor NKG2D. Given the efficiency of NK cells, potential target cells developed multiple protecting mechanisms to overcome NK cells killing on various levels of biogenesis of NKG2D ligands. Targeted cells can degrade ligand transcripts via microRNAs or modify them at protein level to prevent their presence at cell surface via shedding, with added benefit of shed ligands to desensitize NKG2D receptor and avert the threat of destruction via NK cells. NK cells and their activity are also indispensable during hematopoietic stem cell transplantation, crucial treatment option for patients with malignant disease, including acute myeloid leukemia. Function of both NKG2D and its ligands is strongly affected by polymorphisms and particular allelic variants, as different alleles can play variable roles in ligand-receptor interaction, influencing NK cell function and HSCT outcome differently. For example, role of amino acid exchange at position 129 in MICA or at position 98 in MICB, as well as the role of other polymorphisms leading to different shedding of ligands, was described. Finally, match or mismatch between patient and donor in NKG2D ligands affect HSCT outcome. Having the information beyond standard HLA typing prior HSCT could be instrumental to find the best donor for the patient and to optimize effects of treatment by more precise patient-donor match. Here, we review recent research on the NKG2D/NKG2D ligand biology, their regulation, description of their polymorphisms across the populations of patients with AML and the influence of particular polymorphisms on HSCT outcome.
- MeSH
- akutní myeloidní leukemie genetika imunologie mortalita terapie MeSH
- buňky NK imunologie metabolismus MeSH
- individualizovaná medicína metody MeSH
- jednonukleotidový polymorfismus MeSH
- lektinové receptory NK-buněk - podrodina K genetika metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- lokální recidiva nádoru epidemiologie genetika MeSH
- MHC antigeny I. třídy genetika metabolismus MeSH
- přežití bez známek nemoci MeSH
- transplantace hematopoetických kmenových buněk * MeSH
- výběr dárců metody MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
UNLABELLED: Membrane-bound heat shock protein 70 (HSP70) was found to be tumor-specific and was proposed as a target for immunotherapy. In the present study, we analyzed cell surface and relative gene expression of HSP70 in cell lines established from patients with different acute myeloid leukemia (AML) subtypes, together with the expression of natural killer (NK) cell activation/inhibitory ligands. MATERIALS AND METHODS: Six AML cell lines were included in this study. The relative gene expression of HSP70 was analyzed using the real-time reverse-transcriptase polymerase chain reaction. Surface expression of HSP70 and NK cell ligands was analyzed using flow cytometry. RESULTS: All cell lines overexpressed HSP70; however, its mRNA levels were not elevated. The expression of NKG2D activation ligands was heterogeneous. CONCLUSION: Our study is the first to describe long-term stationary cell surface expression of HSP70 in different subtypes of AML. Combined with the results of the gene expression experiments these data provide more evidence to the idea of a self-limiting mechanism for HSP70 expression.
- MeSH
- akutní myeloidní leukemie metabolismus MeSH
- buněčná membrána metabolismus MeSH
- buňky NK cytologie MeSH
- dospělí MeSH
- HL-60 buňky MeSH
- kohortové studie MeSH
- lektinové receptory NK-buněk - podrodina K metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- ligandy MeSH
- mladiství MeSH
- nádorové buněčné linie MeSH
- proteiny tepelného šoku HSP70 metabolismus MeSH
- průtoková cytometrie metody MeSH
- regulace genové exprese u leukemie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
92 s. : il., tab. ; 21 cm
NK buňky hrají u alogenní transplantace kostní dřeně významnou roli, nejen při eradikaci zbývajících nádorových buněk, ale ovlivňují i rozvoj reakce štěpu proti hostiteli. Je tedy třeba porozumět jejich regulaci a tomu, jakým způsobem může reakce imunitního systému pacienta NK buňky dárce ovlivňovat. Inhibice a aktivace NK buněk je řízena celou řadou receptorů, které reagují na široké spektrum ligandů. Ať už inhibičních, které signalizují NK buňkám, že je cílová buňka v pořádku nebo aktivačních, které vyjadřují nějaké poškození cílové buňky. Mezi nejprozkoumanější receptory patří KIR a dále NKG2D se svými ligandy MICA a MICB. Přehledu jejich role v transplantaci kostní dřeně se věnuje tato práce.
NK cells play an important role in allogeneic stem cell transplantation; not only as effector cells in the eradication of remaining cancer cells but also as potential inducers of graft versus host disease. Hence, it is important to understand their regulation and how the patient’s immune system affects donor NK cells. NK cell inhibition or activation is directed by many receptors which interact with a broad spectrum of ligands. Inhibition ligands signal that the target cell is healthy, and activating ligands reflect that the cell is damaged. The most investigated receptors are KIR together with the NKG2D receptor with its ligands MICA and MICB. This work describes their role in stem cell transplantation.
- MeSH
- akutní myeloidní leukemie * imunologie terapie MeSH
- haplotypy genetika MeSH
- HLA antigeny MeSH
- homologní transplantace MeSH
- lektinové receptory NK-buněk - podrodina K analýza genetika MeSH
- lidé MeSH
- ligandy MeSH
- polymorfismus genetický MeSH
- receptory buněk NK * imunologie klasifikace MeSH
- receptory KIR analýza genetika MeSH
- transplantace kostní dřeně MeSH
- transplantační imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Rheumatoid arthritis is an autoimmunity leading to considerable impairment of quality of life. N-acetyl glucosamine (GlcNAc) has been described previously as a potent modulator of experimental arthritis in animal models and is used for osteoarthritis treatment in humans, praised for its lack of adverse effects. In this study we present a comprehensive immunological analysis of multivalent GlcNAc-terminated glycoconjugate (GC) application in the treatment of collagen-induced arthritis (CIA) and its clinical outcome. We used immunohistochemistry and FACS to describe conditions on the inflammation site. Systemic and clinical effects were evaluated by FACS, cytotoxicity assay, ELISA, cytometric bead array (CBA), RT-PCR and clinical scoring. We found reduced inflammatory infiltration, NKG2D expression on NK and suppression of T, B and antigen-presenting cells (APC) in the synovia. On the systemic level, GCs prevented the activation of monocyte- and B cell-derived APCs, the rise of TNF-α and IFN-γ levels, and subsequent type II collagen (CII)-specific IgG2a formation. Moreover, we detected an increase of anti-inflammatory IL-4 mRNA in the spleen. Similar to the synovia, the GCs caused a significant reduction of NKG2D-expressing NK cells in the spleen without influencing their lytic function. GCs effectively postponed the onset of arthritic symptoms, reduced their severity and in 18% (GN8P) and 31% (GN4C) of the cases completely prevented their appearance. Our data prove that GlcNAc glycoconjugates prevent the inflammatory response, involving proinflammatory cytokine rise, APC activation and NKG2D expression, leading to the attenuation of clinical symptoms. These results support the glycobiological approach to the treatment of collagen-induced arthritis/rheumatoid arthritis (CIA/RA) as a way of bringing new prospects for more effective therapeutic interventions.
- MeSH
- acetylglukosamin aplikace a dávkování MeSH
- antigen prezentující buňky účinky léků imunologie MeSH
- artritida experimentální farmakoterapie imunologie MeSH
- B-lymfocyty účinky léků imunologie MeSH
- buněčná diferenciace účinky léků MeSH
- buňky NK účinky léků imunologie MeSH
- cytokiny metabolismus MeSH
- kultivované buňky MeSH
- lektinové receptory NK-buněk - podrodina K metabolismus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední DBA MeSH
- myši MeSH
- revmatoidní artritida farmakoterapie imunologie MeSH
- synoviální membrána účinky léků imunologie MeSH
- T-lymfocyty účinky léků imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
