Mechanisms of T cell-mediated cytotoxicity remain poorly defined at the molecular level. To investigate some of these mechanisms, we used as target cells, on the one hand, thymocytes from lpr and gld mouse mutants, and on the other hand, L1210 cells transfected or not with the apoptosis-inducing Fas molecule. These independent mutant or transfectant-based approaches both led to the conclusion that Fas was involved in the Ca(2+)-independent component of cytotoxicity mediated by at least two sources of T cells, namely nonantigen-specific in vitro activated hybridoma cells, and antigen-specific in vivo raised peritoneal exudate lymphocytes. Thus, in these cases, T cell-mediated cytotoxicity involved transduction via Fas of the target cell death signal. ...
To investigate the molecular mechanisms by which the PBAF complex regulates the sensitivity of B16F10 tumor cells to T cell-mediated killing, we examined the transcriptome of PBAF-deficient B16F10 cells by RNA-seq. Arid2- and Pbrm1-deficient B16F10 cells shared similar gene expression profiles (fig. S12, A and B), consistent with their critical role in the PBAF complex. The transcriptome of Brd7 mutant B16F10 cells was more distinct, suggesting that Brd7 may also have PBAF-independent functions (fig. S12A). mRNAs for a number of metabolic pathways were concordantly down-regulated in Arid2 and Pbrm1 mutant cells compared to control B16F10 tumor cells, in particular gene sets associated with mTORC1 activation and cholesterol homeostasis (fig. S12, C and D, and fig. S13). mTORC1 was also a major resistance pathway for T cell-mediated cytotoxicity in the CRISPR-Cas9 screen (Fig. 1D).. Silencing of BAF200 (Arid2) with a small interfering RNA was shown to reduce the expression of interferon induced ...
Harris, J W., "Response of primary and secondary cytotoxic t lymphocytes to hyperthermia. Abstr." (1977). Subject Strain Bibliography 1977. 2592 ...
B.L.S. conceived and directed the project; M.S., P.W.H., F.M.H., and S.G.D. characterized the participant cohort and procured clinical samples; B.E.K. conducted laboratory assays and data analysis; B.E.K. and B.L.S. prepared, wrote, and edited the manuscript; all authors read and approved the manuscript. ...
T cells are crucial mediators of tissue rejection and long-lived immune protection. While HLA class I-restricted CD8-positive T cells are the primary effectors of tissue destruction, CD4-positive T cells support their expansion and memory formation. The identification of T cell target antigens is a prerequisite for the rational development of specific tumor immunotherapies. T cells recognize peptides bound to and presented by HLA molecules on the surfaces of target cells. The peptides are processed from proteins derived from any subcellular compartment. In this way, T cells sense differences between tumor and normal cells. Their sensitivity is exceptional in several aspects: On the one hand, even changes at single amino acid positions can be detected by T cells; on the other hand, the presence of very few peptide-HLA-complexes on target cell surfaces is sufficient for effective T cell recognition. Since 1991 a variety of T cell-recognized tumor-associated antigens has been published. A current ...
In this study, the in vitro and in vivo antitumor properties of the IL-2-activated MNCs from UCBCs in comparison with IL-2-activated MNCs from PBCs were explored. The NK cytotoxicity levels of UCBCs were very low compared with PBCs prior to in vitro activation (data not shown). After IL-2 activation, however, there was significant antitumor cytotoxicity against NK-sensitive/LAK-resistant and LAK-sensitive tumor target cells (Fig. 1)⇓ . Similar results have been observed by other investigators (20, 21, 22, 23, 24, 25, 26) . The activated UCBCs were not only cytotoxic to hematological malignant cells but also considerably cytotoxic to human breast cancer cells (Fig. 2)⇓ . The level of cytotoxicity of activated cord blood cells against breast cancer was not different from that of similarly activated MNCs from peripheral blood apheresis product. This result is different from what we observed with K562 and Raji tumor targets. The precise reason for this difference is not clear at this ...
We have shown that a "KIR-CAR" can be simply constructed by swapping the two immunoglobulin-like domains of the KIR2DS2 ectodomain with an scFv capable of binding a desired target antigen. When delivered to T cells together with DAP12, this KIR-based CAR triggers antigen-specific cytotoxicity, cytokine production, and proliferation that is comparable with second-generation CD3ζ-based CARs in vitro without the need for additional domains from costimulatory receptors. The ability of a KIR-based CAR to activate T cells in the absence of added costimulation is interesting in light of the critical importance of costimulation for full T-cell activation and acquisition of effector function. KIR2DS2, the natural KIR upon which the presented KIR-CAR is based, has previously been reported to deliver a costimulation-like signal to T cells. In these studies, engagement of the KIR in T-cell clones lacking DAP12 expression augmented anti-CD3-induced IFNγ production (16). The mechanism of this costimulatory ...
Knowledge of the interactions between MHC-unrestricted cytotoxic effector cells and solid tumour cells is essential for introducing more effective NK cell-based immunotherapy protocols into clinical practise. Here, to begin to obtain an overview of the possible universe of molecules that could be in …
RefSeq Summary (NM_005931): This gene encodes a heavily glycosylated protein which is a ligand for the NKG2D type II receptor. Binding of the ligand activates the cytolytic response of natural killer (NK) cells, CD8 alphabeta T cells, and gammadelta T cells which express the receptor. This protein is stress-induced and is similar to MHC class I molecules; however, it does not associate with beta-2-microglobulin or bind peptides. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014 ...
RefSeq Summary (NM_005931): This gene encodes a heavily glycosylated protein which is a ligand for the NKG2D type II receptor. Binding of the ligand activates the cytolytic response of natural killer (NK) cells, CD8 alphabeta T cells, and gammadelta T cells which express the receptor. This protein is stress-induced and is similar to MHC class I molecules; however, it does not associate with beta-2-microglobulin or bind peptides. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014 ...
Anybody that has played the beautiful game at a junior level may have once heard this little chestnut from a well-meaning coach: if you dont shoot, you dont score. True enough, but it is actually good quality shots, e.g. a shot on target, that are the key to scoring.
Protein levels regressed against four cytotoxicity phenotypes using fixed effect or mixed effect models representing the three biological replicates.We analyzed
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TY - JOUR. T1 - Monocyte- and natural killer cell-mediated spontaneous cytotoxicity against human noncultured solid tumor cells. AU - Itoh, Kyogo. AU - Platsoucas, Chris D.. AU - Balch, Charles M.. PY - 1987. Y1 - 1987. N2 - Unstimulated human peripheral blood mononuclear cells from healthy donors exhibited spontaneous cytotoxicity against noncultured solid tumor targets in a 12- to 24-hr 51Cr release or 111In release assay. Both purified monocytes (, 99% monocytes) and natural killer (NK)-enriched lymphocytes exhibited comparable levels of spontaneous cytotoxicity against fresh melanoma tumor targets. This cytotoxicity was observed under endotoxin-free conditions. NK-depleted lymphocytes did not lyse the melanoma targets. Culture supernatants of monocytes incubated with the melanoma tumor cells did not exhibit cytotoxic activity against these targets. Purified monocytes lacked NK activity against the K562 targets in a 4-hr 51Cr release assay. Treatment of the monocytes with anti-Leu 11b and ...
Hence, the hypothesis that UL18 replaces class I MHC molecules to prevent NK cell lysis does not seem to apply to hCMV-infected HFFs and transfected epithelial and ovary cells (293, COS-7, and CHO-K1). It was recently reported that UL18 inhibits NK cell lysis of 721.221 B lymphoblastoid targets, mediated through CD94 ((11)). In repeated studies, we never observed inhibition of NK cell killing against UL18 expressing targets using clones with functional CD94 or KIR. In view of this discrepancy, several aspects of the previous report should be highlighted. First, in the prior study UL18 was transfected into 721.221 targets; however, transfectants were isolated on the basis of surface β2M expression, not UL18. Second, we have failed to generate stable UL18 transfectants in 721.221 or in 15 other human or mouse lines, because it seems that prolonged expression (,2 wk) of UL18 results in cell death. We could only generate UL18 transfectants in high efficiency transient transfection systems such as ...
Ulm C, Saffarzadeh M, Mahavadi P, Müller S, Prem G, Saboor F, Simon P, Middendorff R, Geyer H, Henneke I, Bayer N, Rinné S, Lütteke T, Böttcher-Friebertshäuser E, Gerardy-Schahn R, Schwarzer D, Mühlenhoff M, Preissner KT, Günther A, Geyer R, Galuska SP., Cell Mol Life Sci 70(19), 2013 ...
TY - JOUR. T1 - Characterization of Cord Blood Natural Killer and Lymphokine Activated Killer Lymphocytes Following Ex Vivo Cellular Engineering. AU - Ayello, Janet. AU - van de Ven, Carmella. AU - Fortino, Weiwei. AU - Wade-Harris, Cheryl. AU - Satwani, Prakash. AU - Baxi, Laxmi. AU - Simpson, Lynn L.. AU - Sanger, Warren G. AU - Pickering, Diana. AU - Kurtzberg, Joanne. AU - Cairo, Mitchell S.. PY - 2006/6/1. Y1 - 2006/6/1. N2 - Cord blood (CB) natural killer (NK) and lymphokine-activated killer (LAK) cytotoxic cells are poorly characterized but might be used to treat minimal residual and/or recurrent malignant disease. Currently, there is no mechanism to use CB for adoptive cancer cellular immunotherapy after CB transplantation (CBT). Recognizing this as a deficiency, we hypothesized that CB aliquots could be engineered ex vivo for potential donor lymphocyte infusion after CBT. Cryopreserved CB aliquots were thawed, depleted of monocytes, and cultured in serum-free medium alone or serum-free ...
Several lines of data have suggested a possible link between the indoleamine 2,3-dioxygenase (IDO)-like protein IDO2 and cancer. First, IDO2 expression has been described in human tumors, including renal, gastric, colon, and pancreatic tumors. Second, the apparent selective inhibition of IDO2 by the D stereoisomer of the IDO blocker 1-methyl-tryptophan (1MT), which tends to be more active than the L-isomer in a variety of biological assays for IDO function, suggests that IDO2 may be important to sustain immune escape and growth of tumors. Especially, D-1MT heightens chemotherapeutic efficacy in mouse models of cancer in a nontoxic fashion. Here, we describe the immunogenicity of IDO2 by showing the presence of spontaneous cytotoxic T-cell reactivity against IDO2 in peripheral blood of both healthy donors and cancer patients. Furthermore, we show that these IDO2-specific T cells are cytotoxic effector cells that recognize and kill tumor cells. Our data suggest that IDO2 might be a useful target ...
Insufficient natural killer cell responses against retroviruses: how to improve NK cell killing of retrovirus-infected cells. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Evaluation of adjuvants at the mucosal area for the development of innovative mucosal vaccine against PRRS." Presented at USDA and NPB meeting - Invited Presentation, Des Moines, IA, US,USA. (June 2009). "Alternative models for study of respiratory diseases: Pig is a useful animal model to address both infectious and non-infectious lung diseases." Presented at Immunologists Round Table meeting - Invited Presentation, Columbus, OH, US,USA. (November 2010). "A non-radioactive colorimetric assay to detect Natural Killer cell-mediated cytotoxicity." Presented at Immunologists Round Table Meeting - Invited Presentation, Wooster, OH, US,USA. (February 2010). "Development of novel mucosal vaccines for the control of PRRS outbreaks.." Presented at USDA NPB meeting - Invited Presentation, Des Moines, IA, US,USA. (June 2010). "Mucosal vaccine to protect against porcine reproductive and respiratory syndrome: a new perspective." Presented at 9th International Veterinary Immunology Society (IVIS) meeting - ...
The ligation of CD28 by B7.1 delivers a well-characterized, and perhaps the most potent, antigen-independent costimulatory signal to T cells, resulting in an increase in the production of T-helper 1-associated cytokines important in promoting antitumor CTL responses. B7.1 can also increase expression of the IL-2 receptor on T cells, prevent activation-induced T-cell death, and trigger natural killer cell cytotoxicity (19, 20). Whereas conferring B7 expression on tumor cells can enhance antitumor responses, it is also apparent that provision of B7 expression is not sufficient to induce immunity against nonimmunogenic tumors (21). Combining B7 expression with immune-stimulatory cytokine expression has been shown to augment tumor immunity. Synergy between B7.1 costimulation and IL-12 has been shown in melanoma models as well as models of breast cancer, lymphoma, hepatocellular cancer, head and neck cancer, and multiple myeloma (15, 22-26). We examined the safety and toxicity of the intratumoral ...
Dear all, Our lab would like to use flow cytometry for the measuring natural killer cell cytotoxicity. Does anyone have a working protocol that can share with us? Also, could we use 24 hrs. old human whole blood instead of PBMC for the assay? It will be really appreciated if you can provide us with valuable pointers. Thanks in advance. Lee Lam CDC Atlanta, Georgia Phone: 404-639-2725 Fax: 404-639-4838 E-mail: LXL7 at CDC.GOV ,mailto:LXL7 at CDC.GOV ...
This sensitivity allows natural killer cells to vigorously initiate natural killer cytotoxicity (by emptying granules of porforin and granzyme) and inflammation as soon as pathogenesis is detected, and is essential to protection against viruses and tumors. Natural killer cells have genomic (not needed recombination, or RAG-independent) cell surface receptors which recognize classical Class I MHC molecules (and structural relatives like MICA, RAE-1 and H-60).. Natural killer cells lack TcRs, CD4s and CD8; instead, they have: cell-surface activating receptors, which bind noncovalently to molecules with ITAMs; and on the cytoplasmic side, inhibitory receptors with ITIM(s) which -- upon phosphorylation -- recruit and activate SHP-1 & -2, which inhibit the activating receptors. The balance between activating signals and inhibitory signals is what determines whether a natural killer cell will destroy or bypass a microbe it encounters. ...
Natural killer (NK) cells are innate immune cells that show strong cytolytic function against physiologically stressed cells such as tumor cells and virus-infected cells. NK cells show a broad array of tissue distribution and phenotypic variability. NK cells express several activating and inhibitory receptors that recognize the altered expression of proteins on target cells and control the cytolytic function. NK cells have been used in several clinical trials to control tumor growth. However, the results are encouraging only in hematological malignancies but not very promising in solid tumors. Increasing evidence suggests that tumor microenvironment regulate the phenotype and function of NK cells. In this review, we discussed the NK cell phenotypes and its effector function and impact of the tumor microenvironment on effector and cytolytic function of NK cells. We also summarized various NK cell-based immunotherapeutic strategies used in the past, and the possibilities to improve the function of NK cell
Cytolytic cells of the immune system destroy pathogen-infected cells by polarised exocytosis of secretory lysosomes containing the pore-forming protein perforin. Precise delivery of this lethal hit is essential to ensuring that only the target cell is destroyed. In cytotoxic T lymphocytes (CTLs), this is accomplished by an unusual movement of the centrosome to contact the plasma membrane at the centre of the immunological synapse formed between killer and target cells. Secretory lysosomes are directed towards the centrosome along microtubules and delivered precisely to the point of target cell recognition within the immunological synapse, identified by the centrosome. We asked whether this mechanism of directing secretory lysosome release is unique to CTL or whether natural killer (NK) and invariant NKT (iNKT) cytolytic cells of the innate immune system use a similar mechanism to focus perforin-bearing lysosome release. NK cells were conjugated with B-cell targets lacking major histocompatibility
Cross-sectional studies suggest that moderate physical activity is associated with enhanced resting immune function; however, few randomized controlled trials have investigated this link. We investigated the effect of 12-mo aerobic exercise, relative to stretching control, on in vitro immune function in a randomized, controlled trial of 115 postmenopausal, overweight, or obese sedentary women, aged 50-75 yr. The exercise goal was , or =45 min/day, 5 days/wk. Control women participated in 1 day/wk stretching classes. Immune markers (natural killer cell cytotoxicity, T-lymphocyte proliferation, immune cell counts and phenotypes, and serum immunoglobulins) were assessed at baseline, 3 mo, and 12 mo under strict blood-draw criteria. General estimation equations evaluated intervention effects at 3 and 12 mo, controlling for baseline. Of the 115 women who began the trial, blood samples were available from 109 at 3 mo (95%) and 108 at 12 mo (94%). From baseline to 12 mo, the exercise group participated ...
CD56 is a member of the neural cell adhesion molecule family expressed on cells of the central nervous system and also on NK cells. Previous studies suggest the involvement of CD56 in effector-to-target cell conjugation mediated by NK cells. It was shown recently that CD56 is also expressed by subpopulations of CD8+ and CD4+ T cells. The present study describes the functional characteristics of CD4+CD56+ T cell lines established from blood of multiple sclerosis patients by stimulation with myelin basic protein (MBP). CD4+CD56+, MBP-specific T cell lines were able to lyse MBP-pulsed target cells in an HLA class II-restricted fashion. At the same time, they mediated MHC-unrestricted lysis of CD56+ target cells such as CD56+ lymphoid or glial tumor cells, but not of the typical NK target, K562. A number of experimental results including separation of CD4+CD56+ T cells into CD56 high and low expressing populations, cold target inhibition, as well as killing of CD56-transfected cells indicate that ...
Natural Killer Cells are the most aggressive white cells in the immune system. They make up about 5% to 15% of the total lymphocyte circulating population. They target tumor cell and protect against a wide variety of infectious microbes. Natural Killer Cells are a very important factor in the fight against cancer. Immune Stimulation is the key to keeping the white blood cell count high and giving the Natural Killer Cells a chance to fight cancer and other diseases.. ...
Now, results from a new study carried out using a mouse model, show that modified cells called "super natural killer cells" are able to seek out cancer cells in lymph nodes to destroy them, thus halting the process of metastasis. Michael King, senior author of the study, said in a press release: "We want to see lymph node metastasis become a thing of the past.". The super natural killer cells find the cancerous cells in the lymph nodes and induce apoptosis - in other words, the cancer cells self-destruct and disintegrate, thus averting their further lymphatic spread. But what are these super natural killer cells? They are a modified version of the so-called natural killer cells - or NK cells for short.. NK cells are a type of lymphocytes that play a major role in the killing of cancer cells and virus-infected cells by inducing apoptosis. To obtain the "super" version of these lymphocytes, scientists attached nanoparticles to the NK cell surface. These nanoparticles contain a protein dubbed TRAIL ...
Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit ...
Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in early defenses against both allogeneic (nonself) cells and autologous cells undergoing various forms of stress, such as infection with viruses, bacteria, or parasites or malignant transformation. Although NK cells do not express classical antigen receptors of the immunoglobulin gene family, such as the antibodies produced by B cells or the T cell receptor expressed by T cells, they are equipped with various receptors whose engagement allows them to discriminate between target and nontarget cells. Activating receptors bind ligands on the target cell surface and trigger NK cell activation and target cell lysis. However Inhibitory receptors recognize MHC class I molecules (HLA) and inhibit killing by NK cells by overruling the actions of the activating receptors. This inhibitory signal is lost when the target cells do not express MHC class I and perhaps also in cells infected with virus, which might inhibit ...
TY - JOUR. T1 - Regulation of IFN-γ production following 2B4 activation in human NK cells. AU - Johnson, Lori A.. AU - Goldfarb, Ronald H.. AU - Mathew, Porunelloor. PY - 2000/12/1. Y1 - 2000/12/1. N2 - IFN-γ is a cytokine that regulates various functions of the immune system. The major producers of IFN-γ are T cells and NK cells. 2B4 is a novel activating receptor expressed on all human NK cells, a subset of CD8+ T cells, monocytes and basophils. Activation of human NK cells through surface 2B4 enhances NK cell cytolytic function and secretion of IFN-γ. We have examined the regulation of IFN-γ production by the human NK cell line YT upon activation through surface 2B4. Our data indicate that ligation of surface 2B4 by mAb C1.7, that specifically recognizes 2B4, induces transcriptional activation of IFN-γ. Partial inhibition of transcription did not prevent the transcriptional upregulation of IFN-γ. S1 nuclease protection analysis indicated that transcriptional activation as well as mRNA ...
Adoptive cell transfer of tumor infiltrating lymphocytes has shown clinical efficacy in the treatment of melanoma and is now also being explored in other tumor types. Generation of sufficient numbers of effector T cells requires extensive ex vivo expansion, often at the cost of T cell differentiation and potency. For the past 20 years, IL-2 has been the key cytokine applied in the expansion of TIL for ACT. However, the use of IL-2 has also led to collateral expansion of regulatory T cells (Tregs) and progressive T cell differentiation, factors known to limit in vivo persistence and activity of transferred TIL. The use of alternative T cell growth factors is therefore warranted. Here, we have compared the effects of IL-2, -15 and −21 cytokines on the expansion and activation of TIL from single-cell suspensions of non-small cell lung cancer, ovarian cancer and melanoma. We applied the K562-based artificial APC (aAPC) platform for the direct and rapid expansion of tumor infiltrating lymphocytes isolated
The T- and B-Lymphocyte and Natural Killer Cell Profile includes the following tests:. Percentage CD3+; absolute CD3+; percentage CD3+CD4+; absolute CD3+CD4+; percentage CD3+CD8+; absolute CD3+CD8+; percentage CD3-CD56+ natural killer (NK) cells; absolute CD3-CD56+ natural killer (NK) cells; percentage CD19+; absolute CD19+; CD4:CD8 ratio; CBC. .. HIV-1 infection results in a decrease of CD4 T cells, an increase in CD8 T cells, a decrease in the CD4:CD8 ratio, and a progressive destruction of immune function. Enumeration of CD4 and CD8 T cells in HIV-1 seropositive patients may be used for prognostic purposes and to monitor disease progression and retroviral therapy. Natural killer (NK) cells are large granular lymphocytes that mediate MHC-unrestricted cytotoxicity against virus-infected and malignant cells and manufacture a number of cytokines following stimulation of the immune system.. ...
CD8+ T cells play a crucial role in the host defenses against malignancies in both mice and humans (1). The identification of tumor-associated antigens (TAA) recognized by CD8+ T lymphocytes has permitted potentiation of specific immune responses in immunotherapy strategies. Nevertheless, despite the expression of TAAs, tumor eradication by the immune system is often inefficient (2), which accounts for the disappointing clinical activity of most cancer vaccines (3). Extensive studies have shown that tumor cells themselves play a crucial role in modulating the host immune response, such that they maintain their functional disorder and evade immune surveillance (4). In this regard, it has been suggested that tumor cell growth in vivo is not only influenced by cytotoxic T lymphocyte (CTL) tumor cell recognition but also by tumor susceptibility to cell-mediated death (5). While the resistance of tumor cells to T-cell-mediated cytotoxicity remains a major impediment for cancer immunotherapy, its ...
Natural killer (NK) cells comprise 5-20% of peripheral blood mononuclear cells (PBMC) in humans. In addition to their fundamental roles in the defense against viral infections and tumor surveillance, NK cells help shape adaptive immune responses through their production of cytokines. NK cells are traditionally identified as CD3neg, CD14neg, CD19neg lymphocytes expressing CD56. Using a combination of markers that includes CD56 and CD7 greatly increases the ability to define the phenotype and function of NK cell subsets. Two key markers of NK cell function are the production of IFNγ and the release of cytotoxic granules measured by the expression of CD107a. Here we describe a method to assess IFNγ and CD107a expression in NK cells following stimulation with target cells or cytokines. This method can be used to assess the general functional capacity of NK cells in peripheral blood mononuclear cells from a wide range of study participants.
Histidine-rich glycoproteinはCLEC-1Bを介してPD-1発現を調節することでナチュラルキラー細胞活性を増強す ...
CD57 is a marker of terminal differentiation on human CD8+ T cells and possibly on human NK cells. Newborn and fetal NK cells do not express CD57, however the frequency of CD57-bearing NK cells increases with age. Utilizing PBMC obtained from healthy donors we are assessing the phenotypic and functional differences between CD57+ and CD57neg NK cells. CD57+ NK cells express different activation markers and a distinct repertoire of NK receptors suggestive of a more mature phenotype. Preliminary data also indicate that there is a higher frequency of IFNγ CD57+ NK cells compare to CD57neg NK cells when stimulated through their activating receptors, CD57+ NK cells are less sensitive to activation-induced apoptosis, and interestingly, proliferate less when co-cultured with target cells and/or cytokines. The combination of a more activated phenotype and a decreased capacity to proliferate suggests CD57+ NK cells are terminally differentiated. Studies are underway to assess the phenotypic and ...
Natural killer (NK) cells are a noteworthy lymphocyte subset in cancer adoptive cell therapy. NK cells initiate innate immune responses against infections and malignancies with natural cytotoxicity, which is independent of foreign antigen recognition. Based on these substantive features, genetically modifying NK cells is among the prime goals in immunotherapy but is currently difficult to achieve. Recently, we reported a fully human CAR19 construct (huCAR19) with remarkable function in gene-modified T-cells. Here, we show efficient and stable gene delivery of huCAR19 to primary human NK cells using lentiviral vectors with transduction efficiencies comparable to those achieved with NK cell lines. These huCAR19 NK cells display specific and potent cytotoxic activity against target cells. To improve homing of NK cells to the bone marrow, we augmented huCAR19 NK cells with the human CXCR4 gene, resulting in transgenically augmented CAR NK cells (TRACKs). Compared to conventional CAR NK cells, TRACKs exhibit
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BackgroundCD8+ T cells impact control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. In HIV-1 infection, persistent HIV-1 specific IFN-γ+ CD8+ T cell responses are detected in the setting of disease progression, consistent with functional impairment in vivo. Recent data suggest that impaired maturation, as defined by the lineage markers CD45RA and CCR7, may contribute to a lack of immune control by these responses.Methodology/Principal FindingsWe investigated the maturation phenotype of epitope-specific CD8+ T cell responses directed against HIV-1 in 42 chronically infected, untreated individuals, 22 of whom were
The data suggest serious impairment of NK function in elderly patients with oral carcinoma. Generation of LAK activity with exogenous IL-2 could be an important modality of treatment in these patients.
Natural Killer Cells are also defined as large granular lymphocytes (LGL) and comprise the third kind of cells other than B and T Lymphocytes. They usually...
Assay Kits , Cell Proliferation and Cytotoxicity Kits , Sensolyte Cell Cytotoxicity Assay Kit-Larger size; The damage of cell membrane leads to release of cytoplasmic enzymes. The measurement of released cytoplasmic lactate dehydrogenase (LDH) is a well-accepted assay to estimate cell membrane integrity and quantify cytotoxicity. The SensoLyte Cell Cytotoxicity Assay Kit uses resazurin as a sensitive fluorogenic indicator (Ex/Em=560 nm/590 nm upon conversion) to measure LDH activity. The assay can be performed in a mixed population of damaged and viable cells, but only measure the LDH released from damaged cells. The cytoplasmic LDH in living cells produces little signals under assay condition. There is no need of extra steps to separate living cells and supernatant. The fluorescent signal is proportional to the number of damaged cells (up to 2.5X104 cell, r2>0.95) with the detection limit reaching 100 dead cells. The kit is suitable for high throughput screening of
Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to viral-infected cells, acting at around 3 days aft
The results of the present study extend our previous findings demonstrating that, at diagnosis, patients with locally advanced, HER2-overexpressing BC are characterized by a retained immune proficiency [23], and more importantly, achieve a high rate of pCR (42.5%) after neoadjuvant Trastuzumab and Paclitaxel [35]. These observations, together with the known immune-modulating effects of these drugs [36, 37], prompted us to thoroughly investigate the immune profile of the same cohort of patients along treatment. The time frame in which NC is administered is particularly suitable for immunological studies [36] because it does not suffer from the immune suppression induced by surgery or by advanced metastatic disease.. We herein demonstrate that, in both groups of patients, NC treatment induced significant changes in the relative proportions of circulating immune cells. We first examined what happened within the innate immune compartment, with particular attention to NK cells, given the major role ...
New research out of the Raulet lab suggests a mechanism explaining why Natural Killer cells are sometimes rendered ineffective, and even more excitingly, suggests a therapeutic approach for re-awakening them to attack tumors. Read more...
Cytotoxic T lymphocytes (CTL) eliminate tumor target cells in an antigen and cell-contact dependent manner, both spontaneously and when activated by immunotherapy. Lethal hit delivery is considered to be a rapid and binary "yes/no" process under conditions of high immunogenicity. In tissues, killing efficacy further depends upon sequential conjugation of CTL with multiple target cells, termed "serial killing." Here we show that elimination of cancer cells results from a cooperative process executed by multiple CTL engaging sequentially with the same target cell. Migrating CTL transit between target cells and cooperate to initiate apoptosis by a series of sublethal interactions (additive cytotoxicity), whereas individual conjugations rarely reached thresholds to induce apoptosis. Consequently, in invading B16F10 melanoma tumors treated with adoptive T cell therapy in vivo, serial engagements and tumor-cell apoptosis induction were confined to regions with high CTL density, which supported CTL ...
Natural killer (NK) cell cytotoxicity is highly dependent on the ability of NK cells to migrate through the extracellular matrix (ECM) microenvironment. Traditional imaging studies of NK cell migration and cytotoxicity have utilized 2-D surfaces, which do not properly reproduce the structural and mechanical cues that shape the migratory response of NK cells in vivo. In addition, current in vivo imaging does not allow for the accurate long-term single-cell imaging required to dissect the functional heterogeneity of NK cell populations, and importantly, it does not allow studies of human cells. Therefore, it is desirable to implement in vitro migration and killing assays that better mimic in vivo conditions.. We have combined a microwell assay that allows long-term imaging and tracking of small, well-defined populations of NK cells with an interstitial ECM-like matrix to more closely approximate in vivo conditions. The microwells, which are loaded with a gel mixture containing NK and target cells, ...
Cytotoxic T cell response and thymic hormonal dysfunction in graft-vs-host mice.: As an approach to dissect complex mechanisms that lead to graft-vs-host (GvH)-