scholarly journals High Glucose Enhances Cytotoxic T Lymphocyte-Mediated Cytotoxicity

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Zhu ◽  
Wenjuan Yang ◽  
Xiangda Zhou ◽  
Dorina Zöphel ◽  
Leticia Soriano-Baguet ◽  
...  
Keyword(s):  
High Glucose ◽  
Fas Ligand ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Dependent Manner ◽  
Lytic Granules ◽  
Normal Glucose ◽  
Infected Cells ◽  
Killing Function ◽  
The Impact

Cytotoxic T lymphocytes (CTLs) are key players to eliminate tumorigenic or pathogen-infected cells using lytic granules (LG) and Fas ligand (FasL) pathways. Depletion of glucose leads to severely impaired cytotoxic function of CTLs. However, the impact of excessive glucose on CTL functions still remains largely unknown. Here we used primary human CD8+ T cells, which were stimulated by CD3/CD28 beads and cultured in medium either containing high glucose (HG, 25 mM) or normal glucose (NG, 5.6 mM). We found that in HG-CTLs, glucose uptake and glycolysis were enhanced, whereas proliferation remained unaltered. Furthermore, CTLs cultured in HG exhibited an enhanced CTL killing efficiency compared to their counterparts in NG. Unexpectedly, expression of cytotoxic proteins (perforin, granzyme A, granzyme B and FasL), LG release, cytokine/cytotoxic protein release and CTL migration remained unchanged in HG-cultured CTLs. Interestingly, additional extracellular Ca2+ diminished HG-enhanced CTL killing function. Our findings suggest that in an environment with excessive glucose, CTLs could eliminate target cells more efficiently, at least for a certain period of time, in a Ca2+-dependent manner.

scholarly journals FOXO1 differentially regulates both normal and diabetic wound healing

2015 ◽  
Vol 209 (2) ◽  
pp. 289-303 ◽  
Author(s):  
Chenying Zhang ◽  
Bhaskar Ponugoti ◽  
Chen Tian ◽  
Fanxing Xu ◽  
Rohinton Tarapore ◽  
...  
Keyword(s):  
Wound Healing ◽  
High Glucose ◽  
Dependent Manner ◽  
Downstream Targets ◽  
Keratinocyte Migration ◽  
Normal Wound Healing ◽  
Normal Glucose ◽  
Enhanced Expression ◽  
Diabetic Wounds ◽  
The Impact

Healing is delayed in diabetic wounds. We previously demonstrated that lineage-specific Foxo1 deletion in keratinocytes interfered with normal wound healing and keratinocyte migration. Surprisingly, the same deletion of Foxo1 in diabetic wounds had the opposite effect, significantly improving the healing response. In normal glucose media, forkhead box O1 (FOXO1) enhanced keratinocyte migration through up-regulating TGFβ1. In high glucose, FOXO1 nuclear localization was induced but FOXO1 did not bind to the TGFβ1 promoter or stimulate TGFβ1 transcription. Instead, in high glucose, FOXO1 enhanced expression of serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2), and chemokine (C-C motif) ligand 20 (CCL20). The impact of high glucose on keratinocyte migration was rescued by silencing FOXO1, by reducing SERPINB2 or CCL20, or by insulin treatment. In addition, an advanced glycation end product and tumor necrosis factor had a similar regulatory effect on FOXO1 and its downstream targets and inhibited keratinocyte migration in a FOXO1-dependent manner. Thus, FOXO1 expression can positively or negatively modulate keratinocyte migration and wound healing by its differential effect on downstream targets modulated by factors present in diabetic healing.

scholarly journals High glucose attenuates Ca2+ influx in cytotoxic T lymphocytes upon target recognition

2020 ◽  
Author(s):  
Huajiao Zou ◽  
Gertrud Schwär ◽  
Renping Zhao ◽  
Dalia Alansary ◽  
Deling Yin ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
High Glucose ◽  
Calcium Release ◽  
Target Recognition ◽  
Target Cells ◽  
Calcium Sensors ◽  
Store Operated Calcium Entry ◽  
Normal Glucose ◽  
The Impact

AbstractThe killing efficiency of cytotoxic T lymphocytes (CTLs) is tightly regulated by intracellular Ca2+ concentration. Glucose is the key energy source for CTLs, lack of which significantly impairs CTL activation, proliferation and effector functions. The impact of high glucose on Ca2+ influx in CTLs remains largely elusive. In this work, we stimulated primary human CD8+ T cells in medium containing either 25 mM (high glucose, HG) or 5.6 mM glucose (normal glucose, NG). We found that store-operated calcium entry (SOCE) induced by thapsigargin (Tg) is elevated in HG-cultured CTLs compared to their counterparts in NG. Unexpectedly, the Ca2+ influx elicited by recognition of target cells is reduced in HG-cultured CTLs. Under HG condition, STIM1 and STIM2, the calcium sensors in the endoplasmic reticulum (ER), were down-regulated; ORAI1, the main structural component of calcium-release activated channels, remained unchanged, whereas ORAI2 and ORAI3 were up-regulated. The fraction of necrosis of HG-cultured CTLs was enhanced after killing without affecting glucose uptake. Thus, our findings reveal that HG has a distinctive impact on Tg-evoked SOCE and target recognition-induced Ca2+ influx in CTLs and causes more CTL death after killing, suggesting a novel regulatory role of high glucose on modulating CTL functions.

scholarly journals Massive upregulation of the Fas ligand in lpr and gld mice: implications for Fas regulation and the graft-versus-host disease-like wasting syndrome.

1995 ◽  
Vol 181 (1) ◽  
pp. 393-398 ◽  
Author(s):  
J L Chu ◽  
P Ramos ◽  
A Rosendorff ◽  
J Nikolić-Zugić ◽  
E Lacy ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Fas Ligand ◽  
Target Cells ◽  
Dependent Manner ◽  
Wasting Syndrome ◽  
Positive Target ◽  
Abnormal Cells ◽  
Lymph Node Cells ◽  
Fasl Mrna

Fas-deficient lpr and gld mice develop lymphadenopathy due to the accumulation of T cells with an unusual double negative (DN) (CD4-CD8-) phenotype. Previous studies have shown that these abnormal cells are capable of inducing redirected lysis of certain Fc receptor-positive target cells. Since the Fas ligand (FasL) has recently been shown to be partly responsible for T cell-mediated cytotoxicity, lymph node cells from lpr and gld mice were examined for the expression of FasL mRNA. Northern blot analysis revealed that lymph node cells obtained from lpr and gld mice had a striking increase in the level of expression of FasL mRNA predominantly due to expression in the DN T cells. Furthermore, lpr, but not gld lymph node cells killed the B cell line, A20, in a Fas-dependent manner. These findings indicate that Fas mutations result in a massive up-regulation of FasL which, most likely, results from repetitive exposure to (self) antigen. This phenomenon could explain the lpr-induced wasting syndrome observed when lpr bone marrow-derived cells are adoptively transferred to wild-type recipients.

scholarly journals Fusarubin and Anhydrofusarubin Isolated from A Cladosporium Species Inhibit Cell Growth in Human Cancer Cell Lines

Toxins ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 503 ◽  
Author(s):  
Sabrina Adorisio ◽  
Alessandra Fierabracci ◽  
Isabella Muscari ◽  
Anna Liberati ◽  
Lorenza Cannarile ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Fas Ligand ◽  
Human Cancer ◽  
Dependent Manner ◽  
Food Contaminants ◽  
Human Cancer Cell Lines ◽  
Hematological Cancers ◽  
The Impact

Cladosporium species are endophytic fungi that grow on organic matter and are considered food contaminants. The anti-microbial and anti-tumor naphthoquinones fusarubin (FUS) and anhydrofusarubin (AFU) were isolated using column chromatography from a Cladosporium species residing inside Rauwolfia leaves. The impact of FUS and AFU on cell growth was assessed in acute myeloid leukemia (OCI-AML3) and other hematologic tumor cell lines (HL-60, U937, and Jurkat). Treatment with FUS or AFU reduced the number of OCI-AML3 cells as evaluated by a hemocytometer. Flow cytometry analyses showed that this effect was accompanied by diverse impairments in cell cycle progression. Specifically, FUS (20 or 10 μg/mL significantly decreased the percentage of cells in S phase and increased the percentage of cells in G2/M phase, whereas AFU increased the percentage of cells in G0/G1 phase (50 and 25 μg/mL) and decreased the percentage of cells in S (50 μg/mL) and G2/M (50 and 25 μg/mL) phases. Both substances significantly increased apoptosis at higher concentrations. The effects of FUS were more potent than those of AFU, with FUS up-regulating p21 expression in a p53-dependent manner, as detected by Western blot analyses, likely the consequence of decreased ERK phosphorylation and increased p38 expression (both of which increase p21 stability). FUS also decreased Akt phosphorylation and resulted in increased Fas ligand production and caspase-8/3-dependent apoptosis. These results suggest that FUS and AFU inhibit proliferation and increase apoptosis in cell lines derived from hematological cancers.

scholarly journals The Role of NKG2D Signaling in Inhibition of Cytotoxic T-Lymphocyte Lysis by the Murine Cytomegalovirus Immunoevasin m152/gp40

2007 ◽  
Vol 81 (22) ◽  
pp. 12564-12571 ◽  
Author(s):  
Amelia K. Pinto ◽  
Amanda M. Jamieson ◽  
David H. Raulet ◽  
Ann B. Hill
Keyword(s):  
Mhc Class I ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Murine Cytomegalovirus ◽  
Small Subset ◽  
Small Contribution ◽  
Nkg2d Ligands ◽  
Infected Cells ◽  
The Impact

ABSTRACT Three proteins encoded by murine cytomegalovirus (MCMV)— gp34, encoded by m04 (m04/gp34), gp48, encoded by m06 (m06/gp48), and gp40, encoded by m152 (m152/gp40)—act together to powerfully impact the ability of primed cytotoxic CD8 T lymphocytes (CTL) to kill virus-infected cells. Of these three, the impact of m152/gp40 on CTL lysis appears greater than would be expected based on its impact on cell surface major histocompatibility complex (MHC) class I. In addition to MHC class I, m152/gp40 also downregulates the RAE-1 family of NKG2D ligands, which can provide costimulation for CD8 T cells. We hypothesized that m152/gp40 may impact CTL lysis so profoundly because it inhibits both antigen presentation and NKG2D-mediated costimulation. We therefore tested the extent to which m152/gp40's ability to inhibit CTL lysis of MCMV-infected cells could be accounted for by its inhibition of NKG2D signaling. As was predictable from the results reported in the literature, NKG2D ligands were not detected by NKG2D tetramer staining of cells infected with wild-type MCMV, whereas those infected with MCMV lacking m152/gp40 displayed measurable levels of the NKG2D ligand. To determine whether NKG2D signaling contributed to the ability of CTL to lyse these cells, we used a blocking anti-NKG2D antibody. Blocking NKG2D signaling did affect the killing of MCMV-infected cells for some epitopes. However, for all epitopes, the impact of m152/gp40 on CTL lysis was much greater than the impact of inhibition of NKG2D signaling. We conclude that the downregulation of NKG2D ligands by MCMV makes only a small contribution to the impact of m152/gp40 on CTL lysis and only for a small subset of CTL.

scholarly journals Evaluation of CD8 T cell killing models with computer simulations of 2-photon imaging experiments

2020 ◽  
Vol 16 (12) ◽  
pp. e1008428
Author(s):  
Ananya Rastogi ◽  
Philippe A. Robert ◽  
Stephan Halle ◽  
Michael Meyer-Hermann
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Three Dimensional ◽  
Critical Factor ◽  
Target Cells ◽  
Agent Based ◽  
Multiple Contacts ◽  
Infected Cells ◽  
New Interactions ◽  
Increased Susceptibility

In vivo imaging of cytotoxic T lymphocyte (CTL) killing activity revealed that infected cells have a higher observed probability of dying after multiple contacts with CTLs. We developed a three-dimensional agent-based model to discriminate different hypotheses about how infected cells get killed based on quantitative 2-photon in vivo observations. We compared a constant CTL killing probability with mechanisms of signal integration in CTL or infected cells. The most likely scenario implied increased susceptibility of infected cells with increasing number of CTL contacts where the total number of contacts was a critical factor. However, when allowing in silico T cells to initiate new interactions with apoptotic target cells (zombie contacts), a contact history independent killing mechanism was also in agreement with experimental datasets. The comparison of observed datasets to simulation results, revealed limitations in interpreting 2-photon data, and provided readouts to distinguish CTL killing models.

scholarly journals Epstein–Barr virus-infected cells release Fas ligand in exosomal fractions and induce apoptosis in recipient cells via the extrinsic pathway

2015 ◽  
Vol 96 (12) ◽  
pp. 3646-3659 ◽  
Author(s):  
Waqar Ahmed ◽  
Pretty S. Philip ◽  
Samir Attoub ◽  
Gulfaraz Khan
Keyword(s):  
Epstein Barr Virus ◽  
Fas Ligand ◽  
Type I ◽  
Dependent Manner ◽  
Extrinsic Pathway ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr ◽  
Induced Apoptosis ◽  
Cellular Components

Epstein–Barr virus (EBV; human herpesvirus 4) is an oncogenic herpesvirus implicated in the pathogenesis of several human malignancies. A number of recent studies indicate that EBV can manipulate the local microenvironment by excreting viral and cellular components in nanovesicles called exosomes. In this study, we investigated the impact of EBV-derived exosomes on apoptosis of recipient cells and the molecular pathway involved in this process. Exosomes from EBV-infected but not from non-infected cells induced apoptosis in a number of different cell types, including B-cells, T-cells and epithelial cells. However, this phenomenon was not universal and the Burkitt's lymphoma-derived B-cell line BJAB was found to be resistant to apoptosis. Exosomes from both type I and type III EBV latently infected cells induced apoptosis in a dose- and time-dependent manner. Moreover, cells exposed to EBV exosomes did not form colonies in soft agar assays. We further show that fluorescently labelled exosomes derived from EBV-infected cells are taken up by non-infected cells and induce apoptosis via the extrinsic pathway. Inhibition of caspase-3/7/8 blocks EBV exosome-mediated apoptosis. Furthermore, our data indicate that EBV exosomes trigger apoptosis through the Fas ligand (FasL)-mediated extrinsic pathway, as FasL was present in EBV exosomal fractions and anti-FasL antibodies could block EBV exosome-mediated apoptosis. Together, these data support the notion that EBV hijacks the exosome pathway to excrete viral and cellular components that can modulate its microenvironment.

scholarly journals Cross-Reactions between the Cytotoxic T-Lymphocyte Responses of Human Immunodeficiency Virus-Infected African and European Patients

1998 ◽  
Vol 72 (5) ◽  
pp. 3547-3553 ◽  
Author(s):  
Deniz Durali ◽  
Jacques Morvan ◽  
Franck Letourneur ◽  
Doris Schmitt ◽  
Nelly Guegan ◽  
...  
Keyword(s):  
Immune Response ◽  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Recombinant Virus ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Cross Reactions ◽  
Immunodeficiency Virus ◽  
The Impact ◽  
Hiv 1

ABSTRACT The great variability of protein sequences from human immunodeficiency virus (HIV) type 1 (HIV-1) isolates represents a major obstacle to the development of an effective vaccine against this virus. The surface protein (Env), which is the predominant target of neutralizing antibodies, is particularly variable. Here we examine the impact of variability among different HIV-1 subtypes (clades) on cytotoxic T-lymphocyte (CTL) activities, the other major component of the antiviral immune response. CTLs are produced not only against Env but also against other structural proteins, as well as some regulatory proteins. The genetic subtypes of HIV-1 were determined for Env and Gag from several patients infected either in France or in Africa. The cross-reactivities of the CTLs were tested with target cells expressing selected proteins from HIV-1 isolates of clade A or B or from HIV type 2 isolates. All African patients were infected with viruses belonging to clade A for Env and for Gag, except for one patient who was infected with a clade A Env-clade G Gag recombinant virus. All patients infected in France were infected with clade B viruses. The CTL responses obtained from all the African and all the French individuals tested showed frequent cross-reactions with proteins of the heterologous clade. Epitopes conserved between the viruses of clades A and B appeared especially frequent in Gag p24, Gag p18, integrase, and the central region of Nef. Cross-reactivity also existed among Gag epitopes of clades A, B, and G, as shown by the results for the patient infected with the clade A Env-clade G Gag recombinant virus. These results show that CTLs raised against viral antigens from different clades are able to cross-react, emphasizing the possibility of obtaining cross-immunizations for this part of the immune response in vaccinated individuals.

Accumulation of HIF-1α under the influence of nitric oxide

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 1009-1015 ◽  
Author(s):  
Katrin Britta Sandau ◽  
Joachim Fandrey ◽  
Bernhard Brüne
Keyword(s):  
Nitric Oxide ◽  
Close Correlation ◽  
No Synthase ◽  
Protein Stabilization ◽  
Time Dependent ◽  
Target Cells ◽  
Dependent Manner ◽  
No Donor ◽  
No Donors ◽  
The Impact

Abstract The key player for adaptation to reduced oxygen availability is the transcription factor hypoxia-inducible factor 1 (HIF-1), composed of the redox-sensitive HIF-1α and the constitutively expressed HIF-1β subunits. Under normoxic conditions, HIF-1α is rapidly degraded, whereas hypoxia, CoCl2, or desferroxamine promote protein stabilization, thus evoking its transcriptional activity. Because HIF-1 is regulated by reactive oxygen species, investigation of the impact of reactive nitrogen species was intended. By using different nitric oxide (NO) donors, dose- and time-dependent HIF-1α accumulation in close correlation with the release of NO from chemically distinct NO donors was established. Intriguingly, small NO concentrations induced a faster but transient HIF-1α accumulation than higher doses of the same NO donor. In contrast, NO attenuated up-regulation of HIF-1α evoked by CoCl2 in a concentration- and time-dependent manner, whereas the desferroxamine-elicited HIF-1α signal remained unaltered. To demonstrate an autocrine or paracrine signaling function of NO, we overexpressed the inducible NO synthase and used a coculture system of activated macrophages and tubular cells. Expression of the NO synthase induced HIF-1α accumulation, which underscored the role of NO as an intracellular activator for HIF-1. In addition, macrophage-derived NO triggered HIF-1α up-regulation in LLC-PK1 target cells, which points to intercellular signaling properties of NO in achieving HIF-1 accumulation. Our results show that NO does not only modulate the HIF-1 response under hypoxic conditions, but it also functions as a HIF-1 inducer. We conclude that accumulation of HIF-1 occurs during hypoxia but also under inflammatory conditions that are characterized by sustained NO formation.

scholarly journals Epitope-Dependent Avidity Thresholds for Cytotoxic T-Lymphocyte Clearance of Virus-Infected Cells

2007 ◽  
Vol 81 (10) ◽  
pp. 4973-4980 ◽  
Author(s):  
Michael S. Bennett ◽  
Hwee L. Ng ◽  
Mirabelle Dagarag ◽  
Ayub Ali ◽  
Otto O. Yang
Keyword(s):  
Infected Cell ◽  
Viral Infections ◽  
Cytotoxic T Lymphocyte ◽  
Cell Killing ◽  
Target Cells ◽  
Functional Avidity ◽  
Viral Epitope ◽  
Infected Cells ◽  
Relationship Of ◽  
The Relationship

ABSTRACT Cytotoxic T lymphocytes (CTLs) are crucial for immune control of viral infections. “Functional avidity,” defined by the sensitizing dose of exogenously added epitope yielding half-maximal CTL triggering against uninfected target cells (SD50), has been utilized extensively as a measure of antiviral efficiency. However, CTLs recognize infected cells via endogenously produced epitopes, and the relationship of SD50 to antiviral activity has never been directly revealed. We elucidate this relationship by comparing CTL killing of cells infected with panels of epitope-variant viruses to the corresponding SD50 for the variant epitopes. This reveals a steeply sigmoid relationship between avidity and infected cell killing, with avidity thresholds (defined as the SD50 required for CTL to achieve 50% efficiency of infected cell killing [KE50]), below which infected cell killing rapidly drops to none and above which killing efficiency rapidly plateaus. Three CTL clones recognizing the same viral epitope show the same KE50 despite differential recognition of individual epitope variants, while CTLs recognizing another epitope show a 10-fold-higher KE50, demonstrating epitope dependence of KE50. Finally, the ability of CTLs to suppress viral replication depends on the same threshold KE50. Thus, defining KE50 values is required to interpret the significance of functional avidity measurements and predict CTL efficacy against virus-infected cells in pathogenesis and vaccine studies.

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