Ly-6A-Induced Growth Inhibition and Cell death in a Transformed CD4+ T cell line: Role of Tumor Necrosis Factor-α (TNF-α)

2021 ◽  
Author(s):  
Akshay G Patel ◽  
Sarah Moxham ◽  
Anil K Bamezai
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Growth Inhibition ◽  
Antigen Receptor ◽  
Cd4 T Cell ◽  
Cell Death Pathway ◽  
Growth Inhibitory ◽  
Tnf Α ◽  
Inhibitory Signaling

Engaging the Ly-6A protein, an inhibitory signaling protein, on CD4+ T cell lines triggers apoptosis. Signaling through Ly-6A activates cell-intrinsic apoptotic cell death pathway as indicated by release of cytochrome C, activation of caspase 3 and 9. In addition Ly-6A induces cytokine production and growth inhibition. The mechanism underlying simultaneous distinct cellular responses has remained unknown. To examine the relatedness of distinct responses generated by engaging Ly-6A, we have quantified the secretion of TNFα, TGFβ and a related protein GDF10, the three pro-apoptotic, growth inhibitory and tumor suppressive cytokines. While low levels of TGFβ and GDF10 were detected after engaging Ly-6A, the production of TNF-α was elevated in cell cultures stimulated the Ly-6A protein. Blocking the biological activity of TNFα resulted in reduced apoptosis induced by engaging Ly-6A. In contrast, growth inhibition/apoptosis in response to antigen receptor complex stimulation was not observed. Engaging the antigen receptor through activating the epsilon (ϵ) chain of CD3 generated high levels of TGF-β and GDF10 while decreasing TNFα. These results suggest that the TNF-α cytokine contributes to the Ly-6A-induced growth inhibitory and pro-apoptotic response in CD4+ T cells and provides mechanistic explanation of the observed biologically distinct responses initiated after engaging Ly-6A protein. These findings aid in understanding the inhibitory signaling initiated by Ly-6A protein, especially in the context of its potential immune checkpoint inhibitory role in T cells.

Susceptibility to cell death is a dominant phenotype: triggering of activation-driven T-cell death independent of the T-cell antigen receptor complex

1992 ◽  
Vol 12 (1) ◽  
pp. 379-385
Author(s):  
G Nickas ◽  
J Meyers ◽  
L D Hebshi ◽  
J D Ashwell ◽  
D P Gold ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Interleukin 2 ◽  
Antigen Receptor ◽  
Alternative Activation ◽  
Receptor Complex ◽  
T Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen

The failure of Thy-1 and Ly-6 to trigger interleukin-2 production in the absence of surface T-cell antigen receptor complex (TCR) expression has been interpreted to suggest that functional signalling via these phosphatidylinositol-linked alternative activation molecules is dependent on the TCR. We find, in contrast, that stimulation of T cells via Thy-1 or Ly-6 in the absence of TCR expression does trigger a biological response, the cell suicide process of activation-driven cell death. Activation-driven cell death is a process of physiological cell death that likely represents the mechanism of negative selection of T cells. The absence of the TCR further reveals that signalling leading to activation-driven cell death and to lymphokine production are distinct and dissociable. In turn, the ability of alternative activation molecules to function in the absence of the TCR raises another issue: why immature T cells, thymomas, and hybrids fail to undergo activation-driven cell death in response to stimulation via Thy-1 and Ly-6. One possibility is that these activation molecules on immature T cells are defective. Alternatively, susceptibility to activation-driven cell death may be developmentally regulated by TCR-independent factors. We have explored these possibilities with somatic cell hybrids between mature and immature T cells, in which Thy-1 and Ly-6 are contributed exclusively by the immature partner. The hybrid cells exhibit sensitivity to activation-driven cell death triggered via Thy-1 and Ly-6. Thus, the Thy-1 and Ly-6 molecules of the immature T cells can function in a permissive environment. Moreover, with regard to susceptibility to Thy-1 and Ly-6 molecules of the immature T cells can function in a permissive environment. Moreover, with regard to susceptibility to Thy-1 and Ly-6 triggering, the mature phenotype of sensitivity to cell death is genetically dominant.

scholarly journals Fas-mediated apoptosis of CD4+ and CD8+ T cells from human immunodeficiency virus-infected persons: differential in vitro preventive effect of cytokines and protease antagonists

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 4959-4966 ◽  
Author(s):  
J Estaquier ◽  
M Tanaka ◽  
T Suda ◽  
S Nagata ◽  
P Golstein ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Death Process ◽  
T Cell Apoptosis ◽  
Soluble Fas ◽  
Immunodeficiency Syndrome

Human immunodeficiency syndrome (HIV) infection leads to a progressive loss of T-cell-mediated immunity associated with T-cell apoptosis. We report here that CD4+ and CD8+ T cells from HIV-1-infected persons are sensitive to Fas (CD95/APO-1)-mediated death induced either by an agonistic anti-Fas antibody or by the physiologic soluble Fas ligand, although showing no sensitivity to tumor necrosis factor alpha-induced death. CD4+ and CD8+ T-cell apoptosis induced by Fas ligation was enhanced by inhibitors of protein synthesis and was prevented either by a soluble Fas receptor decoy or an antagonistic anti-Fas antibody. Fas- mediated apoptosis could also be prevented in a CD4+ or CD8+ T-cell- type manner (1) by several protease antagonists, suggesting the involvement of the interleukin-1beta (IL-1beta)-converting enzyme (ICE)- related cysteine protease in CD4+ T-cell death and of both a CPP32- related cysteine protease and a calpain protease in CD8+ T-cell death; and (2) by three cytokines, IL-2, IL-12, and IL-10, that exerted their effects through a mechanism that required de novo protein synthesis. Finally, T-cell receptor (TCR)-induced apoptosis of CD4+ T cells from HIV-infected persons involved a Fas-mediated death process, whereas TCR stimulation of CD8+ T cells led to a different Fas-independent death process. These findings suggest that Fas-mediated T-cell death is involved in acquired immunodeficiency syndrome (AIDS) pathogenesis and that modulation of Fas-mediated signaling may represent a target for new therapeutic strategies aimed at the prevention of CD4+ T-cell death in AIDS.

scholarly journals The Role of β-Catenin in Th1 Immune Response against Tuberculosis and Profiles of Expression in Patients with Pulmonary Tuberculosis

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Kunlong Xiong ◽  
Jinxia Niu ◽  
Ruijuan Zheng ◽  
Zhonghua Liu ◽  
Yanzheng Song ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Mononuclear Cells ◽  
Cd4 T Cell ◽  
Cell Frequency ◽  
Tnf Α ◽  
Ifn Γ

β-Catenin is a key molecule of canonical Wnt/β-catenin pathway. Its roles and expression profiles in T cells of tuberculosis (TB) remain unclear. The aim of this study was to explore the role of β-catenin in CD4+ T cells and its expression characteristics in patients with pulmonary tuberculosis (PTB). In this study, CD4+ T cell-specific β-catenin conditional knockout mice (β-CAT-cKO mice) were aerosol infected with Mycobacteria tuberculosis (Mtb) H37RV with wild-type mice as controls. Four weeks after infection, the mRNA expression of IFN-γ, TNF-α, and TCF-7 in the lungs of mice was measured. CD4, CD8, β-catenin, IFN-γ, and TNF-α in mononuclear cells from the lungs and spleens were measured by flow cytometry, and the pathological changes of lungs were also observed. Patients with PTB were enrolled, with blood samples collected and PBMCs isolated. The expressions of β-catenin, IFN-γ, TNF-α, and PD-1 in CD4+ and CD8+ T cells were measured by flow cytometry. Results showed a decreased frequency of and reduced IFN-γ/TNF-α mRNA expression and secretion by CD4+ T cells in the lungs of infected β-CAT-cKO mice compared with infected wild-type controls, and only slightly more inflammatory changes were observed in the lungs. β-catenin expressions in CD4+ and CD8+ T cells were significantly decreased in blood cells of patients with severe PTB compared with those in mild PTB. The stimulation of peripheral blood mononuclear cells (PBMCs) with lithium chloride (LiCl), a stimulant of β-catenin, resulted in the increase in CD4+ T cell frequency, as well as their secretion of IFN-γ and TNF-α. β-Catenin demonstrated a moderately positive correlation with PD-1 in CD4+ T cells. β-Catenin along with PD-1 and IFN-γ in CD4+ T cells had a high correlation with those in CD8+ T cells. In conclusion, β-catenin may be involved in the regulation of Th1 response and CD4+ T cell frequency in TB.

scholarly journals Streptococcal Pyrogenic Exotoxin A-Stimulated Monocytes Mediate Regulatory T-Cell Accumulation through PD-L1 and Kynurenine

2019 ◽  
Vol 20 (16) ◽  
pp. 3933 ◽  
Author(s):  
Katharina Giesbrecht ◽  
Sandra Förmer ◽  
Aline Sähr ◽  
Klaus Heeg ◽  
Dagmar Hildebrand
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
Mhc Class Ii ◽  
Inflammatory Cytokines ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Exotoxin A ◽  
T Effector Cells

Bacterial superantigens (SAgs) are exotoxins that promote a fulminant activation of the immune system. The subsequent intense release of inflammatory cytokines often results in hypotension, shock, and organ failure with high mortality rates. In the current paradigm, the direct and simultaneous binding of SAgs with T-cell receptor (TCR)-bearing Vβ regions and conserved structures on major histocompatibility complex class II (MHC class II) on antigen-presenting cells (APCs) induces the activation of both cell types. However, by crosslinking MHC class II molecules, APCs can be activated by SAgs independently of T lymphocytes. Recently, we showed that streptococcal pyrogenic exotoxin A (SPEA) of Streptococcus pyogenes stimulates an immunogenic APC phenotype with upregulated costimulatory molecules and inflammatory cytokines. Additionally, we revealed that SPEA triggers immunosuppressive programs in monocytes that facilitate the accumulation of regulatory T cells (Tregs) in in vitro monocyte/CD4+ T-cell cocultures. Immunosuppressive factors include anti-inflammatory interleukin 10 (IL-10), co-inhibitory surface molecule programmed cell death 1 ligand 1 (PD-L1), and the inhibitory indoleamine 2,3-dioxygenase (IDO)/kynurenine effector system. In the present study, we investigated the underlying mechanism of SPEA-stimulated monocyte-mediated accumulation of Tregs. Blood-derived monocytes from healthy donors were stimulated with SPEA for 48 h (SPEA-monocytes). For the evaluation of SPEA-monocyte-mediated modulation of CD4+ T lymphocytes, SPEA was removed from the culture through extensive washing of cells before adding allogeneic CD3/CD28-activated T cells. Results: In coculture with allogeneic CD4+ T cells, SPEA-monocytes mediate apoptosis of CD4+Foxp3− lymphocytes and accumulation of CD4+Foxp3+ Tregs. PD-L1 and kynurenine are critically involved in the mediated cell death because blocking both factors diminished apoptosis and decreased the proportion of the CD25+/Foxp3+ Treg subpopulation significantly. Upregulation of PD-L1 and kynurenine as well as SPEA-monocyte-mediated effects on T cells depend on inflammatory IL-1β. Our study shows that monocytes activated by SPEA mediate apoptosis of CD4+Foxp3− T effector cells through PD-L1 and kynurenine. CD4+Foxp3+ T cells are resistant to apoptosis and accumulate in SPEA-monocyte/CD4+ T-cell coculture.

Intestinal CD14+ Macrophages Protect CD4+ T Cells From Activation-induced Cell Death via Exosomal Membrane TNF in Crohn’s Disease

2020 ◽  
Vol 14 (11) ◽  
pp. 1619-1631 ◽  
Author(s):  
Huashan Liu ◽  
Zhenxing Liang ◽  
Fengwei Wang ◽  
Xiaobin Zheng ◽  
Ziwei Zeng ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Crohn’S Disease ◽  
T Cell ◽  
Crohn's Disease ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Cd4 T Cell ◽  
Activation Induced Cell Death ◽  
Sustained Activation

Abstract Background and aims Sustained activation of CD4+ T cells plays important roles in the pathogenesis of Crohn’s disease [CD]. Under physiologic conditions, activated T cells can be timely eliminated by a process termed activation-induced cell death [AICD], restraining T cell over-activation and preventing immunological destruction. We inquired whether defective AICD might explain CD4+ T cell over-activation in CD and investigated the underlying mechanisms. Methods CD14+ macrophages [Mφ] and CD4+ T cells were isolated from intestinal tissues or peripheral blood of controls and CD patients. An ex vivo evaluation system was employed to simulate AICD and cell apoptosis was measured by flow cytometry. Results CD4+ T cells from CD patients fail to undergo AICD in the ex vivo system. Specifically, proinflammatory type 1 helper T [Th1] and type 17 helper T [Th17] cells, rather than immunosuppressive regulatory T [Treg] cells evade AICD in CD. CD14+ Mφ in the intestinal inflammatory microenvironment of CD promote AICD resistance in CD4+ T cells via a cell-to-cell contact-independent manner. Mechanistically, CD14+ Mφ released exosomes express membrane tumour necrosis factor [TNF] which engages TNFR2 on CD4+ T cells and triggers NF-κB signalling, thereby causing AICD resistance. Importantly, clinically applicable anti-TNF antibodies effectively blocked exosomal membrane TNF-induced CD4+ T cell AICD resistance. Conclusions CD14+ Mφ participate in CD pathogenesis by inducing AICD resistance through release of exosomal membrane TNF to activate the TNFR2/NF-κB pathway in CD4+ T cells. These results present new insights into CD pathogenesis and extend mechanistic understanding of anti-TNF agents. Proposed model CD14+ Mφ in the intestinal microenvironment of CD patients maintain the sustained activation of CD4+ T cells through exosomal membrane TNF to induce apoptosis resistance via TNFR2/NF-κB signalling, which could be effectively blocked by clinically applicable anti-TNF agents.

scholarly journals Ineffective Cellular Immune Response Associated with T-Cell Apoptosis in Susceptible Mycobacterium bovisBCG-Infected Mice

2000 ◽  
Vol 68 (7) ◽  
pp. 4264-4273 ◽  
Author(s):  
Laurent Kremer ◽  
Jérôme Estaquier ◽  
Isabelle Wolowczuk ◽  
Franck Biet ◽  
Jean-Claude Ameisen ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Proliferation ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cell Apoptosis ◽  
T Cell Proliferation ◽  
T Cell Apoptosis ◽  
Tnf Α

ABSTRACT It has previously been reported that inhibition of delayed-type hypersensitivity-mediating functions of T cells during mycobacterial infection in mice is haplotype dependent. In the present study, we show that Mycobacterium bovis BCG infection induced, in susceptible C57BL/6 and BALB/c mice but not in resistant C3H/HeJ and DBA/2 mice, an important splenomegaly. An in vitro defect in T-cell proliferation in response to T-cell receptor (TCR) stimulation with mitogens or anti-CD3 antibodies was associated with enhanced levels of CD4+ and CD8+ T-cell apoptosis in susceptible but not in resistant mice 2 weeks after infection. Further investigations of C57BL/6 and C3H/HeJ mice revealed that in vivo splenomegaly was associated with destruction of the lymphoid tissue architecture, liver cellular infiltrates, and increased numbers of apoptotic cells in both spleen and liver tissue sections. Infection of C57BL/6 mice but not of C3H/HeJ mice induced massive production of tumor necrosis factor alpha (TNF-α) in serum, as well as an increase in Fas and Fas ligand (FasL) expression in T cells. In vitro addition of neutralizing anti-TNF-α antibodies led to a significant reduction in CD3-induced T-cell apoptosis of both CD4+ and CD8+ T cells of C57BL/6 mice, while the blockade of Fas-FasL interactions reduced apoptosis only in CD4+ but not in CD8+ T cells. Together, these results suggest that TNF-α and Fas-FasL interactions play a role in the activation-induced cell death (AICD) process associated with a defect in T-cell proliferation of the susceptible C57BL/6 mice. T-cell death by apoptosis may represent one of the important components of the ineffective immune response against mycobacterium-induced immunopathology in susceptible hosts.

scholarly journals IFN-γ expression in CD8+ T cells regulated by IL-6 signal is involved in superantigen-mediated CD4+ T cell death

2008 ◽  
Vol 21 (1) ◽  
pp. 73-80 ◽  
Author(s):  
Toru Atsumi ◽  
Masae Sato ◽  
Daisuke Kamimura ◽  
Arisa Moroi ◽  
Yoichiro Iwakura ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cell ◽  
Ifn Γ

scholarly journals Association between serum sST2 levels and CD4+T cells in patients with organ failure: a pilot study

2021 ◽  
Author(s):  
qisong Peng ◽  
guoyou Shi ◽  
hongxiang lu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Organ Failure ◽  
Normal Control ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tnf Α ◽  
Normal Controls

Background: The importance of sST2 has been increasingly appreciated because of its associated with the development of heart failure and related diseases. Objective: The aim of this study was to evaluate the association of sST2 with CD4+T cells in patients with organ failure. Methods: 100 (M:F=60:40) organ failure patients aged (mean±SD=69.08±16.68) and 30 (M:F=14:16) normal control aged (mean±SD=60.23±13.99) serum sST2 were detected by chemiluminescence assay (CLIA) and the expression of serum IL-1, IL-6 and TNF-α were analyzed by enzyme-linked immunosorbent assay (ELISA). The proportion of CD4+T cells in peripheral blood was determined by flow cytometry (FCM). Association of sST2 with CD4+T cells in organ failure patents were analyzed by SPASS. Results: The expression of sST2 in organ failure patients (107.4±5.79ng/mL) was significantly higher than normal control (8.57±0.35ng/mL). Inflammatory factors IL-1 and IL-6 in patients were also increased than normal controls (IL-1: 0.33±0.04pg/mL vs 0.14±0.02pg/mL. IL-6: 165.7±10.53pg/mL vs 95.33±7.42pg/mL. TNF-α: 1.57±0.14pg/mL vs 6.11±0.77pg/mL). In patients, the results showed CD4+T cells were reduced compare with normal control (238.3±13.67/μL vs 1081±39.13/μL). Additionally, sST2 was found to be inversely associated with CD4+T cell in patients with organ failure. Conclusion: sST2 level was closely related to the development of organ failure and sST2 was obviously correlated with CD4+T cell in patients with organ failure.

scholarly journals Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals.

1992 ◽  
Vol 175 (2) ◽  
pp. 331-340 ◽  
Author(s):  
H Groux ◽  
G Torpier ◽  
D Monté ◽  
Y Mouton ◽  
A Capron ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cell Population ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Death Process ◽  
Immunodeficiency Virus ◽  
Asymptomatic Individuals

In immature thymocytes, T cell receptor for antigen (TCR) mobilization leads to an active T cell suicide process, apoptosis, which is involved in the selection of the T cell repertoire. We have proposed that inappropriate induction of such a cell death program in the mature CD4+ T cell population could account for both early qualitative and late quantitative CD4+ T lymphocyte defects of human immunodeficiency virus (HIV)-infected individuals (Ameisen, J.C., and A. Capron. 1991. Immunol. Today. 4:102). Here, we report that the selective failure of CD4+ T cells from 59 clinically asymptomatic HIV-infected individuals to proliferate in vitro to TCR mobilization by major histocompatibility complex class II-dependent superantigens and to pokeweed mitogen (PWM) is due to an active CD4+ T cell death process, with the biochemical and ultrastructural features of apoptosis. Activation-induced cell death occurred only in the CD4+ T cell population from HIV-infected asymptomatic individuals and was not observed in T cells from any of 58 HIV-seronegative controls, including nine patients with other acute or chronic infectious diseases. Activation-induced CD4+ T cell death was prevented by cycloheximide, cyclosporin A, and a CD28 monoclonal antibody (mAb). The CD28 mAb not only prevented apoptosis but also restored T cell proliferation to stimuli, including PWM, superantigens, and the tetanus and influenza recall antigens. These findings may have implications for the understanding of the pathogenesis of acquired immune deficiency syndrome and for the design of specific therapeutic strategies.

scholarly journals A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells

2004 ◽  
Vol 11 (9) ◽  
pp. 1017-1027 ◽  
Author(s):  
J D Lelièvre ◽  
F Mammano ◽  
D Arnoult ◽  
F Petit ◽  
A Grodet ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Dying Cells
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