scholarly journals Infection of Human Monocyte-Derived Macrophages with Chlamydia trachomatis Induces Apoptosis of T Cells: a Potential Mechanism for Persistent Infection

2000 ◽  
Vol 68 (12) ◽  
pp. 6704-6711 ◽  
Author(s):  
Michael C. Jendro ◽  
Tobias Deutsch ◽  
Britta Körber ◽  
Lars Köhler ◽  
Jens G. Kuipers ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Cell Apoptosis ◽  
Chlamydial Infection ◽  
Human Monocyte ◽  
T Cell Response ◽  
T Cell Apoptosis ◽  
Frequent Event

ABSTRACT Viruses can escape T-cell surveillance by infecting macrophages and thereby induce apoptosis of noninfected T cells. This ability had not been demonstrated for bacteria. We investigated whether infection of macrophages with the important human pathogen Chlamydia trachomatis can induce T-cell apoptosis. BecauseChlamydia-Mycoplasma coinfection is a frequent event, the ability of Mycoplasma fermentans-infected macrophages to induce T-cell apoptosis was also studied. Infected macrophages were cocultivated with autologous T cells in different activation states. Propidium iodide-based fluorescence-activated cell sorter analysis demonstrated that macrophages infected with viable chlamydiae induced T-cell death. Apoptosis was identified as the mode of death induction by using a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay. Induction of T-cell death was macrophage dependent. Incubation of T cells with infectious chlamydiae in the absence of macrophages did not lead to T-cell apoptosis. UV irradiation of chlamydiae diminished the ability to induce death. T-cell death was induced by a cell-free supernatant of infected macrophages. Not only phytohemagglutinin-preactivated T cells but also non-mitogen-preactivated T cells were susceptible to C. trachomatis-induced apoptosis. In contrast, M. fermentans infection of macrophages did not induce T-cell death. Coinfection had no additional effect. In summary, intracellular chlamydial infection of macrophages can induce T-cell apoptosis. Apoptosis induction by chlamydiae possibly explains how persistently infected macrophages escape T-cell surveillance and why theChlamydia-specific T-cell response is diminished during persistent chlamydial infection.

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 Soluble Egg Antigen-Stimulated T Helper Lymphocyte Apoptosis and Evidence for Cell Death Mediated by FasL+ T and B Cells during Murine Schistosoma mansoni Infection

2001 ◽  
Vol 69 (1) ◽  
pp. 271-280 ◽  
Author(s):  
Steven K. Lundy ◽  
Stephen P. Lerman ◽  
Dov L. Boros
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
B Cells ◽  
Cell Apoptosis ◽  
Granuloma Formation ◽  
Fasl Expression ◽  
T Cell Apoptosis ◽  
Th Cell ◽  
Th Lymphocytes

ABSTRACT Granuloma formation around schistosomal eggs is induced by soluble egg antigens (SEA) and mediated by the activity of CD4+ Th lymphocytes and their cytokines. Regulation of the inflammatory Th cell response during infection is still insufficiently understood. The hypothesis of this study was that activation-induced cell death (AICD) of CD4+ T cells is involved in the immune inflammatory response. This study investigated the dynamics of splenic and granuloma CD4+ Th cell apoptosis and Fas ligand (FasL) expression during the acute and chronic stages of murine schistosomal infection. Enhanced apoptosis of freshly isolated CD4+ Th lymphocytes commenced after egg deposition and persisted during the peak and modulated phases of granuloma formation. After oviposition, CD4+, CD8+, and CD19+ splenocytes and granuloma cells expressed elevated levels of FasL but FasL expression declined during the downmodulated stage of infection. In culture, SEA induced splenic and granuloma CD4+ T-cell apoptosis and stimulated expression of FasL on splenic but not granuloma CD4+ T cells, CD8+ T cells, and CD19+ B cells. SEA-stimulated splenocytes and granuloma cells preferentially lysed a Fas-transfected target cell line. Depletion of B cells from SEA-stimulated splenic cultures decreased CD4+ T cell apoptosis. Coculture of purified splenic B cells with CD4+ T cells and adoptive transfer of purified B cells indicated that antigen-stimulated B cells can kill CD4+ Th cells. However, CD4+ T cells were the dominant mediators of apoptosis in the granuloma. This study indicates that AICD is involved in the apoptosis of CD4+ T cells during schistosomal infection.

scholarly journals Effect of Clostridium difficile Toxin A on Human Colonic Lamina Propria Cells: Early Loss of Macrophages Followed by T-Cell Apoptosis

1998 ◽  
Vol 66 (11) ◽  
pp. 5462-5469 ◽  
Author(s):  
Y. R. Mahida ◽  
A. Galvin ◽  
S. Makh ◽  
S. Hyde ◽  
L. Sanfilippo ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Clostridium Difficile ◽  
Basement Membrane ◽  
Lamina Propria ◽  
Cell Apoptosis ◽  
Toxin A ◽  
T Cell Apoptosis

ABSTRACT We have previously shown that Clostridium difficiletoxin A induces detachment of human colonic epithelial cells from the basement membrane and subsequent cell death by apoptosis. Because these cells require adhesion-dependent signalling from the extracellular matrix for survival, their detachment from the basement membrane by other means also induces apoptosis. The role of toxin A in the induction of apoptosis therefore remains to be determined. In addition, sensitivities to C. difficiletoxin A of lamina propria lymphocytes, macrophages, and eosinophils, which lie below the surface epithelium, are not known. In contrast to epithelial cells, these lamina propria cells do not require adhesion-dependent signalling from the extracellular matrix for survival, and this may allow the mechanisms of toxin A-induced cell death to be further investigated. The aim of this study was to investigate the effect of purified C. difficile toxin A on human colonic lamina propria T cells, macrophages, and eosinophils. We show that C. difficile toxin A induces loss of viability in isolated colonic lamina propria cell preparations containing the three different cell types in a dose- and time-dependent fashion. Exposure to high concentrations of the toxin led to loss of macrophages within 72 h. T-lymphocyte and eosinophil cell death was prominent at later time points and occurred by apoptosis. Exposure to toxin A also induced the production of tumor necrosis factor alpha by the isolated colonic lamina propria cells. However, the presence of neutralizing antibodies to this cytokine did not influenceC. difficile toxin A-induced T-cell apoptosis. Moreover, purified T cells also underwent apoptosis following exposure to toxin A, implying that apoptosis occurred as a consequence of a direct interaction between T cells and the toxin. Our studies suggest that C. difficile toxin A is capable of suppressing human colonic mucosal immune responses by inducing early loss of macrophages followed by T-cell apoptosis.

scholarly journals 596 Combining Bempegaldesleukin (CD122-preferential IL-2 pathway agonist) and NKTR-262 (TLR7/8 agonist) pairs local innate activation with systemic CD8+ T cell expansion to enhance anti-tumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A626-A626
Author(s):  
Annah Rolig ◽  
Daniel Rose ◽  
Grace Helen McGee ◽  
Saul Kivimae ◽  
Werner Rubas ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cycle Phase ◽  
Tumor Cell Death ◽  
Specific Immunity

BackgroundTumor cell death caused by radiation therapy (RT) can trigger anti-tumor immune responses in part because dying cells release adjuvant factors that amplify and sustain DC and T cell responses. We previously demonstrated that bempegaldesleukin (BEMPEG:NKTR-214, a first-in-class CD122-preferential IL-2 pathway agonist), significantly enhanced the anti-tumor efficacy of RT through a T cell-dependent mechanism. Because RT can induce either immunogenic or tolerogenic cell death, depending on a multitude of factors (radiation dose, cell cycle phase, and tumor microenvironment), we hypothesized that providing a specific immunogenic adjuvant, like intratumoral NKTR-262, a novel toll-like receptor (TLR) 7/8 agonist, to the tumor site would further improve systemic tumor-specific immunity by promoting synergistic activation of local immunostimulatory innate immune responses. Therefore, we evaluated whether intratumoral NKTR-262, combined with systemic BEMPEG treatment would result in improved tumor-specific immunity and survival compared to BEMPEG combined with RT.MethodsTumor-bearing mice (CT26; EMT6) received BEMPEG (0.8 mg/kg; iv), RT (16 Gy x 1), and/or intratumoral NKTR-262 (0.5 mg/kg). Flow cytometry was used to evaluate CD4+ and CD8+ T cell activation status in the blood and tumor (7 days post-treatment). The contribution of specific immune subsets was determined by depletion of CD4+, CD8+, or NK cells. CD8+ T cell cytolytic activity was determined in vitro with an Incucyte assay. Data are representative of 1–2 independent experiments (n=5–14/group) and statistical significance was determined by 1-way ANOVA (p-value cut-off of 0.05).ResultsBEMPEG/NKTR-262 resulted in significantly improved survival compared to BEMPEG/RT. Both combination therapies were CD8+ T cell dependent. However, response to BEMPEG/NKTR-262 was characterized by a significant expansion of activated CD8+ T cells (GzmA+; Ki-67+; ICOS+; PD-1+) in the blood, which correlated with reduced tumor size (p<0.05). In the tumor, BEMPEG/NKTR-262 induced higher frequencies of GzmA+ CD8+ T cells exhibiting reduced expression of suppressive molecules (PD-1+, TIM-3+), compared to BEMPEG/RT. Additionally, CD8+ T cells isolated from BEMPEG/NKTR-262-treated tumors had greater cytolytic capacity than those from BEMPEG/RT-treated mice.ConclusionsCombining BEMPEG with NKTR-262 lead to a more robust expansion of activated CD8+ T cells compared to the BEMPEG/RT combination. Enhancement of the activated CD8+ T cell response in mice treated with NKTR-262 in combination with BEMPEG suggests that intratumoral TLR stimulation provides superior antigen presentation and costimulatory activity compared to RT. A clinical trial of BEMPEG/NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).

The cell death regulator GRIM-19 is involved in HIV-1 induced T-cell apoptosis

APOPTOSIS ◽  
2010 ◽  
Vol 15 (12) ◽  
pp. 1453-1460 ◽  
Author(s):  
Manoj Kumar Tripathy ◽  
Zulfazal Ahmed ◽  
Jayashree Sashikant Ladha ◽  
Debashis Mitra
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Cell Apoptosis ◽  
T Cell Apoptosis ◽  
Hiv 1

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.

Apoptotic elimination of peripheral T lymphocytes in patients with primary intracranial tumors

1999 ◽  
Vol 91 (6) ◽  
pp. 935-946 ◽  
Author(s):  
Lorri A. Morford ◽  
Amy R. Dix ◽  
William H. Brooks ◽  
Thomas L. Roszman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Apoptosis ◽  
Cell Culture Supernatant ◽  
Cell Mediated Immunity ◽  
U937 Cells ◽  
Activated T Cells ◽  
Content Type ◽  
T Cell Apoptosis ◽  
Fine Print

Object. Patients with gliomas exhibit severe T lymphopenia during the course of the disease. This study was conducted to determine the mechanism(s) responsible for the lymphopenia.Methods. Using two-color fluorescent staining techniques, the authors show that significant numbers of T cells undergo apoptosis in the peripheral blood of patients with gliomas. To determine whether a glioma-derived factor(s) induces this apoptosis, rosette-purified T cells obtained from healthy donors were treated with glioma cell culture supernatant (GCCS) and examined for apoptosis. It is demonstrated that treatment of normal T cells with GCCS induced apoptosis only with concurrent stimulation of the T-cell receptor/CD3 complex. The addition of neutralizing antibodies to interleukin (IL)-10, IL-4, transforming growth factor-α, or tumor necrosis factor-β (lymphotoxin) did not rescue these T cells from apoptosis. Experiments were also conducted in which the degree of monocyte involvement in the induction of T-cell apoptosis was explored. The U937 cells were pretreated for 20 hours with a 1:20 dilution of GCCS. After the removal of GCCS, the U937 cells were cultured in transwell assays with stimulated T cells. Although control U937 cells did not induce apoptosis of the activated T cells, GCCS-pretreated U937 cells induced appreciable apoptosis in normal, stimulated T-cell cultures.Conclusions. These data indicate that one mechanism by which gliomas cause immunosuppressive effects is the induction of monocytes to release soluble factors that promote activated T-cell apoptosis. The loss of activated T cells leads to T lymphopenia and contributes to the deficiencies in cell-mediated immunity that have been observed during testing of glioma patients' immune function.

scholarly journals CD4+CD25+ Regulatory T Cells Resist a Novel Form of CD28- and Fas-Dependent p53-Induced T Cell Apoptosis

2009 ◽  
Vol 184 (1) ◽  
pp. 94-104 ◽  
Author(s):  
Nagendra Singh ◽  
Mutsumi Yamamoto ◽  
Mariko Takami ◽  
Yoichi Seki ◽  
Mayuko Takezaki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Apoptosis ◽  
T Cell Apoptosis

Increased apoptosis of peripheral blood T cells following allogeneic hematopoietic cell transplantation

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3832-3839 ◽  
Author(s):  
Ming-Tseh Lin ◽  
Li-Hui Tseng ◽  
Haydar Frangoul ◽  
Ted Gooley ◽  
Ji Pei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transplantation ◽  
Cell Apoptosis ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Cd4 T Cell ◽  
Spontaneous Apoptosis ◽  
T Cell Apoptosis

Lymphopenia and immune deficiency are significant problems following allogeneic hematopoietic cell transplantation (HCT). It is largely assumed that delayed immune reconstruction is due to a profound decrease in thymus-dependent lymphopoiesis, especially in older patients, but apoptosis is also known to play a significant role in lymphocyte homeostasis. Peripheral T cells from patients who received HCT were studied for evidence of increased cell death. Spontaneous apoptosis was measured in CD3+ T cells following a 24-hour incubation using 7-amino-actinomycin D in conjunction with the dual staining of cell surface antigens. Apoptosis was significantly greater among CD3+ T cells taken from patients 19-23 days after transplantation (30.4% ± 12.5%,P < .05), and 1 year after transplantation (9.7% ± 2.8%, P < .05) compared with healthy controls (4.0% ± 1.5%). Increased apoptosis occurred preferentially in HLA (human leukocyte antigen)-DR positive cells and in both CD3+/CD4+ and CD3+/CD8+ T-cell subsets, while CD56+/CD3− natural killer cells were relatively resistant to apoptosis. The extent of CD4+T-cell apoptosis was greater in patients with grade II-IV acute graft-versus-host disease (GVHD) (33.9% ± 11.3%) compared with grade 0-I GVHD (14.6 ± 6.5%, P < .05). T-cell apoptosis was also greater in patients who received transplantations from HLA-mismatched donors (39.5% ± 10.4%,P < .05) or HLA-matched unrelated donors (32.1% ± 11.4%, P < .05) compared with patients who received transplantations from HLA-identical siblings (19.6% ± 6.7%). The intensity of apoptosis among CD4+ T cells was significantly correlated with a lower CD4+ T-cell count. Together, these observations suggest that activation of T cells in vivo, presumably by alloantigens, predisposes the cells to spontaneous apoptosis, and this phenomenon is associated with lymphopenia. Activation-induced T-cell apoptosis may contribute to delayed immune reconstitution following HCT.

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