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

Galectin-9 Ameriorates Acute GVHD by Inducing T-Cell Apoptosis and Increasing Regulatory T Cell.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1338-1338
Author(s):  
Kazuki Sakai ◽  
Eri Kawata ◽  
Eishi Ashihara ◽  
Akira Yamauchi ◽  
Shinya Kimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Apoptosis ◽  
Flow Cytometric Analysis ◽  
Recipient Mouse ◽  
Dependent Manner ◽  
T Cell Apoptosis ◽  
Splenic Cells ◽  
Dose Dependent

Abstract Abstract 1338 Poster Board I-360 Galectins are a family of soluble animal lectins that differ in their affinity for b-galactosides. Fifteen members of the human galectin family have been described to date. Galectin-9 (Gal-9) is a tandem-repeat-type galectin that was recently found to serve as a ligand for T cell immunoglobulin and mucin domain-3 (Tim-3), which is a Th1-specific type 1 membrane protein. Gal-9 modulates immune reactions, such as induction of apoptosis in Th1 cells. We herein investigated the effects of Gal-9 treatment on acute graft-versus-host disease (aGVHD) in a murine model. First, we assessed whether recombinant human (rh) Gal-9 can inhibit the mixed lymphocyte reaction (MLR) by culturing irradiated (30 Gy) splenic cells from 7- to 8-week-old female BDF1 mice with splenic cells from 7- to 8-week-old female C57BL/6J mice in the presence of various concentrations of Gal-9 for 10 days. rhGal-9 inhibited MLR in a dose-dependent manner. We then studied whether this effect was mediated by rhGal-9-induced apoptosis by culturing splenic cells from BDF1 mice with plate-bound anti-CD3 monoclonal antibody and Gal-9. Flow cytometric analysis revealed that rhGal-9 increased the number of Annexin-V+ cells in a dose-dependent manner (Figure. 1A). Thus, rhGal-9 inhibited MLR by inducing splenic cell apoptosis. This suppressive effect of Gal-9 on MLR was inhibited by lactose but not by sucrose (Figure. 1B). Taken together, Gal-9 induces T cell apoptosis through Ca2+ influx induced by binding to b-galactoside, resulting in the suppression of MLR. We then assessed whether rhGal-9 treatment altered aGVHD. Recipient B6D2F1 mice received a myeloablative dose (9 Gy) of total body irradiation from an X-ray irradiator. Six to eight hours later, each recipient mouse was injected i.v. with 4 × 106 TCD-BM cells and 5 × 106 mononuclear splenocytes. aGVHD clinical scores were evaluated once or twice a week. After aGVHD developed, recipient mice were treated with rhGal-9 (30 mg/mouse) or vehicle by i.p. injection for 14 consecutive days. The administration of rhGal-9 significantly attenuated aGVHD as compared to vehicle-treated mice (Figure. 2). Histological analyses also confirmed that aGVHD was declined by rhGal-9 treatment. Additionally, we investigated the effects of Gal-9 treatment on different T ell subsets. To analyze the effect of Gal-9 on donor lymphocytes, splenic mononuclear cells from GFP Tg mice were used for the induction of aGVHD. The gating parameter was first set to isolate the lymphocyte population of peripheral blood leukocytes, and then set for GFP+ cells. Gal-9 treatment decreased the frequency of CD4+/Tim-3+ cells and CD8+/intracellular IFN-g+ cells, whereas CD4+/CD25+ and CD25+/Foxp3+ Treg cells were increased by rhGal-9 treatment. These results suggest that Gal-9 regulates aGVHD by increasing regulatory T cells. In conclusion, Gal-9 ameliorates aGVHD by inducing T-cell apoptosis and also by increasing regulatory T cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Local blockade of IL-6R signaling induces lung CD4+ T cell apoptosis in a murine model of asthma via regulatory T cells

2007 ◽  
Vol 19 (6) ◽  
pp. 685-693 ◽  
Author(s):  
S. Finotto ◽  
T. Eigenbrod ◽  
R. Karwot ◽  
I. Boross ◽  
A. Doganci ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Murine Model ◽  
Cell Apoptosis ◽  
Cd4 T Cell ◽  
T Cell Apoptosis

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.

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.

scholarly journals Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis

2009 ◽  
Vol 206 (7) ◽  
pp. 1515-1523 ◽  
Author(s):  
Divya Purushothaman ◽  
Apurva Sarin
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nadph Oxidase ◽  
Cell Apoptosis ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Activated T Cells ◽  
T Cell Apoptosis ◽  
Mitochondrial Superoxide ◽  
Activated T Cell

Cellular dependence on growth factors for survival is developmentally programmed and continues in adult metazoans. Antigen-activated T cell apoptosis in the waning phase of the immune response is thought to be triggered by depletion of cytokines from the microenvironment. T cell apoptosis resulting from cytokine deprivation is mediated by reactive oxygen species (ROS), but their source and position in the apoptotic cascade is poorly understood. RNA interference approaches implicated the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neglect-induced apoptosis in T cells. Using mice deficient for the catalytic subunit gp91phox to characterize the molecular link to activated T cell apoptosis, we show that gp91phox-deficient T (T−/−) cells generated mitochondrial superoxide but had diminished hydrogen peroxide production in response to neglect, which, in turn, regulated Jun N-terminal kinase–dependent Bax activation and apoptosis. Activated T−/− cells were distinguished by improved survival after activation by superantigens in vivo, adoptive transfers into congenic hosts, and higher recall responses after immunization. Thus, the NADPH oxidase may regulate adaptive immunity in addition to its previously well-characterized role in the innate response.

scholarly journals Locally produced C5a binds to T cell–expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 1759-1766 ◽  
Author(s):  
Peter N. Lalli ◽  
Michael G. Strainic ◽  
Min Yang ◽  
Feng Lin ◽  
M. Edward Medof ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Apoptosis ◽  
Cell Expansion ◽  
Immune Cell ◽  
Regulatory Protein ◽  
T Cell Apoptosis ◽  
T Cell Expansion

Abstract Our recent studies have shown that immune cell–produced complement provides costimulatory and survival signals to naive CD4+ T cells. Whether these signals are similarly required during effector cell expansion and what molecular pathways link locally produced complement to T-cell survival were not clarified. To address this, we stimulated monoclonal and polyclonal T cells in vitro and in vivo with antigen-presenting cells (APCs) deficient in the complement regulatory protein, decay accelerating factor (DAF), and/or the complement component C3. We found that T-cell expansion induced by DAF-deficient APCs was augmented with diminished T-cell apoptosis, whereas T-cell expansion induced by C3−/− APCs was reduced because of enhanced T-cell apoptosis. These effects were traced to locally produced C5a, which through binding to T cell–expressed C5aR, enhanced expression of Bcl-2 and prevented Fas up-regulation. The results show that C5aR signal transduction in T cells is important to allow optimal T-cell expansion, as well as to maintain naive cell viability, and does so by suppressing programmed cell death.

scholarly journals High-Affinity Anti-VISTA Antibody Protects against Sepsis by Inhibition of T Lymphocyte Apoptosis and Suppression of the Inflammatory Response

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Tianzhu Tao ◽  
Lulong Bo ◽  
Teng Li ◽  
Longbao Shi ◽  
Hui Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Cell Apoptosis ◽  
Expression Profiles ◽  
Cytokine Expression ◽  
Lymphocyte Apoptosis ◽  
T Cell Apoptosis ◽  
High Affinity

Background. B7 family members and ligands have been identified as critical checkpoints in orchestrating the immune response during sepsis. V-domain Ig suppressor of T cell activation (VISTA) is a new inhibitory immune checkpoint involved in restraining T cell response. Previous studies demonstrated that VISTA engagement on T cells and myeloid cells could transmit inhibitory signals, resulting in reduced activation and function. The current study was designed to determine the potential therapeutic effects of a high-affinity anti-VISTA antibody (clone MH5A) in a murine model of sepsis. Methods. Polymicrobial sepsis was induced in male C57BL/6 mice via cecal ligation and puncture. Expression profiles of VISTA on T lymphocytes and macrophage were examined at 24 and 72 h postsurgery. The effects of anti-VISTA mAb on the 7-day survival, lymphocyte apoptosis, cytokine expression, bacterial burden, and vital organ damage were determined. Furthermore, the effects of anti-VISTA mAb on CD3+ T cell apoptosis and macrophage activation were determined in vitro. Results. VISTA was substantially expressed on T cells and macrophages in sham-operated mice; septic peritonitis did not induce significant changes in the expression profiles. Treatment with MH5A improved the survival of septic mice, accompanied by reduced lymphocyte apoptosis, decreased cytokine expression, and enhanced bacterial clearance. Engagement of VISTA receptor with MH5A mitigated CD3+ T cell apoptosis cultured from CLP mice and suppressed LPS-induced cytokine production by macrophage in vitro. Conclusion. The present study identified VISTA as a novel immune checkpoint in the regulation of T cell and macrophage response during sepsis. Modulation of the VISTA pathway might offer a promising opportunity in the immunotherapy for sepsis.

scholarly journals Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals.

1995 ◽  
Vol 181 (6) ◽  
pp. 2029-2036 ◽  
Author(s):  
P D Katsikis ◽  
E S Wunderlich ◽  
C A Smith ◽  
L A Herzenberg ◽  
L A Herzenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Apoptosis ◽  
Cd4 T Cell ◽  
Tnf Receptor ◽  
Hiv Disease ◽  
T Cell Apoptosis ◽  
Immunodeficiency Virus ◽  
Induced Apoptosis

Apoptosis (programmed cell death) of T lymphocytes has been proposed as a mechanism which plays an important role in the pathogenesis of human immunodeficiency virus (HIV) disease. Activation of Fas (CD95) can either result in costimulation of proliferation and cytokine production or in the induction of apoptosis of T lymphocytes. This raises the possibility that Fas is involved in the observed T cell apoptosis during HIV disease. In this report we show that peripheral blood CD4+ and CD8+ T lymphocytes from HIV-infected individuals undergo apoptosis in vitro in response to antibody stimulation (cross-linking) of Fas at a much higher frequency than from uninfected controls. This anti-Fas-induced T cell apoptosis is markedly higher than spontaneous T cell apoptosis in HIV-infected individuals. Antibodies against other members of the tumor necrosis factor (TNF)/nerve growth factor receptor family such as CD27, CD30, CD40, 4-1BB, p55 TNF receptor, p75 TNF receptor, and TNF receptor-related protein did not result in any increase of T cell apoptosis above that spontaneously observed in HIV+ individuals. Anti-Fas-induced apoptosis was much higher in symptomatic HIV-infected individuals; and the magnitude of anti-Fas-induced CD4+ T cell apoptosis correlated inversely with peripheral blood CD4+ T cell absolute counts. Surface expression of Fas on T cells was also found to be higher in HIV-infected individuals. Resting and activated CD4+ and CD8+ T cells both underwent apoptosis in response to anti-Fas antibody. L-Selectin positive memory CD4+ T cells were especially susceptible to anti-Fas-induced apoptosis. These findings show that CD4+ and CD8+ T lymphocytes in HIV-infected individuals are primed in vivo to undergo apoptosis in response to Fas stimulation, suggesting that Fas signaling may be responsible for the T lymphocyte functional defects and depletion observed in HIV disease.

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