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 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

scholarly journals Formaldehyde exposure induces regulatory T cell-mediated immunosuppression via calcineurin-NFAT signalling pathway

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jeongsik Park ◽  
Hyo-Seon Yang ◽  
Mi-Kyung Song ◽  
Dong Im Kim ◽  
Kyuhong Lee
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Mrna Expression ◽  
Regulatory T Cell ◽  
Cell Activity ◽  
Helper T Cells ◽  
Dependent Manner ◽  
Dose Dependent

Abstract In this study, we investigated the effects of Formaldehyde (FA) exposure on splenic immune responses wherein helper T cells become activated and differentiate into effector T and regulatory T cells. BALB/c mice were exposed to two FA concentrations (1.38 mg/m3 and 5.36 mg/m3) for 4 h/day and 5 days/week for 2 weeks. FA-induced immune responses were examined by the production of cytokines, expression of mRNAs, and distributions of helper T cells and regulatory T cells. Moreover, expression of calcineurin and NFATs, regulatory T cell-related signalling proteins, were evaluated. FA exposure suppressed Th2-, Th1-, and Th17-related splenic cytokines in a dose-dependent manner. mRNA expression of splenic cytokines was also decreased by FA exposure, which correlated with decreased cytokine expression. In parallel, FA exposure promoted T cell differentiation into regulatory T cells in a dose-dependent manner supported by the expression of calcineurin and NFAT1. Taken together, our results indicated that FA exposure increases the number of regulatory T cells via calcineurin-NFAT signalling, thereby leading to effector T cell activity suppression with decreased T cell-related cytokine secretion and mRNA expression. These findings provide insight into the mechanisms underlying the adverse effects of FA and accordingly have general implications for human health, particularly in occupational settings.

Effects of CD4+CD25+Foxp3+regulatory T cells on earlyPlasmodium yoelii17XL infection in BALB/c mice

Parasitology ◽  
2009 ◽  
Vol 136 (10) ◽  
pp. 1107-1120 ◽  
Author(s):  
GUANG CHEN ◽  
JUN LIU ◽  
QING-HUI WANG ◽  
YI WU ◽  
HUI FENG ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Early Stage ◽  
Plasmodium Yoelii ◽  
Dependent Manner ◽  
T Cell Apoptosis

SUMMARYThe outcome ofPlasmodium yoelii17XL-infected BALB/c and DBA/2 mice, ranging from death to spontaneous cure, respectively, depends largely on the establishment of effective pro-inflammatory type 1 responses during the early stages of infection and associates with CD4+CD25+Foxp3+regulatory T cells (Tregs). Here, effects of Tregs were analysed on earlyP. yoelii17XL infection in BALB/c and DBA/2 mice.In vivodepletion of Tregs significantly reversed the inhibited establishment of effective pro-inflammatory type 1 responses in BALB/c mice, indicating that this cell population contributed to the suppression of T-cell function in malaria. Moreover, the proportion and absolute numbers of IL-10-secreting Tregs in BALB/c mice were significantly higher than that found in DBA/2 mice by intracytoplasmic staining, and IL-10 production was correlated with the Tregs population. In addition,in vivoTregs depletion decreased the production of IL-10 and the apoptosis of CD4+T cells. Consistently, IL-10R blockade also had the same effect as that of Tregs depletion inP. yoelii17XL-infected BALB/c mice. Our data demonstrate that Tregs perhaps have an important role in regulating pro-inflammatory type 1 responses in an IL-10-dependent manner and induce CD4+T cell apoptosis during the early stage ofP. yoelii17XL infection.

scholarly journals Lipopolysaccharide Stimulates Butyric Acid-Induced Apoptosis in Human Peripheral Blood Mononuclear Cells

1999 ◽  
Vol 67 (1) ◽  
pp. 22-29 ◽  
Author(s):  
Tomoko Kurita-Ochiai ◽  
Kazuo Fukushima ◽  
Kuniyasu Ochiai
Keyword(s):  
T Cells ◽  
T Cell ◽  
Butyric Acid ◽  
Cell Apoptosis ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
T Cell Apoptosis ◽  
Blood Mononuclear Cells ◽  
Induced Apoptosis ◽  
Dose Dependent

ABSTRACT We previously reported that butyric acid, an extracellular metabolite from periodontopathic bacteria, induced apoptosis in murine thymocytes, splenic T cells, and human Jurkat T cells. In this study, we examined the ability of butyric acid to induce apoptosis in peripheral blood mononuclear cells (PBMC) and the effect of bacterial lipopolysaccharide (LPS) on this apoptosis. Butyric acid significantly inhibited the anti-CD3 monoclonal antibody- and concanavalin A-induced proliferative responses in a dose-dependent fashion. This inhibition of PBMC growth by butyric acid depended on apoptosis in vitro. It was characterized by internucleosomal DNA digestion and revealed by gel electrophoresis followed by a colorimetric DNA fragmentation assay to occur in a concentration-dependent fashion. Butyric acid-induced PBMC apoptosis was accompanied by caspase-3 protease activity but not by caspase-1 protease activity. LPS potentiated butyric acid-induced PBMC apoptosis in a dose-dependent manner. Flow-cytometric analysis revealed that LPS increased the proportion of sub-G1 cells and the number of late-stage apoptotic cells induced by butyric acid. Annexin V binding experiments with fractionated subpopulations of PBMC in flow cytometory revealed that LPS accelerated the butyric acid-induced CD3+-T-cell apoptosis followed by similar levels of both CD4+- and CD8+-T-cell apoptosis. The addition of LPS to PBMC cultures did not cause DNA fragmentation, suggesting that LPS was unable to induce PBMC apoptosis directly. These data suggest that LPS, in combination with butyric acid, potentiates CD3+ PBMC T-cell apoptosis and plays a role in the apoptotic depletion of CD4+ and CD8+ cells.

scholarly journals Human Gingival Fibroblasts Rescue Butyric Acid-Induced T-Cell Apoptosis

2002 ◽  
Vol 70 (5) ◽  
pp. 2361-2367 ◽  
Author(s):  
Tomoko Kurita-Ochiai ◽  
Kuniyasu Ochiai ◽  
Naoto Suzuki ◽  
Kichibee Otsuka ◽  
Kazuo Fukushima
Keyword(s):  
T Cells ◽  
T Cell ◽  
Butyric Acid ◽  
Cell Apoptosis ◽  
Jurkat Cell ◽  
Jurkat Cells ◽  
Human Gingival Fibroblasts ◽  
Gingival Fibroblasts ◽  
T Cell Apoptosis ◽  
Dose Dependent

ABSTRACT We previously demonstrated that butyric acid, an extracellular metabolite from periodontopathic bacteria, induces cytotoxicity and apoptosis in murine thymocytes, splenic T cells, and human Jurkat T cells. In this study, we used a cell-to-cell interaction system to examine the contribution of gingival fibroblasts to the regulation of T-cell death induced by butyric acid. Butyric acid slightly suppressed fibroblast viability in a concentration-dependent fashion. However, DNA fragmentation assays indicated that butyric acid did not induce apoptosis for up to 21 h in human gingival fibroblasts (Gin 1, F41-G, and H. pulp cells). The culture supernatants were assayed for interleukin 1α (IL-1α), IL-1β, IL-6, IL-8, IL-11, tumor necrosis factor alpha, and transforming growth factor β, but only the IL-6, IL-8, and IL-11 levels were significantly increased by addition of butyric acid. Butyric acid- or Fas-induced Jurkat-cell apoptosis was attenuated when Jurkat cells were cocultured with either F41-G or Gin 1 cells that had been preincubated for 6 h with butyric acid. IL-8 slightly stimulated butyric acid- or Fas-induced Jurkat-cell apoptosis in a dose-dependent manner, although a low dose of IL-8 had a mildly inhibitory effect on apoptosis. In contrast, IL-6 and IL-11 significantly suppressed butyric acid- or Fas-induced apoptosis in a dose-dependent fashion. Furthermore, the addition of monoclonal antibodies against human IL-6 and IL-11 to cocultures of gingival fibroblasts and Jurkat cells partially eliminated T-cell recovery. These results suggest that the proinflammatory cytokines such as IL-6 and IL-11, produced in fibroblasts stimulated with butyric acid, are involved in the attenuation of T-cell apoptosis by gingival fibroblasts.

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.

Regulatory T Cells Expanded by Autologous Mature Human Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase Are Potent Suppressors of T Cell Proliferation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1553-1553
Author(s):  
Davi d J. Chung ◽  
Marco Rossi ◽  
Emanuela Romano ◽  
Jennifer Pressley ◽  
Christophe Antczak ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
De Novo ◽  
T Cell Proliferation ◽  
Indoleamine 2,3 Dioxygenase ◽  
Naturally Occurring ◽  
Dose Dependent

Abstract Best characterized as initiators of immunity, dendritic cells (DCs) also play an integral role in immune modulation. Immature DCs, for example, process self-antigens to induce and maintain tolerance. The immunoregulatory effects of DCs, however, are not limited to immature subtypes. Immunogenic mature DCs can also induce T regs to curb immune responses. We have found that human monocyte-derived DCs (moDCs) upregulate the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) with maturation and expand functionally active, naturally occurring as well as inducible regulatory T cells (T regs) in an IDO-dependent manner. Priming of resting bulk T cells with autologous, IDO-expressing, mature moDCs in the absence of exogenous cytokines results in up to 10-fold expansion of CD4+CD25hiFoxp3+CD127neg T cells that mediate significant dose-dependent suppression of both allogeneic and autologous T cells stimulated de novo by DCs. The expansion of T regs by IDO-expressing moDCs involves cell-to-cell contact, CD80/CD86 ligation, and IL-2. Autologous priming in the presence of a competitive inhibitor of IDO, 1-methyl-tryptophan, diminishes T reg expansion. Candidate T regs were further characterized after cytofluorographic sorting primed bulk T cells into CD4+CD25hi, CD4+CD25int, and CD4+CD25neg subpopulations. Post-sort analysis showed that >60% of the CD4+CD25hi cells coexpressed Foxp3, which was not present in the CD4+CD25neg cells. CD4+CD25hi T regs exerted dose-dependent inhibition of DC-stimulated allogeneic T cell proliferation, with >90% inhibition at a suppressor to responder T cell ratio of 1:1 and ~50% inhibition at a ratio of 1:25. CD4+CD25int cells produced intermediate suppression depending on dose, and CD4+CD25neg cells were not inhibitory. CD4+CD25hi T regs mediated similar suppression of autologous T cell responses to stimulation de novo by DCs. CD4+CD25hi T regs also inhibited the generation of cytotoxic T lymphocytes (CTLs) specific for the Wilms’ tumor gene product (WT-1). The addition of CD4+CD25hi T regs to CTL-priming cultures resulted in a >80% decrease in specific target cell lysis of a WT-1-expressing cell line. Separate studies showed that T reg-mediated suppression is contact dependent and also requires TGF-beta, suggesting inhibition by naturally occurring and inducible T regs, respectively. Depletion of CD4+CD25hi T cells from bulk T cells by negative immunoselection with anti-CD25 magnetic beads at the outset of autologous priming significantly blunts T reg expansion, indicating a requirement for pre-existing T regs in the bulk T cell population. T reg expansion also occurs in priming cultures using cytofluorographically-sorted CD4+CD25neg T cells, indicating de novo generation of T regs from CD4+CD25neg precursors. In summary, our results demonstrate a mechanism by which mature, IDO-expressing, human moDCs expand autologous, naturally occurring as well as inducible T regs that functionally suppress the proliferation of both autologous and allogeneic T cells. Inhibition of this counter-regulatory pathway should result in more sustained benefit from active DC-based immunotherapy.

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