scholarly journals Requirement for Transforming Growth Factor β1 in Controlling T Cell Apoptosis

2001 ◽  
Vol 194 (4) ◽  
pp. 439-454 ◽  
Author(s):  
WanJun Chen ◽  
Wenwen Jin ◽  
Hongsheng Tian ◽  
Paula Sicurello ◽  
Mark Frank ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Cell Apoptosis ◽  
Transforming Growth Factor ◽  
Death Receptor ◽  
Cell Receptor ◽  
Transforming Growth Factor Β1 ◽  
T Cell Apoptosis ◽  
Tgf Β1

Transforming growth factor (TGF)-β1, a potent immunoregulatory molecule, was found to control the life and death decisions of T lymphocytes. Both thymic and peripheral T cell apoptosis was increased in mice lacking TGF-β1 (TGF-β1−/−) compared with wild-type littermates. Engagement of the T cell receptor enhanced this aberrant T cell apoptosis, as did signaling through either the death receptor Fas or the tumor necrosis factor α receptor in peripheral T cells. Strikingly, TGF-β was localized within the mitochondria of normal T cells, and the absence of TGF-β1 resulted in disruption of mitochondrial membrane potential (Δψm), which marks the point of no return in a cell condemned to die. This TGF-β–dependent regulation of viability appears dissociable from the TGF-β1 membrane receptor–Smad3 signaling pathway, but associated with a mitochondrial antiapoptotic protein Bcl–XL. Thus, TGF-β1 may protect T cells at multiple sites in the death pathway, particularly by maintaining the essential integrity of mitochondria. These findings may have broad implications not only for T cell selection and death in immune responses and in the generation of tolerance, but also for defining the mechanisms of programmed cell death in general.

scholarly journals Transforming Growth Factor β1 Inhibits Fas Ligand Expression and Subsequent Activation-induced Cell Death in T Cells via Downregulation of c-Myc

1999 ◽  
Vol 189 (2) ◽  
pp. 231-239 ◽  
Author(s):  
Laurent Genestier ◽  
Shailaja Kasibhatla ◽  
Thomas Brunner ◽  
Douglas R. Green
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Growth Factor ◽  
Fas Ligand ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
T Cell Response ◽  
Activation Induced Cell Death ◽  
Tgf Β1

Activation-induced cell death (AICD) is a process that regulates the size and the duration of the primary immune T cell response. In this report, we investigated the mechanisms involved in the regulation of AICD by transforming growth factor β1 (TGF-β1). We found that TGF-β1 decreased apoptosis of human T cells or T cell hybridomas after activation by anti-CD3. This decrease was associated with inhibition of Fas (Apo-1/CD95) ligand (FasL) expression, whereas Fas signaling was not affected by TGF-β1. In parallel, TGF-β1 inhibited c-Myc expression in T cell hybridomas, and ectopic expression of a chimeric molecule composed of c-Myc and the steroid binding domain of the estrogen receptor (Myc-ER) blocked both the inhibition of FasL and the decrease of AICD induced by TGF-β1, providing that 4-hydroxytamoxifen was present. These results identify one mechanism by which TGF-β1 blocks AICD to allow the clonal expansion of effector T cells and the generation of memory T cells during immune responses.

scholarly journals Interaction of Mycobacterium tuberculosis-Induced Transforming Growth Factor β1 and Interleukin-10

1999 ◽  
Vol 67 (11) ◽  
pp. 5730-5735 ◽  
Author(s):  
Catherine Othieno ◽  
Christina S. Hirsch ◽  
Beverly D. Hamilton ◽  
Katalin Wilkinson ◽  
Jerrold J. Ellner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Growth Factor ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Transforming Growth Factor Β1 ◽  
Ifn Γ ◽  
Tgf Β1

ABSTRACT Mycobacterium tuberculosis is associated with the activation of cytokine circuits both at sites of active tuberculosis in vivo and in cultures of mononuclear cells stimulated by M. tuberculosis or its components in vitro. Interactive stimulatory and/or inhibitory pathways are established between cytokines, which may result in potentiation or attenuation of the effects of each molecule on T-cell responses. Here we examined the interaction of transforming growth factor β1 (TGF-β1) and interleukin-10 (IL-10) in purified protein derivative (PPD)-stimulated human mononuclear cell cultures in vitro. TGF-β1 induced monocyte IL-10 (but not tumor necrosis factor alpha) production (by 70-fold, P < 0.02) and mRNA expression in the absence but not in the presence of PPD. Both exogenous recombinant (r) IL-10 and rTGF-β1 independently suppressed the production of PPD-induced gamma interferon (IFN-γ) in mononuclear cells from PPD skin test-positive individuals. Synergistic suppression of IFN-γ in cultures containing both rTGF-β1 and rIL-10 was only seen when the responder cell population were peripheral blood mononuclear cells (PBMC) and not monocyte-depleted mononuclear cells and when PBMC were pretreated with rTGF-β1 but not with rIL-10. Suppression of PPD-induced IFN-γ in PBMC containing both rTGF-β1 (1 ng/ml) and rIL-10 (100 pg/ml) was 1.5-fold higher (P< 0.05) than cultures containing TGF-β1 alone and 5.7-fold higher (P < 0.004) than cultures containing IL-10 alone. Also, neutralization of endogenous TGF-β1 and IL-10 together enhanced PPD-induced IFN-γ in PBMC in a synergistic manner. Thus, TGF-β1 and IL-10 together potentiate the downmodulatory effect on M. tuberculosis-induced T-cell production of IFN-γ, and TGF-β1 alone enhances IL-10 production. At sites of active M. tuberculosis infection, these interactions may be conducive to the suppression of mononuclear cell functions.

Nasal administration of transforming growth factor-β1 induces dendritic cells and inhibits protracted-relapsing experimental allergic encephalomyelitis

1999 ◽  
Vol 5 (3) ◽  
pp. 184-191 ◽  
Author(s):  
Mikio Ishikawa ◽  
Yuxuen Jin ◽  
Hong Guo ◽  
Hans Link ◽  
Bao-Guo Xiao
Keyword(s):  
Dendritic Cells ◽  
Growth Factor ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Nasal Administration ◽  
Low Doses ◽  
T Cell Apoptosis ◽  
The Central Nervous System ◽  
Tgf Β1

Cytokines have a crucial role in initiation and perturbation of EAE that represents an animal model of multiple sclerosis (MS). Administration of transforming growth factor-β1 (TGF-β1) to EAE mice improves clinical EAE and prevents relapses by unknown mechanisms. Administering low doses of TGF-β1 nasally, we confirmed that TGF-β1 inhibited development and relapse of protracted-relapsing EAE (PR-EAE) in DA rats. Infiltration of CD4+ T-cells and macrophages within the central nervous system was clearly reduced, while proliferation and IFN-g secretion of mononuclear cells (MNC) was augmented in TGF-β1-treated EAE rats compared to PBS-treated control EAE rats. TGF-β1 administered nasally also increased nitric oxide production and CD4+ T cell apoptosis. TGF-β1 treated rats showed augmented proliferation of dendritic cells (DC) compared to MNC. These data imply that low doses of TGF-β1 given by the nasal route prevent PR-EAE and upregulate DC functions that may be involved for disease prevention.

scholarly journals Structural and Mechanistic Features of Protein O Glycosylation Linked to CD8+ T-Cell Apoptosis

2006 ◽  
Vol 27 (3) ◽  
pp. 1096-1111 ◽  
Author(s):  
Steven J. Van Dyken ◽  
Ryan S. Green ◽  
Jamey D. Marth
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Apoptosis ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Lymphocytic Choriomeningitis ◽  
Apoptotic Pathway ◽  
Contraction Phase ◽  
T Cell Apoptosis

ABSTRACT CD8+ T-cell apoptosis is essential for the contraction phase of the immune response, yet the initiating signals and precise pathways involved are unresolved. The ST3Gal-I sialyltransferase is a candidate mechanistic component and catalyzes sialic acid addition to core 1 O-glycans during protein O glycosylation. ST3Gal-I inactivation or enzymatic removal of its product renders CD8+ T cells, but not CD4+ T cells, susceptible to apoptosis by differential cross-linking of O-glycoproteins in the absence of interleukin-2 and T-cell receptor (TCR) signaling. This results in caspase activation, DNA fragmentation, and phosphatidylserine externalization prior to cell death. We further show that ST3Gal-I function is regulated by a posttranscriptional mechanism operating distal to Golgi core 2 O glycosylation and is invariably linked to CD8+ T-cell contraction following viral (lymphocytic choriomeningitis virus) infection and bacterial (staphylococcal enterotoxin B) antigen immunization. The mechanism does not involve the ST3Gal-I substrate CD43 or core 2 O-glycan induction and overcomes the ability of Bcl-2 to inhibit the contraction phase in vivo. Loss of ST3Gal-I function further reduces Bim-deficient CD8+ T-cell accumulation without diminishing apoptotic sensitivity. We propose that an endogenous lectin activates an apoptotic pathway constructed in CD8+ T cells following TCR stimulation and enables contraction upon attenuation of immune signaling.

scholarly journals Induction of FOXP3 expression in naive human CD4+FOXP3− T cells by T-cell receptor stimulation is transforming growth factor-β–dependent but does not confer a regulatory phenotype

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2983-2990 ◽  
Author(s):  
Dat Q. Tran ◽  
Heather Ramsey ◽  
Ethan M. Shevach
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
T Cell Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Foxp3 Expression ◽  
Cell Receptor ◽  
T Regulatory Cell ◽  
Regulatory Phenotype

Abstract Thymic-derived natural T-regulatory cells (nTregs) are important for the induction of self-tolerance and the control of autoimmunity. Murine CD4+CD25−Foxp3− cells can be induced to express Foxp3 after T-cell receptor (TCR) activation in the presence of transforming growth factor β (TGFβ) and are phenotypically similar to nTregs. Some studies have suggested that TCR stimulation of human CD4+CD25− cells results in the induction of transient expression of FOXP3, but that the induced cells lack a regulatory phenotype. We demonstrate here that TCR stimulation alone was insufficient to induce FOXP3 expression in the absence of TGFβ, whereas high levels of FOXP3 expression could be induced in the presence of TGFβ. Although FOXP3 expression was stable, the TGFβ-induced FOXP3+ T cells were neither anergic nor suppressive and produced high levels of effector cytokines. These results suggest that even high levels of FOXP3 expression are insufficient to define a human CD4+ T cell as a T-regulatory cell.

scholarly journals Hepatocellular Carcinoma Cells Induce Regulatory T Cells and Lead to Poor Prognosis via Production of Transforming Growth Factor-β1

2016 ◽  
Vol 38 (1) ◽  
pp. 306-318 ◽  
Author(s):  
Yi Wang ◽  
Taotao Liu ◽  
Wenqing Tang ◽  
Bin Deng ◽  
Yanjie Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Poor Prognosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
In Vivo Experiments ◽  
Tgf Β1

Background/Aims: Regulatory T cells (Tregs) are associated with a poor prognosis in hepatocellular carcinoma (HCC). The purpose of the study was to explore the mechanisms of Tregs accumulation in HCC. Methods: We analyzed the frequency of Tregs in HCC by flow cytometry and immunohistochemistry. We also established a transforming growth factor (TGF)-β1-knockdown cell line by lentivirus-mediated RNA interference. Mouse CD4+CD25- T cells were cultured in supernatants from various cell lines. Results: HCC patients had a high frequency of Tregs, and high numbers of Tregs correlated with a poor prognosis. Liver cancer cells induced Treg production by secreting TGF-β1. In vivo experiments indicated that knockdown of TGF-β1 reduced the numbers of Tregs and metastatic nodules in mice. Conclusions: These results indicate that cancer-secreted TGF-β1 may increase Tregs, and TGF-β1 knockdown might impair immunosuppression in the tumor microenvironment by decrease Tregs.

scholarly journals Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases Transforming Growth Factor β1 (TGF-β1) Production in Human Regulatory T Cells

2015 ◽  
Vol 290 (33) ◽  
pp. 20105-20116 ◽  
Author(s):  
Caroline Huygens ◽  
Stéphanie Liénart ◽  
Olivier Dedobbeleer ◽  
Julie Stockis ◽  
Emilie Gauthy ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
Transmembrane Protein ◽  
Transforming Growth Factor Β1 ◽  
Tgf Β1
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