scholarly journals Fibroblasts mediate T cell survival: a proposed mechanism for retention of primed T cells.

1990 ◽  
Vol 172 (6) ◽  
pp. 1873-1876 ◽  
Author(s):  
S Scott ◽  
F Pandolfi ◽  
J T Kurnick
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Lymphocytes ◽  
Cell Survival ◽  
Conditioned Medium ◽  
Stromal Cell ◽  
Interleukin 2 ◽  
Salvage Pathway ◽  
Activated T Lymphocytes ◽  
T Cell Survival

This report describes a salvage pathway whereby activated T lymphocytes revert to nonproliferating cells in the absence of antigen or mitogenic signals. After the removal of mitogenic cytokines, cultured T lymphocytes cease dividing and rapidly begin to undergo cell death. However, the addition of fibroblasts to interleukin 2 (IL-2)-propagated T cells results in prolonged survival of the previously activated T lymphocytes in the absence of proliferation. The prevention of cell death is also achieved by conditioned medium from the fibroblasts. T lymphocytes cultured with fibroblasts or the conditioned medium retain the ability to be restimulated if mitogenic stimuli are added to the culture. The activity is not accounted for by IL-1-7. The studies suggest a stromal cell-mediated, nonspecific mechanism for survival of primed T lymphocytes in a nonproliferating state.

GILZ, a new target for the transcription factor FoxO3, protects T lymphocytes from interleukin-2 withdrawal–induced apoptosis

Blood ◽  
2004 ◽  
Vol 104 (1) ◽  
pp. 215-223 ◽  
Author(s):  
Marie-Liesse Asselin-Labat ◽  
Muriel David ◽  
Armelle Biola-Vidamment ◽  
Damiana Lecoeuche ◽  
Maria-Christina Zennaro ◽  
...  
Keyword(s):  
Cell Death ◽  
T Lymphocytes ◽  
Leucine Zipper ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Forkhead Box ◽  
Activated T Lymphocytes ◽  
Functional Consequences ◽  
Induced Apoptosis

Abstract Interleukin-2 (IL-2) withdrawal is a physiologic process inducing cell death in activated T lymphocytes. Glucocorticoid-induced leucine zipper (GILZ) has recently been identified as a protein modulating T-cell receptor activation by repressing various signaling pathways. We report here that IL-2 deprivation leads to expression of GILZ in T lymphocytes. We then characterized the human gilz promoter and showed that FoxO3 (Forkhead box class O3) binding to the Forkhead responsive elements identified in the promoter is necessary for induction of gilz expression upon IL-2 withdrawal. To assess the functional consequences of this induction, we used 2 strategies, GILZ overexpression and GILZ silencing in murine IL-2–dependent CTLL-2 cells. GILZ overexpression protects CTLL-2 cells from IL-2 withdrawal–induced apoptosis, whereas cell death is accelerated in cells unable to express GILZ. Concomitantly, the expression of Bim is inhibited in GILZ-overexpressing cells and enhanced when GILZ expression is impaired. Furthermore, GILZ inhibits FoxO3 transcriptional activity that leads to inhibition of Bim expression but also to down-regulation of GILZ itself. Therefore, GILZ is a transiently expressed protein induced upon IL-2 withdrawal that protects T cells from the onset of apoptosis.

An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 265-273 ◽  
Author(s):  
Graziella Curtale ◽  
Franca Citarella ◽  
Claudia Carissimi ◽  
Marina Goldoni ◽  
Nicoletta Carucci ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Activation Induced Cell Death

Abstract Activation of the T cell–mediated immune response has been associated with changes in the expression of specific microRNAs (miRNAs). However, the role of miRNAs in the development of an effective immune response is just beginning to be explored. This study focuses on the functional role of miR-146a in T lymphocyte–mediated immune response and provides interesting clues on the transcriptional regulation of miR-146a during T-cell activation. We show that miR-146a is low in human naive T cells and is abundantly expressed in human memory T cells; consistently, miR-146a is induced in human primary T lymphocytes upon T-cell receptor (TCR) stimulation. Moreover, we identified NF-kB and c-ETS binding sites as required for the induction of miR-146a transcription upon TCR engagement. Our results demonstrate that several signaling pathways, other than inflammation, are influenced by miR-146a. In particular, we provide experimental evidence that miR-146a modulates activation-induced cell death (AICD), acting as an antiapoptotic factor, and that Fas-associated death domain (FADD) is a target of miR-146a. Furthermore, miR-146a enforced expression impairs both activator protein 1 (AP-1) activity and interleukin-2 (IL-2) production induced by TCR engagement, thus suggesting a role of this miRNA in the modulation of adaptive immunity.

scholarly journals Upregulation of Intracellular Glutathione by Fibroblast-Derived Factor(s): Enhanced Survival of Activated T Cells in the Presence of Low Bcl-2

Blood ◽  
1997 ◽  
Vol 89 (7) ◽  
pp. 2453-2460 ◽  
Author(s):  
Helena Hyde ◽  
Nicola J. Borthwick ◽  
George Janossy ◽  
Michael Salmon ◽  
Arne N. Akbar
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Interleukin 2 ◽  
Buthionine Sulfoximine ◽  
Activated T Cells ◽  
Large Molecular Weight ◽  
Low Levels ◽  
T Cell Survival

Abstract Activated interleukin-2 (IL-2)–dependent T cells express high levels of Bcl-2 protein. On cytokine withdrawal, Bcl-2 expression decreases and the cells die rapidly by apoptosis. We have previously shown that the survival of IL-2–deprived T cells can be promoted by factor(s) secreted by fibroblasts. Here we report that reduced glutathione (GSH), but not its oxidized counterpart GSSG, also enhances the in vitro survival of these cells. Exogenous GSH mediates its effect intracellularly, as (1) endogenous glutathione concentrations are increased up to fivefold in the presence of GSH, and (2) acivicin, an inhibitor of transmembrane GSH transport, abrogates GSH-dependent survival. The GSH-rescued T cells do not proliferate and express only low levels of Bcl-2, resembling WI38 fibroblast-rescued T cells. We, therefore, investigated a role for GSH in fibroblast-promoted T-cell survival. We show that WI38-promoted survival results in elevated GSH levels in surviving T cells and is abrogated by buthionine sulfoximine (BSO), an inhibitor of GSH synthesis. Furthermore, both WI38-promoted T-cell survival and GSH upregulation are associated with large molecular weight molecules (<30 kD). Thus, the upregulation of GSH by WI38 fibroblasts appears to be crucial in their ability to enhance the survival of cytokine-deprived activated T cells in vitro.

scholarly journals Kynurenine Reduces Memory CD4 T-Cell Survival by Interfering with Interleukin-2 Signaling Early during HIV-1 Infection

2016 ◽  
Vol 90 (17) ◽  
pp. 7967-7979 ◽  
Author(s):  
Xavier Dagenais-Lussier ◽  
Mouna Aounallah ◽  
Vikram Mehraj ◽  
Mohamed El-Far ◽  
Cecile Tremblay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Cd4 T Cell ◽  
Tryptophan Catabolism ◽  
T Cell Survival ◽  
Memory Cd4 T Cells ◽  
Hiv 1

ABSTRACTEarly HIV-1 infection is characterized by enhanced tryptophan catabolism, which contributes to immune suppression and disease progression. However, the mechanism by which kynurenine, a tryptophan-related metabolite, induces immune suppression remains poorly understood. Herein, we show that the increased production of kynurenine correlates with defective interleukin-2 (IL-2) signaling in memory CD4 T cells from HIV-infected subjects. Defective IL-2 signaling in these subjects, which drives reduced protection from Fas-mediated apoptosis, was also associated with memory CD4 T-cell loss. Treatment of memory CD4 T cells with the concentration of kynurenine found in plasma inhibited IL-2 signaling through the production of reactive oxygen species. We further show that IL-2 signaling in memory CD4 T cells is improved by the antioxidantN-acetylcysteine. Early initiation of antiretroviral therapy restored the IL-2 response in memory CD4 T cells by reducing reactive oxygen species and kynurenine production. The study findings provide a kynurenine-dependent mechanism through IL-2 signaling for reduced CD4 T-cell survival, which can be reversed by early treatment initiation in HIV-1 infection.IMPORTANCEThe persistence of functional memory CD4 T cells represents the basis for long-lasting immune protection in individuals after exposure to HIV-1. Unfortunately, primary HIV-1 infection results in the massive loss of these cells within weeks of infection, which is mainly driven by inflammation and massive infection by the virus. These new findings show that the enhanced production of kynurenine, a metabolite related to tryptophan catabolism, also impairs memory CD4 T-cell survival and interferes with IL-2 signaling early during HIV-1 infection.

Interleukin 2- and polyomavirus middle T antigen-induced modification of phosphatidylinositol 3-kinase activity in activated T lymphocytes

1991 ◽  
Vol 11 (9) ◽  
pp. 4431-4440
Author(s):  
J A Augustine ◽  
S L Sutor ◽  
R T Abraham
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Kinase Activity ◽  
Interleukin 2 ◽  
T Antigen ◽  
Threefold Increase ◽  
Activated T Lymphocytes ◽  
Polyomavirus Middle T Antigen ◽  
Middle T Antigen ◽  
Stimulation Of

Stimulation of activated T lymphocytes with interleukin 2 (IL-2) results in rapid increases in intracellular protein tyrosine phosphorylation. Both the identity of the protein tyrosine kinase (PTK) activated by IL-2 receptor ligation and the identities of the critical target proteins for this PTK remain largely undefined. In this article, we demonstrate that stimulation of activated murine or human T cells with IL-2 for 10 to 30 min induces two- to threefold increases in the level of phosphatidylinositol (PtdIns) 3-kinase activity present in antiphosphotyrosine (p-Tyr) antibody immunoprecipitates from these cells. Furthermore, substantial levels of PtdIns 3-kinase activity were coprecipitated from IL-2-deprived T cells by antibodies to the src-related PTK p59fyn. Cellular stimulation with IL-2 induced a two- to threefold increase in the level of p59fyn-associated PtdIns 3-kinase activity. To examine the effect of a constitutive increase in PtdIns 3-kinase activity on the growth factor responsiveness of activated T cells, murine CTLL-2 cells were transfected with a polyomavirus middle T antigen (MTAg) expression vector. Anti-p-Tyr and anti-p59fyn immunoprecipitates from MTAg-transfected CTLL-2 cells contained three- to sixfold higher levels of PtdIns 3-kinase activity than wild-type cells. Immune complex kinase assays revealed that MTAg expression concomitantly induced a constitutive threefold increase in the PTK activity of p59fyn in these cells. However, stable MTAg expression did not abrogate the dependence of CTLL-2 cells on exogenous IL-2 for continued growth and proliferation.

scholarly journals Interleukin 2- and polyomavirus middle T antigen-induced modification of phosphatidylinositol 3-kinase activity in activated T lymphocytes.

1991 ◽  
Vol 11 (9) ◽  
pp. 4431-4440 ◽  
Author(s):  
J A Augustine ◽  
S L Sutor ◽  
R T Abraham
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Kinase Activity ◽  
Interleukin 2 ◽  
T Antigen ◽  
Threefold Increase ◽  
Activated T Lymphocytes ◽  
Polyomavirus Middle T Antigen ◽  
Middle T Antigen ◽  
Stimulation Of

Stimulation of activated T lymphocytes with interleukin 2 (IL-2) results in rapid increases in intracellular protein tyrosine phosphorylation. Both the identity of the protein tyrosine kinase (PTK) activated by IL-2 receptor ligation and the identities of the critical target proteins for this PTK remain largely undefined. In this article, we demonstrate that stimulation of activated murine or human T cells with IL-2 for 10 to 30 min induces two- to threefold increases in the level of phosphatidylinositol (PtdIns) 3-kinase activity present in antiphosphotyrosine (p-Tyr) antibody immunoprecipitates from these cells. Furthermore, substantial levels of PtdIns 3-kinase activity were coprecipitated from IL-2-deprived T cells by antibodies to the src-related PTK p59fyn. Cellular stimulation with IL-2 induced a two- to threefold increase in the level of p59fyn-associated PtdIns 3-kinase activity. To examine the effect of a constitutive increase in PtdIns 3-kinase activity on the growth factor responsiveness of activated T cells, murine CTLL-2 cells were transfected with a polyomavirus middle T antigen (MTAg) expression vector. Anti-p-Tyr and anti-p59fyn immunoprecipitates from MTAg-transfected CTLL-2 cells contained three- to sixfold higher levels of PtdIns 3-kinase activity than wild-type cells. Immune complex kinase assays revealed that MTAg expression concomitantly induced a constitutive threefold increase in the PTK activity of p59fyn in these cells. However, stable MTAg expression did not abrogate the dependence of CTLL-2 cells on exogenous IL-2 for continued growth and proliferation.

scholarly journals NLRP6 Deficiency in CD4 T Cells Decreases T Cell Survival Associated with Increased Cell Death

2019 ◽  
Vol 203 (2) ◽  
pp. 544-556 ◽  
Author(s):  
Katarina Radulovic ◽  
C. Korcan Ayata ◽  
Rachel Mak'Anyengo ◽  
Kristina Lechner ◽  
Philipp Wuggenig ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Cell Survival ◽  
Cd4 T Cells ◽  
T Cell Survival

scholarly journals Cytotoxic T cells both produce and respond to interleukin 2

1984 ◽  
Vol 159 (2) ◽  
pp. 647-652 ◽  
Author(s):  
L Andrus ◽  
A Granelli-Piperno ◽  
E Reich
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Cells ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Activated T Cells ◽  
Activated T Lymphocytes ◽  
In Vitro Response

Interleukin 2 (IL-2) is a T cell-derived lymphokine that serves as a cofactor for the in vitro response of T lymphocytes to antigen and plays an important role in regulating the growth and/or differentiation of these cells (1, 2). It has been postulated (2, 3) that IL-2 is produced by a discrete regulatory T cell subset, with its effects being exerted on a second, functionally distinct subpopulation of T cells. Cytotoxic T cells have been included in the IL-2-responsive subset (3). Several models of immune regulation have further assumed that the T lymphocyte pool is divided into a complex array of genetically preprogrammed T cell subtypes, each performing a specific regulatory or effector function (4, 5). However, recent results from several laboratories (6-8) have failed to support such a strict functional subdivision of the T cell pool. The availability of highly purified mouse IL-2 (1) prompted us to reevaluate the distinction, if any, between IL-2-producing and IL-2- responsive T cells. For this purpose, we resorted to a cell-cloning procedure using activated T lymphocytes that were maintained only for short periods in culture. T cell clones were tested for cytotoxic activity, responsiveness to IL-2, and for the capacity to produce IL-2 after appropriate stimulation. We found no evidence for the existence of a major functional subdivision involving these parameters among alloantigen-activated T cells: the majority of clones analyzed could perform all three functions.

scholarly journals CD27 Expression Promotes Long-Term Survival of Functional Effector–Memory CD8+Cytotoxic T Lymphocytes in HIV-infected Patients

2004 ◽  
Vol 200 (11) ◽  
pp. 1407-1417 ◽  
Author(s):  
Adrian F. Ochsenbein ◽  
Stanley R. Riddell ◽  
Michele Brown ◽  
Lawrence Corey ◽  
Gabriela M. Baerlocher ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Receptor ◽  
Effector Memory ◽  
Term Survival ◽  
Functional Consequences

Human immunodeficiency virus (HIV)-specific CD8+ T cells persist in high frequencies in HIV-infected patients despite impaired CD4+ T helper response to the virus, but, unlike other differentiated effector cytotoxic T lymphocytes, most continue to express the tumor necrosis factor receptor family member CD27. Because the ligand for CD27 (CD70) is also overexpressed in HIV-infected hosts, we examined the nature of expression and potential functional consequences of CD27 expression on HIV-specific CD8+ T cells. Analysis of CD27+ and CD27− T cells derived from the same HIV-specific clone revealed that retention of CD27 did not interfere with acquisition of effector functions, and that after T cell receptor stimulation, CD27+ cells that concurrently were triggered via CD27 exhibited more resistance to apoptosis, interleukin 2 production, and proliferation than CD27− T cells. After transfer back into an HIV-infected patient, autologous HIV-specific CD27− T cells rapidly disappeared, but CD27+ T cells derived from the same clone persisted at high frequency. Our findings suggest that the CD27–CD70 interaction in HIV infection may provide CD27+ CD8+ T cells with a survival advantage and compensate for limiting or absent CD4+ T help to maintain the CD8 response.

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