Interleukin-6 (IL-6) Prevents Activation-Induced Cell Death: IL-2–Independent Inhibition of Fas/fasL Expression and Cell Death

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4212-4219 ◽  
Author(s):  
Emira Ayroldi ◽  
Ornella Zollo ◽  
Lorenza Cannarile ◽  
Francesca D’ Adamio ◽  
Ursula Grohmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Specific Antigen ◽  
General Mechanism ◽  
Activation Induced Cell Death ◽  
Induced Apoptosis

Abstract Triggering of the TCR/CD3 complex with specific antigen or anti-CD3 monoclonal antibody initiates activation-induced cell death (AICD) in mature T cells, an effect also mediated by the Fas/FasL system. We have previously shown that CD2 stimulation rescues T cells from TCR/CD3-induced apoptosis by decreasing the expression of Fas and FasL. In the present study, we examined whether the endogenous production of IL-2 plays a role in the effects mediated by CD2 triggering. The results indicated that transcription of Fas/FasL is controlled by interleukin-2 (IL-2) production and that CD2 triggering rescues a T-cell hybridoma from AICD via decreased production of IL-2. To ascertain whether modulation of IL-2 may be a general mechanism of AICD control, we examined other stimuli, capable of modulating the expression of the Fas/FasL system and the ensuing AICD, for ability to affect production of IL-2. We found that IL-6 reduced the level of TCR/CD3-induced apoptosis and the expression of Fas/FasL, yet failed to inhibit IL-2 production. Because IL-2 is involved in both apoptosis and activation events, these results indicate that, in contrast to CD2, which inhibits apoptosis and T cell activation, IL-6 inhibits apoptosis but not IL-2–induced activation. These observations may provide the basis for differential control of T-cell activation and apoptosis.

Interleukin-6 (IL-6) Prevents Activation-Induced Cell Death: IL-2–Independent Inhibition of Fas/fasL Expression and Cell Death

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4212-4219 ◽  
Author(s):  
Emira Ayroldi ◽  
Ornella Zollo ◽  
Lorenza Cannarile ◽  
Francesca D’ Adamio ◽  
Ursula Grohmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Specific Antigen ◽  
General Mechanism ◽  
Activation Induced Cell Death ◽  
Induced Apoptosis

Triggering of the TCR/CD3 complex with specific antigen or anti-CD3 monoclonal antibody initiates activation-induced cell death (AICD) in mature T cells, an effect also mediated by the Fas/FasL system. We have previously shown that CD2 stimulation rescues T cells from TCR/CD3-induced apoptosis by decreasing the expression of Fas and FasL. In the present study, we examined whether the endogenous production of IL-2 plays a role in the effects mediated by CD2 triggering. The results indicated that transcription of Fas/FasL is controlled by interleukin-2 (IL-2) production and that CD2 triggering rescues a T-cell hybridoma from AICD via decreased production of IL-2. To ascertain whether modulation of IL-2 may be a general mechanism of AICD control, we examined other stimuli, capable of modulating the expression of the Fas/FasL system and the ensuing AICD, for ability to affect production of IL-2. We found that IL-6 reduced the level of TCR/CD3-induced apoptosis and the expression of Fas/FasL, yet failed to inhibit IL-2 production. Because IL-2 is involved in both apoptosis and activation events, these results indicate that, in contrast to CD2, which inhibits apoptosis and T cell activation, IL-6 inhibits apoptosis but not IL-2–induced activation. These observations may provide the basis for differential control of T-cell activation and 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.

Role of GITR in activation response of T lymphocytes

Blood ◽  
2002 ◽  
Vol 100 (1) ◽  
pp. 350-352 ◽  
Author(s):  
Simona Ronchetti ◽  
Giuseppe Nocentini ◽  
Carlo Riccardi ◽  
Pier Paolo Pandolfi
Keyword(s):  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Tumor Necrosis Factor Receptor ◽  
Cell Receptor ◽  
Activation Induced Cell Death ◽  
Activation Response

Abstract In this study, we describe the generation and characterization of mice in which GITR gene (TNFRSF18 [tumor necrosis factor receptor superfamily 18]), a member of the TNFRSF expressed mainly on T lymphocytes, has been ablated (GITR−/− mice). Results indicate that GITR inactivation does not impair the normal development of the lymphoid organs but modulates T-cell activation. In fact, whenGITR−/− T lymphocytes are activated by treatment with an anti-CD3 monoclonal antibody they proliferate more than wild-type cells. Moreover, activatedGITR−/− T lymphocytes express higher levels of interleukin-2 receptor, produce larger amounts of interleukin-2, and are more sensitive to activation-induced cell death than controls. These results suggest that GITR is involved in the regulation of T-cell receptor/CD3–driven T-cell activation and programmed cell death.

scholarly journals The HECT-Type E3 Ubiquitin Ligase AIP2 Inhibits Activation-Induced T-Cell Death by Catalyzing EGR2 Ubiquitination

2009 ◽  
Vol 29 (19) ◽  
pp. 5348-5356 ◽  
Author(s):  
An Chen ◽  
Beixue Gao ◽  
Jingping Zhang ◽  
Tamara McEwen ◽  
Shui Q. Ye ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Fas Ligand ◽  
Interleukin 2 ◽  
Ubiquitin Ligases ◽  
E3 Ubiquitin Ligases ◽  
Fasl Expression

ABSTRACT E3 ubiquitin ligases, which target specific molecules for proteolytic destruction, have emerged as key regulators of immune functions. Several E3 ubiquitin ligases, including c-Cbl, Cbl-b, GRAIL, Itch, and Nedd4, have been shown to negatively regulate T-cell activation. Here, we report that the HECT-type E3 ligase AIP2 positively regulates T-cell activation. Ectopic expression of AIP2 in mouse primary T cells enhances their proliferation and interleukin-2 production by suppressing the apoptosis of T cells. AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand (FasL) expression during activation-induced T-cell death. Suppression of AIP2 expression by small RNA interference upregulates EGR2, inhibits EGR2 ubiquitination and FasL expression, and enhances the apoptosis of T cells. Therefore, AIP2 regulates activation-induced T-cell death by suppressing EGR2-mediated FasL expression via the ubiquitin pathway.

scholarly journals CD28-B7 interactions allow the induction of CD8+ cytotoxic T lymphocytes in the absence of exogenous help.

1993 ◽  
Vol 177 (6) ◽  
pp. 1791-1796 ◽  
Author(s):  
F A Harding ◽  
J P Allison
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Histocompatibility Complex ◽  
Necessary And Sufficient ◽  
Additional Antigen

The activation requirements for the generation of CD8+ cytotoxic T cells (CTL) are poorly understood. Here we demonstrate that in the absence of exogenous help, a CD28-B7 interaction is necessary and sufficient for generation of class I major histocompatibility complex-specific CTL. Costimulation is required only during the inductive phase of the response, and not during the effector phase. Transfection of the CD28 counter receptor, B7, into nonstimulatory P815 cells confers the ability to elicit P815-specific CTL, and this response can be inhibited by anti-CD28 Fab or by the chimeric B7-binding protein CTLA4Ig. Anti-CD28 monoclonal antibody (mAb) can provide a costimulatory signal to CD8+ T cells when the costimulatory capacity of splenic stimulators is destroyed by chemical fixation. CD28-mediated signaling provokes the release of interleukin 2 (IL-2) from the CD8+ CTL precursors, as anti-CD28 mAb could be substituted for by the addition of IL-2, and an anti-IL-2 mAb can block the generation of anti-CD28-induced CTL. CD4+ cells are not involved in the costimulatory response in the systems examined. We conclude that CD8+ T cell activation requires two signals: an antigen-specific signal mediated by the T cell receptor, and an additional antigen nonspecific signal provided via a CD28-B7 interaction.

scholarly journals SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity

Science ◽  
2021 ◽  
Vol 372 (6543) ◽  
pp. eaba4220 ◽  
Author(s):  
Tao Yue ◽  
Xiaoming Zhan ◽  
Duanwu Zhang ◽  
Ruchi Jain ◽  
Kuan-wen Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Cell Mediated Immunity ◽  
Activated T Cells ◽  
Granule Formation

Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support T cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response that leads to translation repression. This response is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) to protect them from cleavage by the ribonuclease angiogenin. T cell–specific SLFN2 deficiency results in the accumulation of tRNA fragments, which inhibit translation and promote stress-granule formation. Interleukin-2 receptor β (IL-2Rβ) and IL-2Rγ fail to be translationally up-regulated after T cell receptor stimulation, rendering SLFN2-deficient T cells insensitive to interleukin-2’s mitogenic effects. SLFN2 confers resistance against the ROS-mediated translation-inhibitory effects of oxidative stress normally induced by T cell activation, permitting the robust protein synthesis necessary for T cell expansion and immunity.

scholarly journals Antigen-independent activation of naive and memory resting T cells by a cytokine combination.

1994 ◽  
Vol 180 (3) ◽  
pp. 1159-1164 ◽  
Author(s):  
D Unutmaz ◽  
P Pileri ◽  
S Abrignani
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Effector Function ◽  
Necrosis Factor Alpha ◽  
Naive T Cells ◽  
Naïve T Cells

We investigated whether human resting T cells could be activated to proliferate and display effector function in the absence of T cell receptor occupancy. We report that combination of interleukin 2 (IL-2), tumor necrosis factor alpha, and IL-6 activated highly purified naive (CD45RA+) and memory (CD45RO+) resting CD4+ T cells to proliferate. Under this condition, memory resting T cells could also display effector function as measured by lymphokine synthesis and help for immunoglobulin production by B cells. This novel Ag-independent pathway of T cell activation may play an important role in vivo in recruiting effector T cells at the site of immune response and in maintaining the clonal size of memory T cells in the absence of antigenic stimulation. Moreover, cytokines can induce proliferation of naive T cells without switch to memory phenotype and this may help the maintenance of the peripheral pool of naive T cells.

Abstract 449: Novel Role of Bim in the Regulation of Allogeneic T-Cell Activation and Development of Transplant Vasculopathy

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Anna von Rossum ◽  
Winnie Enns ◽  
Yu P Shi ◽  
Jonathan C Choy
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Responses ◽  
Intimal Thickening ◽  
Cell Responses ◽  
Transplant Vasculopathy

Transplant vasculopathy (TV) is an arteriosclerotic disease characterized by intimal thickening of allograft arteries and is a leading cause of heart transplant rejection. T cell responses towards allograft arteries are responsible for the development of TV and understanding the regulatory pathways controlling T cell activation in allograft arteries provides opportunities for the therapeutic attenuation of TV as well as other arteriosclerotic diseases. Bim is a pro-apoptotic Bcl-2 protein known to down-regulate immune responses after viral infections by inducing cell death of effector T cells but its role in regulating allogeneic T cell responses is not known. We compared cell death and alloantigen-driven activation of T cells from Bim +/+ (wild-type), Bim +/- and Bim -/- mice as well as the development of TV in these mice. Bim was required for cell death of both CD4 and CD8 T cells in response to cytokine deprivation in vitro . Unexpectedly, Bim was also required for alloantigen-induced proliferation of both CD4 and CD8 T cells as well as for IL-2 production. When TV was examined in aortic interposition grafts implanted into complete major histocompatibility complex-mismatched mice, intimal thickening was significantly reduced in Bim +/- but not Bim -/- recipients as compared to Bim +/+ counterparts. There was signficantly less CD4 T cell accumulation in the intima of arteries from Bim +/- as compared to Bim +/+ recipients but this effect was not observed in Bim -/- recipients. The accumulation of CD8 T cells in allograft arteries was not affected by differences in Bim expression. Taken together, our data support a novel role for Bim in driving T cell activation in response to allogeneic stimuli and indicate that the effects of this Bcl-2 protein in the pathogenesis of TV likely depends on its dual role in supporting T cell activation and death.

Effect of CD28 signal transduction on c-Rel in human peripheral blood T cells

1994 ◽  
Vol 14 (12) ◽  
pp. 7933-7942
Author(s):  
R G Bryan ◽  
Y Li ◽  
J H Lai ◽  
M Van ◽  
N R Rice ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Nuclear Translocation ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Cd28 Costimulation

Optimal T-cell activation requires both an antigen-specific signal delivered through the T-cell receptor and a costimulatory signal which can be delivered through the CD28 molecule. CD28 costimulation induces the expression of multiple lymphokines, including interleukin 2 (IL-2). Because the c-Rel transcription factor bound to and activated the CD28 response element within the IL-2 promoter, we focused our study on the mechanism of CD28-mediated regulation of c-Rel in human peripheral blood T cells. We showed that CD28 costimulation accelerated the kinetics of nuclear translocation of c-Rel (and its phosphorylated form), p50 (NFKB1), and p65 (RelA). The enhanced nuclear translocation of c-Rel correlated with the stimulation of Il-2 production and T-cell proliferation by several distinct anti-CD28 monoclonal antibodies. This is explained at least in part by the long-term downregulation of I kappa B alpha following CD28 signalling as opposed to phorbol myristate acetate alone. Furthermore, we showed that the c-Rel-containing CD28-responsive complex is enhanced by, but not specific to, CD28 costimulation. Our results indicate that c-Rel is one of the transcription factors targeted by CD28 signalling.

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