scholarly journals Cellular-FLIP, Raji isoform (c-FLIPR) modulates cell death induction upon T-cell activation and infection

2013 ◽  
Vol 43 (6) ◽  
pp. 1499-1510 ◽  
Author(s):  
Tanja Telieps ◽  
Frida Ewald ◽  
Marcus Gereke ◽  
Michaela Annemann ◽  
Yvonne Rauter ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cellular Flip

scholarly journals Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

2012 ◽  
Vol 209 (6) ◽  
pp. 1201-1217 ◽  
Author(s):  
Tadashi Yokosuka ◽  
Masako Takamatsu ◽  
Wakana Kobayashi-Imanishi ◽  
Akiko Hashimoto-Tane ◽  
Miyuki Azuma ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tyrosine Phosphatase ◽  
Cell Receptor ◽  
Programmed Cell Death 1

Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.

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.

CD4+ T cell activation and concomitant mTOR metabolic inhibition can ablate microbiota-specific memory cells and prevent colitis

2020 ◽  
Vol 5 (54) ◽  
pp. eabc6373
Author(s):  
Qing Zhao ◽  
Lennard W. Duck ◽  
Fengyuan Huang ◽  
Katie L. Alexander ◽  
Craig L. Maynard ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Formation ◽  
Metabolic Inhibition ◽  
T Cell Epitopes ◽  
Specific Memory

Microbiota-reactive CD4+ T memory (TM) cells are generated during intestinal infections and inflammation, and can revert to pathogenic CD4+ T effector (TE) cells, resulting in chronicity of inflammatory bowel disease (IBD). Unlike TE cells, TM cells have a low rate of metabolism unless they are activated by reencountering cognate antigen. Here, we show that the combination of cell activation and metabolic checkpoint inhibition (CAMCI), by targeting key metabolic regulators mTORC and AMPK, resulted in cell death and anergy, but enhanced the induction of the regulatory subset. Parenteral application of this treatment with a synthetic peptide containing multiple flagellin T cell epitopes (MEP1) and metabolic inhibition successfully prevented the development of CD4+ T cell–driven colitis. Microbiota-specific CD4+ T cells, especially the pathogenic TE subsets, were decreased 10-fold in the intestinal lamina propria. Furthermore, using the CAMCI strategy, we were able to prevent antigen-specific TM cell formation upon initial antigen encounter, and ablate existing TM cells upon reactivation in mice, leading to an altered transcriptome in the remaining CD4+ T cells after ablation. Microbiota flagellin–specific CD4+ T cells from patients with Crohn’s disease were ablated in a similar manner after CAMCI in vitro, with half of the antigen-specific T cells undergoing cell death. These results indicate that parenteral activation of microbiota-specific CD4+ T cells with concomitant metabolic inhibition is an effective way to ablate pathogenic CD4+ TM cells and to induce T regulatory (Treg) cells that provide antigen-specific and bystander suppression, supporting a potential immunotherapy to prevent or ameliorate IBD.

scholarly journals Cellular FLIP (Long Form) Regulates CD8+ T Cell Activation through Caspase-8-Dependent NF-κB Activation

2005 ◽  
Vol 174 (9) ◽  
pp. 5270-5278 ◽  
Author(s):  
Austin Dohrman ◽  
Takao Kataoka ◽  
Solange Cuenin ◽  
Jennifer Q. Russell ◽  
Jurg Tschopp ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Caspase 8 ◽  
Long Form ◽  
Cellular Flip

p38 MAPK Mediates Inhibition of Activation Induced Cell Death in T Lymphocytes Via Upregulation of Bcl-xL and FLIPshort upon Ligation of CD137/4-1BB or CD28.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3320-3320
Author(s):  
Christian Scholz ◽  
Lilian Stärck ◽  
Mario Lehmann ◽  
Bernd Dörken ◽  
Peter T. Daniel
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Protein Kinase ◽  
T Lymphocytes ◽  
Family Member ◽  
P38 Mapk ◽  
T Cell Activation ◽  
Cell Activation ◽  
Activation Induced Cell Death ◽  
Costimulatory Signals

Abstract Costimulation is essential for the induction of proliferation in naive T cells and for the inhibition of activation induced cell death (AICD) in activated T lymphocytes. While costimulatory signals mediated through the immunglobulin family member CD28 play a prominent role during primary T cell activation, ligation of the tumor necrosis factor receptor family member CD137/4-1BB is more important during late primary and secondary T cell activation. Signals mediated through either costimulatory protein block AICD. Inhibition of AICD through ligation of CD137/4-1BB or CD28 involves upregulation of Bcl-xL and FLIPshort (Eur J Immunol 2005, 35: 1257–66). We further demonstrated that costimulatory signals mediated through CD137/4-1BB or CD28 depend on the activity of phosphatidylinositol 3-kinase and AKT/protein kinase B, two kinases that had formerly been implied in CD28-induced signaling, indicating that CD28- and CD137/4-1BB-mediated signals share downstream signaling pathways. Here, we demonstrate that p38 mitogen-activated protein kinase (MAPK) mediates CD137/4-1BB-induced as well as CD28-mediated costimulation of cell proliferation and inhibition of AICD. This coincides with upregulation of Bcl-xL and FLIPshort. Inhibition of p38 MAPK abrogates T cell receptor induced proliferation and antagonizes costimulation mediated survival. Thus, p38 MAPK, which was previously thought to be primarily involved in CD137/4-1BB-mediated signaling, is similarly important for CD28-induced costimulation and survival. This indicates that, while involving different protein families, signal transduction by CD28 and CD137/4-1BB depends on a common upstream and downstream network of survival kinases.

scholarly journals Manganese superoxide dismutase: A regulator of T cell activation-induced oxidative signaling and cell death

2012 ◽  
Vol 1823 (5) ◽  
pp. 1041-1052 ◽  
Author(s):  
Marcin Mikołaj Kamiński ◽  
Daniel Röth ◽  
Sabine Sass ◽  
Sven Wolfgang Sauer ◽  
Peter Heinrich Krammer ◽  
...  
Keyword(s):  
Cell Death ◽  
Superoxide Dismutase ◽  
T Cell ◽  
T Cell Activation ◽  
Manganese Superoxide Dismutase ◽  
Cell Activation ◽  
Oxidative Signaling ◽  
Manganese Superoxide

scholarly journals Dendritic Cells and Stat3 Are Essential for CD137-Induced CD8 T Cell Activation-Induced Cell Death

2010 ◽  
Vol 184 (9) ◽  
pp. 4770-4778 ◽  
Author(s):  
Benyue Zhang ◽  
Yuanyuan Zhang ◽  
Liguo Niu ◽  
Anthony T. Vella ◽  
Robert S. Mittler
Keyword(s):  
Cell Death ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Activation Induced Cell Death

scholarly journals Indirect involvement of allergen-captured mast cells in antigen presentation

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1489-1496 ◽  
Author(s):  
Taku Kambayashi ◽  
Jan D. Baranski ◽  
Rebecca G. Baker ◽  
Tao Zou ◽  
Eric J. Allenspach ◽  
...  
Keyword(s):  
Cell Death ◽  
Mast Cell ◽  
T Cell ◽  
Mast Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Complex Class ◽  
Cell Responses ◽  
Histocompatibility Complex

Abstract It is generally thought that mast cells influence T-cell activation nonspecifically through the release of inflammatory mediators. In this report, we provide evidence that mast cells may also affect antigen-specific T-cell responses by internalizing immunoglobulin E–bound antigens for presentation to antigen-specific T cells. Surprisingly, T-cell activation did not require that mast cells express major histocompatibility complex class II, indicating that mast cells were not involved in the direct presentation of the internalized antigens. Rather, the antigen captured by mast cells is presented by other major histocompatibility complex class II+ antigen-presenting cells. To explore how this may occur, we investigated the fate of mast cells stimulated by antigen and found that FcϵRI crosslinking enhances mast cell apoptosis. Cell death by antigen-captured mast cells was required for efficient presentation because protection of mast cell death significantly decreased T-cell activation. These results suggest that mast cells may be involved in antigen presentation by acting as an antigen reservoir after antigen capture through specific immunoglobulin E molecules bound to their FcϵRI. This mechanism may contribute to how mast cells impact the development of T-cell responses.

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.

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