Apoptosis in Activated T Cells – What Are the Triggers, and What the Signal Transducers?

Häcker, Georg; Bauer, Andreas; Villunger, Andreas

doi:10.4161/cc.5.21.3397

Cited by 24 publications

(26 citation statements)

References 49 publications

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“…Loss of Bim and/or PUMA causes significant changes in cell levels in various hematopoietic compartments [24,52]. These proteins ensure the proper functioning of the immune system and prevent pathological conditions such as neoplasia or autoimmunity [68][69][70][71]. The results of experiments on mice infected with human herpes virus (HSV-1) revealed that T cells isolated from animals lacking PUMA were characterized by an abnormally long life span.…”

Section: Immune Modulation Infectionsmentioning

confidence: 92%

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Puma, a critical mediator of cell death — one decade on from its discovery

Hikisz

Kiliańska

2012

Cellular and Molecular Biology Letters

104

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Abbreviations used: ADI/II -activation domain I/II; Apaf-1 -apoptosis protease activating factor-1; Bad -Bcl-2 associated death promoter; Bak -Bcl-2 antagonist killer; Bax -Bcl-2 associated protein x; Bcl-2 -B-cell leukemia/lymphoma-2; BH1-4 -Bcl-2 homology domains 1-4; Bid -BH3 interacting domain death agonist; Bik -Bcl-2 interacting killer; Bim -Bcl-2 interacting mediator of cell death; Bmf -Bcl-2 modifying factor; Bod -Bcl-2-related ovarian death gene; Bok -Bcl-2 ovarian killer; BS1/2 -p53 binding site 1/2; CHOP -C/EBP homologous protein; DEN -diethylnitrosamine; GSK-3 -glycogen synthase kinase-3; HRK -harakiri, activator of apoptosis ; HSPCs -hematopoietic stem/progenitor cells; HSV-1 -human herpes virus; IKK -IκB kinase; IL-3 -interleukin 3; Lys -lysine; Mcl-1 -myeloid cell leukemia-1; MEFs -mouse embryo fibroblasts; miRNA/miR -microRNA; MLS -mitochondrial localization signal; MOMPmitochondrial outer membrane permeabilization; NOXA (PMAP1) -phorbol-12-myristate-13-acetate-induced protein 1; OMM -outer mitochondrial membrane; PCDprogrammed cell death; PI3K -phosphoinositide 3-kinase; PUMA -p53 upregulated modulator of apoptosis; ROS -reactive oxygen species; Ser -serine; Smac/DIABLOsecond mitochondria-derived activator or caspases/direct IAP binding protein with low pI; TRB3 -tribbles 3 homolog; UV-IR -ultraviolet-gamma irradiation Abstract: PUMA (p53 upregulated modulator of apoptosis) is a pro-apoptotic member of the BH3-only subgroup of the Bcl-2 family. It is a key mediator of p53-dependent and p53-independent apoptosis and was identified 10 years ago. The PUMA gene is mapped to the long arm of chromosome 19, a region that is frequently deleted in a large number of human cancers. PUMA mediates apoptosis thanks to its ability to directly bind known anti-apoptotic members of the Bcl-2 family. It mainly localizes to the mitochondria. The binding of PUMA to the inhibitory members of the Bcl-2 family (Bcl-2-like proteins) via its BH3 domain seems to be a critical regulatory step in the induction of apoptosis. It results in the displacement of the proteins Bax and/or Bak. This is followed by their activation and the formation of pore-like structures on the mitochondrial Unauthenticated Download Date | 5/11/18 3:27 AM CELLULAR & MOLECULAR BIOLOGY LETTERS 647 membrane, which permeabilizes the outer mitochondrial membrane, leading to mitochondrial dysfunction and caspase activation. PUMA is involved in a large number of physiological and pathological processes, including the immune response, cancer, neurodegenerative diseases and bacterial and viral infections.

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Section: Immune Modulation Infectionsmentioning

confidence: 92%

“…The obtained data indicate a key role of PUMA in immune response regulation. Control of PUMA transcription in antigen-activated T cells that undergo PCD is driven mainly by p53 and FOXO3a transcription factors [68][69][70].…”

Section: Immune Modulation Infectionsmentioning

confidence: 99%

Puma, a critical mediator of cell death — one decade on from its discovery

Hikisz

Kiliańska

2012

Cellular and Molecular Biology Letters

104

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“…To evaluate effects of the various treatments on CL1 survival, we first checked activation of the AKT signaling pathway (also known as PKB) that is directly associated with enhanced T cell survival after exposure to inflammatory adjuvants (22) and is reduced as a consequence of cytokine withdrawal (21). Phosphorylation of AKT was not detectable in CL1 cells taken from the spleen 3 days after exposure to peptide and IL-2c (Fig.…”

Section: Increased Proliferation and Survival Of Cl1 Cells After Treamentioning

confidence: 99%

“…In the experiments described above, IL-2c was provided for 3 days, after which CD8 cells become susceptible to death induced by cytokine withdrawal (21). To evaluate effects of the various treatments on CL1 survival, we first checked activation of the AKT signaling pathway (also known as PKB) that is directly associated with enhanced T cell survival after exposure to inflammatory adjuvants (22) and is reduced as a consequence of cytokine withdrawal (21).…”

Section: Increased Proliferation and Survival Of Cl1 Cells After Treamentioning

confidence: 99%

Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy

Verdeil

Marquardt²,

Surh³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Because of mechanisms of self-tolerance, many tumor-specific CD8 T cells exhibit low avidity for tumor antigens and would benefit from strategies that enhance their numbers and effector function. Here we demonstrate that the combined use of two different types of immune adjuvants, one that directly targets the CD8 cell, IL-2/anti-IL-2 mAb complexes, and one that targets the innate immune system, poly(I:C), can achieve this goal. Provision of IL-2/mAb complexes was found to enhance the activation and effector function of low-avidity tumor-specific T cells, yet this was insufficient to achieve tumor eradication. The addition of poly(I:C) further increased the accumulation of granzyme B-expressing effectors within the tumor and resulted in tumor eradication. This strategy presents many of the benefits of whole-body irradiation, including the provision of high levels of homeostatic cytokines, enhanced expansion of effector cells relative to regulatory T cells, and provision of inflammatory cytokines, and is therefore likely to serve as a strategy for both tumor vaccines and adoptive immunotherapy of cancer.CD8 T cells ͉ cytokine complexes ͉ interleukin-2 ͉ TLR ͉ tumor immunity A ctivation of T cells by chronically expressed tumor antigens results in tolerance through deletion, anergy, and immunoregulation (1-3). As a result, residual tumor-specific T cells are generally of low avidity or anergic (4, 5). A goal of cancer immunotherapy is to identify immune adjuvants that can activate and amplify these residual low-avidity tumor-reactive T cells. Recent studies have revealed that cytokines of the common ␥ chain receptor family, including IL-2, IL-4, IL-7, and IL-15, promote expansion and survival of CD8 T cells (6). Their receptor is composed of the common ␥ chain (CD132), the ␤ chain (CD122) for IL-2 and IL-15, and a cytokine-specific receptor subunit, IL-2R␣ (CD25), IL-4R␣ (CD124), and IL-7R␣ (CD127). Regulated expression of the specific receptor subunits by different T cell subsets determines which cytokines are used for survival and proliferation.IL-2 is commonly used as an adjuvant in immunotherapy protocols (7). In addition to playing a critical role in survival of CD8 T cells, when presented at high levels to antigen-activated CD8 cells, IL-2 can also promote the induction of effector functions, such as granzyme B (gzmB) via STAT5 signaling, thereby functioning as a costimulatory molecule (8). However, controversy about the dual role of IL-2 in enhancing proliferation of both CD8 effector cells and CD4 regulatory T cells (Tregs), both of which express high levels of CD25, has raised some questions about the use of this cytokine in vivo (9). Recent studies have shown that the effect of the cytokine can be amplified and directed more specifically to CD8 cells rather than Tregs if IL-2 is complexed with the mAB S4B6 (10, 11). IL-15 bound to IL-15R␣, its natural ''presenting'' receptors, has been shown to have a similar effect on CD8 memory cells and tumor-infiltrated cells (12)(13)(14), and IL-7/anti-IL-7 mAb comp...

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“…A combination of T-cell-intrinsic and T-cell-extrinsic mechanisms drive the attrition of expanded T cells (1)(2)(3)(4). Proapoptotic signaling receptor CD95 (Fas) regulates the fate of immunocytes, and animals and humans with systemic deficiency of Fas or its ligand (FasL) have been shown to develop lymphoproliferative diseases (5)(6)(7)(8).…”

mentioning

confidence: 99%

Loss of the death receptor CD95 (Fas) expression by dendritic cells protects from a chronic viral infection

Varanasi¹,

Khan

Chervonsky³

2014

Proc. Natl. Acad. Sci. U.S.A.

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Chronic viral infections incapacitate adaptive immune responses by "exhausting" virus-specific T cells, inducing their deletion and reducing productive T-cell memory. Viral infection rapidly induces death receptor CD95 (Fas) expression by dendritic cells (DCs), making them susceptible to elimination by the immune response. Lymphocytic choriomeningitis virus (LCMV) clone 13, which normally establishes a chronic infection, is rapidly cleared in C57Black6/J mice with conditional deletion of Fas in DCs. The immune response to LCMV is characterized by an extended survival of virus-specific effector T cells. Moreover, transfer of Fas-negative DCs from noninfected mice to preinfected animals results in either complete clearance of the virus or a significant reduction of viral titers. Thus, DC-specific Fas expression plays a role in regulation of antiviral responses and suggests a strategy for stimulation of T cells in chronically infected animals and humans to achieve the clearance of persistent viruses.

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Apoptosis in Activated T Cells – What Are the Triggers, and What the Signal Transducers?

Cited by 24 publications

References 49 publications

Puma, a critical mediator of cell death — one decade on from its discovery

Puma, a critical mediator of cell death — one decade on from its discovery

Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy

Loss of the death receptor CD95 (Fas) expression by dendritic cells protects from a chronic viral infection

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