Extracellular Nicotinamide Adenine Dinucleotide Induces T Cell Apoptosis In Vivo and In Vitro

Abstract Our recent studies have shown that immune cell–produced complement provides costimulatory and survival signals to naive CD4+ T cells. Whether these signals are similarly required during effector cell expansion and what molecular pathways link locally produced complement to T-cell survival were not clarified. To address this, we stimulated monoclonal and polyclonal T cells in vitro and in vivo with antigen-presenting cells (APCs) deficient in the complement regulatory protein, decay accelerating factor (DAF), and/or the complement component C3. We found that T-cell expansion induced by DAF-deficient APCs was augmented with diminished T-cell apoptosis, whereas T-cell expansion induced by C3−/− APCs was reduced because of enhanced T-cell apoptosis. These effects were traced to locally produced C5a, which through binding to T cell–expressed C5aR, enhanced expression of Bcl-2 and prevented Fas up-regulation. The results show that C5aR signal transduction in T cells is important to allow optimal T-cell expansion, as well as to maintain naive cell viability, and does so by suppressing programmed cell death.

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Capecitabine Can Induce T Cell Apoptosis: A Potential Immunosuppressive Agent With Anti-Cancer Effect

Frontiers in Immunology ◽

10.3389/fimmu.2021.737849 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sai Zhang ◽

Zhenglu Wang ◽

Shunli Fan ◽

Tao Liu ◽

Sei Yoshida ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Cell Apoptosis ◽

Immunosuppressive Agent ◽

Bone Marrow Tissue ◽

T Cell Apoptosis ◽

Anti Cancer

Capecitabine (CAP) is now widely used in the comprehensive treatment of digestive system tumors. Some clinical observations have shown that CAP may have immunosuppressive effects, but there is still a lack of clear experimental verification. In this study, different doses of CAP were administered to normal mice by gavage. Our results confirmed that CAP did not cause myelosuppression in bone marrow tissue; CAP selectively reduced the proportion of T cells and the concentration of related pro-inflammatory cytokines, while it increased the concentration of anti-inflammatory cytokines. Thymidylate phosphorylase (TP) is the key enzyme for the transformation of CAP in vivo; this study confirmed that T cells express TP, but the bone marrow tissue lacks TP expression, which explains the selectivity in pharmacodynamic effects of CAP. In addition, it was confirmed that CAP can induce T cell apoptosis in vivo and in vitro. In vitro experiments showed that CAP-induced T cell apoptosis was related to TP expression, endoplasmic reticulum stress (ERS) induction, reactive oxygen species (ROS) production, and mitochondria-mediated apoptosis activation. Therefore, this study confirmed that the differential expression of TP in cells and tissues explains why CAP avoids the toxic effects of myelosuppression while inducing T cell apoptosis to exert the immunosuppressive effect. Therefore, CAP may become an immunosuppressive agent with a simultaneous anti-cancer effect, which is worthy of further studies.

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Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors

Biochemical Journal ◽

10.1042/bj20050698 ◽

2005 ◽

Vol 392 (1) ◽

pp. 135-143 ◽

Cited By ~ 52

Author(s):

Yu Yang ◽

Zeyu Xiong ◽

Sheng Zhang ◽

Yan Yan ◽

Justin Nguyen ◽

...

Keyword(s):

Growth Factors ◽

T Cell ◽

Cell Apoptosis ◽

Sars Coronavirus ◽

T Cell Apoptosis ◽

E Protein ◽

Domain 3 ◽

Induced Apoptosis

One of the hallmark findings in patients suffering from SARS (severe acute respiratory syndrome) is lymphopenia, which is the result of massive lymphocyte death. SARS-CoV (SARS coronavirus), a novel coronavirus that has been etiologically associated with SARS cases, is homologous with MHV (murine hepatitis coronavirus), and MHV small envelope E protein is capable of inducing apoptosis. We hypothesized that SARS-CoV encodes a small envelope E protein that is homologous with MHV E protein, thus inducing T-cell apoptosis. To test this hypothesis, a cDNA encoding SARS-CoV E protein was created using whole gene synthesis. Our results showed that SARS-CoV E protein induced apoptosis in the transfected Jurkat T-cells, which was amplified to higher apoptosis rates in the absence of growth factors. However, apoptosis was inhibited by overexpressed antiapoptotic protein Bcl-xL. Moreover, we found that SARS-CoV E protein interacted with Bcl-xL in vitro and endogenous Bcl-xL in vivo and that Bcl-xL interaction with SARS-CoV E protein was mediated by BH3 (Bcl-2 homology domain 3) of Bcl-xL. Finally, we identified a novel BH3-like region located in the C-terminal cytosolic domain of SARS-CoV E protein, which mediates its binding to Bcl-xL. These results demonstrate, for the first time, a novel molecular mechanism of T-cell apoptosis that contributes to the SARS-CoV-induced lymphopenia observed in most SARS patients.

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Functional relevance of the multi-drug transporter abcg2 on teriflunomide therapy in an animal model of multiple sclerosis

Journal of Neuroinflammation ◽

10.1186/s12974-019-1677-z ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Lisa Thiele née Schrewe ◽

Kirsten Guse ◽

Silvia Tietz ◽

Jana Remlinger ◽

Seray Demir ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

T Cells ◽

T Cell ◽

Cell Apoptosis ◽

Multi Drug Resistance ◽

T Cell Apoptosis ◽

Functional Relevance

Abstract Background The multi-drug resistance transporter ABCG2, a member of the ATP-binding cassette (ABC) transporter family, mediates the efflux of different immunotherapeutics used in multiple sclerosis (MS), e.g., teriflunomide (teri), cladribine, and mitoxantrone, across cell membranes and organelles. Hence, the modulation of ABCG2 activity could have potential therapeutic implications in MS. In this study, we aimed at investigating the functional impact of abcg2 modulation on teri-induced effects in vitro and in vivo. Methods T cells from C57BL/6 J wild-type (wt) and abcg2-knockout (KO) mice were treated with teri at different concentrations with/without specific abcg2-inhibitors (Ko143; Fumitremorgin C) and analyzed for intracellular teri concentration (HPLC; LS-MS/MS), T cell apoptosis (annexin V/PI), and proliferation (CSFE). Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6J by active immunization with MOG35–55/CFA. Teri (10 mg/kg body weight) was given orally once daily after individual disease onset. abcg2-mRNA expression (spinal cord, splenic T cells) was analyzed using qRT-PCR. Results In vitro, intracellular teri concentration in T cells was 2.5-fold higher in abcg2-KO mice than in wt mice. Teri-induced inhibition of T cell proliferation was two fold increased in abcg2-KO cells compared to wt cells. T cell apoptosis demonstrated analogous results with 3.1-fold increased apoptosis after pharmacological abcg2-inhibition in wt cells. abcg2-mRNA was differentially regulated during different phases of EAE within the central nervous system and peripheral organs. In vivo, at a dosage not efficacious in wt animals, teri treatment ameliorated clinical EAE in abcg2-KO mice which was accompanied by higher spinal cord tissue concentrations of teri. Conclusion Functional relevance of abcg2 modulation on teri effects in vitro and in vivo warrants further investigation as a potential determinant of interindividual treatment response in MS, with potential implications for other immunotherapies.

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Rapid Induction of Naive T Cell Apoptosis by Ecto-Nicotinamide Adenine Dinucleotide: Requirement for Mono(ADP-Ribosyl)Transferase 2 and a Downstream Effector

The Journal of Immunology ◽

10.4049/jimmunol.167.1.196 ◽

2001 ◽

Vol 167 (1) ◽

pp. 196-203 ◽

Cited By ~ 49

Author(s):

Sahil Adriouch ◽

Wiebke Ohlrogge ◽

Friedrich Haag ◽

Friedrich Koch-Nolte ◽

Michel Seman

Keyword(s):

T Cell ◽

Nicotinamide Adenine Dinucleotide ◽

Cell Apoptosis ◽

Nicotinamide Adenine ◽

T Cell Apoptosis ◽

Rapid Induction ◽

Downstream Effector ◽

Naïve T Cell ◽

Naive T Cell

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TDAG51 Is Not Essential for Fas/CD95 Regulation and Apoptosis In Vivo

Molecular and Cellular Biology ◽

10.1128/mcb.21.24.8365-8370.2001 ◽

2001 ◽

Vol 21 (24) ◽

pp. 8365-8370 ◽

Cited By ~ 28

Author(s):

Jaerang Rho ◽

Shiaoching Gong ◽

Nacksung Kim ◽

Yongwon Choi

Keyword(s):

T Cell ◽

Cell Apoptosis ◽

Northern Blotting ◽

Lymphoid Organs ◽

Developmental Abnormalities ◽

T Cell Apoptosis ◽

Secondary Lymphoid Organs

ABSTRACT Fas/CD95 is a key regulator of apoptotic signaling, which is crucial for the maintenance of homeostasis in peripheral lymphoid organs. TDAG51 has been shown to play critical roles in the up-regulation of Fas gene expression and T-cell apoptosis in vitro. In order to identify the role of TDAG51 in vivo, we generated TDAG51-deficient (TDAG51−/−) mice. Northern blotting revealed no expression of TDAG51 in TDAG51−/− mice, indicating that the TDAG51 gene was successfully targeted. TDAG51−/− mice were healthy and showed no gross developmental abnormalities. While Fas-deficient mice display marked lymphadenopathy, splenomegaly, and lymphocytosis, TDAG51−/− mice had no apparent defects in secondary lymphoid organs. Although TDAG51 is required for up-regulation of Fas expression in T-cell hybridomas, TDAG51−/− mice expressed normal levels of Fas and had normal T-cell apoptosis. Therefore, we conclude that TDAG51 is not essential for Fas up-regulation and T-cell apoptosis in vivo. There are several known homologs of TDAG51, and these homologs may substitute for TDAG51 in TDAG51−/−mice.

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SATB1 Cleavage by Caspase 6 Disrupts PDZ Domain-Mediated Dimerization, Causing Detachment from Chromatin Early in T-Cell Apoptosis

Molecular and Cellular Biology ◽

10.1128/mcb.21.16.5591-5604.2001 ◽

2001 ◽

Vol 21 (16) ◽

pp. 5591-5604 ◽

Cited By ~ 85

Author(s):

Sanjeev Galande ◽

Liliane A. Dickinson ◽

I. Saira Mian ◽

Marianna Sikorska ◽

Terumi Kohwi-Shigematsu

Keyword(s):

T Cell ◽

Dna Binding ◽

Cell Apoptosis ◽

Pdz Domain ◽

Dna Binding Domains ◽

T Cell Apoptosis ◽

Binding Domains ◽

Caspase 6 ◽

Loop Domains

ABSTRACT SATB1 is expressed primarily in thymocytes and orchestrates temporal and spatial expression of a large number of genes in the T-cell lineage. SATB1 binds to the bases of chromatin loop domains in vivo, recognizing a special DNA context with strong base-unpairing propensity. The majority of thymocytes are eliminated by apoptosis due to selection processes in the thymus. We investigated the fate of SATB1 during thymocyte and T-cell apoptosis. Here we show that SATB1 is specifically cleaved by a caspase 6-like protease at amino acid position 254 to produce a 65-kDa major fragment containing both a base-unpairing region (BUR)-binding domain and a homeodomain. We found that this cleavage separates the DNA-binding domains from amino acids 90 to 204, a region which we show to be a dimerization domain. The resulting SATB1 monomer loses its BUR-binding activity, despite containing both its DNA-binding domains, and rapidly dissociates from chromatin in vivo. We found this dimerization region to have sequence similarity to PDZ domains, which have been previously shown to be involved in signaling by conferring protein-protein interactions. SATB1 cleavage during Jurkat T-cell apoptosis induced by an anti-Fas antibody occurs concomitantly with the high-molecular-weight fragmentation of chromatin of ∼50-kb fragments. Our results suggest that mechanisms of nuclear degradation early in apoptotic T cells involve efficient removal of SATB1 by disrupting its dimerization and cleavage of genomic DNA into loop domains to ensure rapid and efficient disassembly of higher-order chromatin structure.

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Tumor-Related Exosomes Contribute to Tumor-Promoting Microenvironment: An Immunological Perspective

Journal of Immunology Research ◽

10.1155/2017/1073947 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 28

Author(s):

Wuzhen Chen ◽

Jingxin Jiang ◽

Wenjie Xia ◽

Jian Huang

Keyword(s):

T Cell ◽

Cell Activation ◽

Nk Cell ◽

Immune Surveillance ◽

Suppressor Cells ◽

Effector T Cell ◽

T Cell Apoptosis ◽

And Function

Exosomes are a kind of cell-released membrane-form structures which contain proteins, lipids, and nucleic acids. These vesicular organelles play a key role in intercellular communication. Numerous experiments demonstrated that tumor-related exosomes (TEXs) can induce immune surveillance in the microenvironment in vivo and in vitro. They can interfere with the maturation of DC cells, impair NK cell activation, induce myeloid-derived suppressor cells, and educate macrophages into protumor phenotype. They can also selectively induce effector T cell apoptosis via Fas/FasL interaction and enhance regulatory T cell proliferation and function by releasing TGF-β. In this review, we focus on the TEX-induced immunosuppression and microenvironment change. Based on the truth that TEXs play crucial roles in suppressing the immune system, studies on modification of exosomes as immunotherapy strategies will also be discussed.

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Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis

Journal of Experimental Medicine ◽

10.1084/jem.20082851 ◽

2009 ◽

Vol 206 (7) ◽

pp. 1515-1523 ◽

Cited By ~ 33

Author(s):

Divya Purushothaman ◽

Apurva Sarin

Keyword(s):

T Cells ◽

T Cell ◽

Nadph Oxidase ◽

Cell Apoptosis ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Activated T Cells ◽

T Cell Apoptosis ◽

Mitochondrial Superoxide ◽

Activated T Cell

Cellular dependence on growth factors for survival is developmentally programmed and continues in adult metazoans. Antigen-activated T cell apoptosis in the waning phase of the immune response is thought to be triggered by depletion of cytokines from the microenvironment. T cell apoptosis resulting from cytokine deprivation is mediated by reactive oxygen species (ROS), but their source and position in the apoptotic cascade is poorly understood. RNA interference approaches implicated the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in neglect-induced apoptosis in T cells. Using mice deficient for the catalytic subunit gp91phox to characterize the molecular link to activated T cell apoptosis, we show that gp91phox-deficient T (T−/−) cells generated mitochondrial superoxide but had diminished hydrogen peroxide production in response to neglect, which, in turn, regulated Jun N-terminal kinase–dependent Bax activation and apoptosis. Activated T−/− cells were distinguished by improved survival after activation by superantigens in vivo, adoptive transfers into congenic hosts, and higher recall responses after immunization. Thus, the NADPH oxidase may regulate adaptive immunity in addition to its previously well-characterized role in the innate response.

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