Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T lymphocyte survival, proliferation, and death in the periphery are dependent on several cytokines. Many of these cytokines induce the expression of suppressor of cytokine signaling-1 (SOCS1), a feedback inhibitor of JAK kinases. However, it is unclear whether the cytokines that regulate T lymphocyte homeostasis are critically regulated by SOCS1 in vivo. Using SOCS1(-/-)IFN-gamma(-/-) mice we show that SOCS1 deficiency causes a lymphoproliferative disorder characterized by decreased CD4/CD8 ratio due to chronic accumulation of CD8+CD44(high) memory phenotype T cells. SOCS1-deficient CD8+ T cells express elevated levels of IL-2Rbeta, show increased proliferative response to IL-15 and IL-2 in vitro, and undergo increased bystander proliferation and vigorous homeostatic expansion in vivo. Sorted CD8+CD44(high) T cells from SOCS1(-/-)IFN-gamma(-/-) mice respond 5 times more strongly than control cells, indicating that SOCS1 is a critical regulator of IL-15R signaling. Consistent with this idea, IL-15 stimulates sustained STAT5 phosphorylation in SOCS1-deficient CD8+ T cells. IL-15 strongly induces TNF-alpha production in SOCS1-deficient CD8+ T cells, indicating that SOCS1 is also a critical regulator of CD8+ T cell activation by IL-15. However, IL-15 and IL-2 induce comparable levels of Bcl-2 and Bcl-x(L) in SOCS1-deficient and SOCS1-sufficient CD8+ T cells, suggesting that cytokine receptor signals required for inducing proliferation and cell survival signals are not identical. These results show that SOCS1 differentially regulates common gamma-chain cytokine signaling in CD8+ T cells and suggest that CD8+ T cell homeostasis is maintained by distinct mechanisms that control cytokine-mediated survival and proliferation signals.
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PMID:Suppressor of cytokine signaling 1 regulates IL-15 receptor signaling in CD8+CD44high memory T lymphocytes. 1292 91

We analyzed regulation of the prosurvival Bcl-2 homologue A1, following T-cell receptor (TCR) or cytokine receptor engagement. Activation of CD4(+) or CD8(+) T cells by antigenic peptides induced an early but transient IL-2-independent expression of A1 and Bcl-xl mRNA and proteins, whereas expression of Bcl-2 was delayed and required IL-2. Cytokines such as IL-2, IL-4, IL-7 or IL-15 prevented apoptosis of activated T cells that effect being associated with the maintenance of Bcl-2, but not of A1 expression. However, restimulation of activated or posteffector T cells with antigenic peptide strongly upregulated A1 mRNA and maintained A1 protein expression. IL-4, IL-7 or IL-15 also prevented cell death of naive T cells. In those cells, cytokines upregulated Bcl-2, but not A1 expression. Therefore, in naive, activated and posteffector T cells, expression of A1 is dependent on TCR but not on cytokine receptor engagement, indicating that A1 is differently regulated from Bcl-xl and Bcl-2.
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PMID:A1/Bfl-1 expression is restricted to TCR engagement in T lymphocytes. 1293 80

The mechanism of induction of apoptosis by double-stranded RNA (dsRNA) is not fully characterized. The dsRNA is normally present in extremely low quantities in cells, but following infection with RNA viruses, large quantities of the dsRNA viral replicative intermediate may be produced triggering the antiviral response as well as cell death. In this report, transfection of polyinosinic-polycytidylic acid [poly(I:C)] into NIT 1 cells has been used as a model of intracellular dsRNA-induced beta-cell apoptosis. At 18 h post transfection, 45% of the cells were apoptotic as indicated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining, and this was accompanied by an increase in nuclear factor kappaB (NF-kappaB) p50/p65 nuclear translocation and cleavage of caspases 3 and 8. The NF-kappaB inhibitor peptide, SN50, significantly reduced caspase-3 activity and the percentage of TUNEL-positive cells, substantiating a role for NF-kappaB in inducing intracellular dsRNA-mediated apoptosis. Concomitantly, RNA-dependent protein kinase activity was observed at 3 h post transfection along with phosphorylation and degradation of inhibitory kappaB-alpha. Expression of TRAIL (TNF-related apoptosis-inducing ligand), Fas, IL-15, and caspase-12 mRNAs was up-regulated in the presence of poly(I:C) but not when SN50 was also added. In contrast, there was no change detected in Fas, Fas-associated death domain, Bcl-2, Bcl-xl, Bax, p53, or XIAP(X-linked inhibitor of apoptosis protein) expression up to 12 h after poly(I:C) transfection. In addition, caspase-12 was cleaved, and phosphorylation of eukaryotic initiation factor 2alpha occurred, suggesting that an endoplasmic reticulum stress pathway was involved in addition to NF-kappaB induction of an extrinsic pathway, possibly mediated by TNF-related apoptosis-inducing ligand.
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PMID:Nuclear factor-kappaB translocation mediates double-stranded ribonucleic acid-induced NIT-1 beta-cell apoptosis and up-regulates caspase-12 and tumor necrosis factor receptor-associated ligand (TRAIL). 1296 48

Human-virus-specific CD8+ T cells that are found during primary infection have been studied almost exclusively in the peripheral blood, and it is unclear whether these cells are regulated in the same way as those in secondary lymphoid tissue. We investigated, therefore, the control of apoptosis and telomere erosion of Epstein-Barr virus (EBV)-specific CD8+ T cells found in the blood and tonsils of the same patients during acute infectious mononucleosis (AIM). Although the clonal composition of CD8+ T cells as determined by heteroduplex analysis was similar in both compartments, there was greater CD28 expression in the tonsil population, indicating that they were less differentiated. EBV-specific CD8+ T cells in both tissue types were extremely susceptible to apoptosis related to low Bcl-2 expression and were dependent on exogenous cytokines such as interleukin-2 (IL-2), IL-15, and interferon-alpha/beta (IFN-alpha/beta) for survival. In both compartments, however, these cells maintained their telomere lengths through telomerase induction. Thus, apoptosis-prone EBV-specific CD8+ T cells found during acute infection have to be rescued from death to persist as a memory population. However, signals that induce telomerase ensure that the rescued cells retain their replicative capacity. Significantly, these processes operate identically in cells found in blood and secondary lymphoid tissue.
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PMID:Integration of apoptosis and telomere erosion in virus-specific CD8+ T cells from blood and tonsils during primary infection. 1296 61

An important prerequisite in using regulatory T cells for immunotherapy is their ex vivo expansion without loss of suppressor function. Human anergic regulatory T cells are expandable by Ag-specific stimulation in the presence of IL-2. IL-15, like IL-2, is a T cell growth factor that, in contrast to IL-2, stimulates survival of T cells. In this study, we examined whether IL-15 could be exploited as a superior growth factor of human CD4(+) anergic regulatory T cells that were generated by costimulation blockade. Next, IL-15, as compared with IL-2, was investigated with respect to expansion and function of these regulatory T cells. Optimal expansion required cognate allogeneic stimulation in the presence of exogenous IL-15. IL-15 resulted in enhanced survival that was paralleled by an increased number of Bcl-2-expressing cells. Moreover, IL-15 induced a distinct type of anergy characterized by hyperreactivity to IL-15, resulting in improved expansion. This is likely attributed to increased propensity of these cells to up-regulate both alpha- and gamma-chains of the IL-2 and IL-15 receptor. Notably, IL-15-expanded regulatory CD4(+) T cells suppressed both naive and memory T cells in a superior way. Immunosuppression required alloantigen-specific stimulation and appeared gamma-irradiation resistant and independent of IL-10, TGFbeta, or CTLA-4 interactions. These regulatory T cells were stable suppressors, mediating bystander suppression upon TCR stimulation, but leaving recall responses unaffected in the absence of cognate Ag. Finally, human naturally occurring regulatory CD4(+)CD25(+) T cells appeared important in generating regulatory T cells by costimulation blockade. In conclusion, IL-15-expanded, de novo-induced human anergic regulatory CD4(+) T cells are of interest in Ag-specific immunotherapy.
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PMID:IL-15 and cognate antigen successfully expand de novo-induced human antigen-specific regulatory CD4+ T cells that require antigen-specific activation for suppression. 1466 42

To evaluate the in vivo effect of immunosuppressive glucocorticoids on CD4+CD25+ T regulatory cells, we injected dexamethasone (Dex) into BALB/c mice. Administration of Dex enhanced the proportion of CD4+CD25+ cells and the ratio of CD4+CD25+ cells to CD4+CD25- cells in the lymphoid organs, especially in the thymus. This correlates with our in vitro observation that CD4+CD25+ T cells express higher levels of glucocorticoid receptor and Bcl-2, and are therefore more resistant to Dex-mediated cell death than CD4+CD25- T cells. Furthermore, IL-2 selectively protected CD4+CD25+ T cells from Dex-induced cell death, while IL-7 and IL-15 did not exert preferential protective effects. Dex-treated CD4+CD25+ T cells expressed higher levels of intracellular CTLA-4 and surface glucocorticoid-induced TNF receptor than fresh CD4+CD25+ T cells, but still failed to respond to TCR stimulation and inhibited proliferation of CD4+CD25- T cells. These results suggest that, in addition to suppressing cytokine transcription, Dex treatment is permissive for the survival of functional CD4+CD25+ T regulatory cells, and this property may contribute to the anti-inflammatory and immunosuppressive efficacy of glucocorticoids. Our data also suggest that selective protection of CD4+CD25+ T cell from apoptosis may constitute a role in immune tolerance for IL-2.
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PMID:Differential response of murine CD4+CD25+ and CD4+CD25- T cells to dexamethasone-induced cell death. 1499 16

The factors affecting T cell viability vary depending on the type and status of the T cell involved. Naive T cells die via a Bcl-2/Bim dependent route. Their deaths are prevented in animals by IL-7 and contact with MHC. Activated T cells die in many different ways. Among these is a pathway involving signals that come from outside the T cell and affect it via surface receptors such as Fas. Activated T cells also die through a pathway driven by signals generated within the T cell itself, a cell autonomous route. This pathway involves members of the Bcl-2 family, in particular Bcl-2, Bcl-xl, Bim, and probably Bak. The viability of CD8+ and CD4+ memory T cells is controlled in different ways. CD8+ memory T cells are maintained by IL-15 and IL-7. The control of CD4+ memory T cells is more mysterious, with roles reported for IL-7 and/or contact via the TCR.
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PMID:Control of T cell viability. 1503 96

Human immunodeficiency virus-specific CD8(+) T cells are highly sensitive to spontaneous and CD95/Fas-induced apoptosis, and this sensitivity may impair their ability to control HIV infection. To elucidate the mechanism behind this sensitivity, in this study we examined the levels of antiapoptotic molecules Bcl-2 and Bcl-x(L) in HIV-specific CD8(+) T cells from HIV-infected individuals. Bcl-2 expression was markedly decreased in HIV-specific CD8(+) T cells compared with CMV-specific and total CD8(+) T cells from HIV-infected individuals as well as total CD8(+) T cells from healthy donors. CD8(+) T cell Bcl-2 levels inversely correlated with spontaneous and CD95/Fas-induced apoptosis of CD8(+) T cells from HIV-infected individuals. HIV-specific CD8(+) T cells also had significantly lower levels of Bcl-x(L) compared with CMV-specific CD8(+) T cells. Finally, IL-15 induces both Bcl-2 and Bcl-x(L) expression in HIV-specific and total CD8(+) T cells, and this correlated with apoptosis inhibition and increased survival in both short- and long-term cultures. Our data indicate that reduced Bcl-2 and Bcl-x(L) may play an important role in the increased sensitivity to apoptosis of HIV-specific CD8(+) T cells and suggest a possible mechanism by which IL-15 increases their survival.
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PMID:HIV-specific CD8+ T cells exhibit markedly reduced levels of Bcl-2 and Bcl-xL. 1503 60

Correlates of immune reconstitution after highly active antiretroviral therapy (HAART) are not completely understood, in particular as far as viro-immunological discordant responses are concerned. HIV-positive patients on stable HAART for > or = 1 year were recruited. Viro-immunological responses were categorized according to positive or negative area under the curve (AUC) variations for HIV plasma viral load (pVL) and CD4+ T-cell counts measured at least every 4 months. The following parameters were evaluated: lymphocyte spontaneous apoptosis (LSA), intracellular Bcl-2 expression in both CD4-CD45RA+ and CD4-CD45R0+, IL-7 and IL-15 plasma concentrations, and lymphocyte TRECs levels. Sixty-one patients were enrolled. A significant inverse correlation was found between CD4+ T-cell count and pVL AUC (r = 0.45; p = 0.0003). Patients with pVL response had higher levels of Bcl-2 in CD4-CD45R0+ (mean 65,409 MESF vs. 54,018 MESF; p = 0.089) and higher IL-15 (mean 1.34 pg/mL vs. 1.05 pg/mL; p = 0.069, respectively). Higher LSA and lower TRECs levels were found in viro-immunological non-responder patients with respect to those who had viro-immunological response (mean 24.84% vs. 14.89%; p = 0.01, and mean 17,796 copies/10(6) cells vs. 29,251 copies/10(6) cells; p = 0.68, respectively). Virological suppression may allow Bcl-2 and IL-15 hyperexpression during incomplete immune-reconstitution phase, while more complete immune reconstitution appeared to be marked by both high TRECs and low LSA levels, possibly indicating both central and peripheral CD4+ T-cell repopulations at this stage.
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PMID:Immune correlates of virological response in HIV-positive patients after highly active antiretroviral therapy (HAART). 1527 5

Interleukin (IL)-15 plays an important role in the survival of human natural killer (NK) cells. We investigated IL-2/15 signaling in NK cell neoplasms from five patients and in five cell lines (NK-92, KHYG-1, SNK-6, HANK1 and MOTN-1) compared to mature peripheral NK cells from 10 healthy subjects. Apoptosis of NK cell lines was prevented by addition of IL-15 in vitro. Blocking IL-2/15Rbeta on IL-2-stimulated NK-92 cells resulted in reduced expression of Bcl-X(L) and phosphorylated Stat5, which paralleled early apoptosis without altering Bcl-2 expression. These data add IL-2/15Rbeta to the list of factors important for the survival of NK cell neoplasms.
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PMID:Growth and apoptosis of human natural killer cell neoplasms: role of interleukin-2/15 signaling. 1528 13


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