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

Immature CD4/CD8 double-positive (DP) thymocytes expressing self MHC-restricted TCR are positively selected in response to TCR signals to survive and differentiate into functionally competent CD4 or CD8 single positive (SP) T cells. In contrast, DP precursors expressing autoreactive TCR are clonally deleted in response to TCR signals. We show here that in vitro TCR engagement of TCR(low) DP thymocytes rapidly triggers a variety of events considered to be hallmarks of positive selection in vivo. These include increased expression of CD5 and Bcl-2, termination of RAG-1 and pre-T(alpha) gene expression, and a switch in lck promoter usage. We also demonstrate that CD4- or CD28-mediated signals synergize with TCR signals to induce these outcomes. Finally, we show that the response of DP thymocytes to TCR engagement is selective in that clonal deletion, CD4/CD8 lineage commitment, and other events associated with maturation, such as changes in expression of Thy-1, HSA, MHC class I, and CD45-RB, were not induced. Thus, only subsets of maturational processes associated with positive selection in vivo were shown to be directly coupled to TCR signaling pathways at the DP stage. These observations support conclusions from in vivo systems suggesting that multiple, temporally separated TCR engagements are required to effect the entire spectrum of developmental changes associated with positive selection, and provide a conceptual and experimental framework for unraveling the complexity of positive selection.
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PMID:TCR engagement of CD4+CD8+ thymocytes in vitro induces early aspects of positive selection, but not apoptosis. 897 76

Bcl-2 plays a critical role in regulating cell survival and apoptosis. We examined Bcl-2 expression in virus-specific CD8 T cells during the expansion, death, and memory phases of the T cell response following infection of mice with lymphocytic choriomeningitis virus (LCMV). Naive CD8 T cells expressed a basal level of Bcl-2 that was down-regulated in effector CD8 T cells just before the death phase. Bcl-2 levels remained low during the death phase but surviving memory CD8 T cells expressed higher levels of Bcl-2 than naive cells. These changes were shown to occur in LCMV TCR transgenic cells as well as virus-specific CD8 T cells in C57BL/6 and BALB/c mice identified by MHC class I tetramers. In all instances, memory CD8 T cells expressed higher levels of Bcl-2, suggesting that increased Bcl-2 expression plays a role in the long-term maintenance of memory CD8 T cells in vivo.
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PMID:Cutting edge: increased expression of Bcl-2 in antigen-specific memory CD8+ T cells. 1075 84

Following infection with intracellular pathogens, Ag-specific CD8(+) T cells become activated and begin to proliferate. As these cells become activated, they elaborate effector functions including cytokine production and cytolysis. After the infection has been cleared, the immune system returns to homeostasis through apoptosis of the majority of the Ag-specific effector cells. The surviving memory cells can persist for extended periods and provide protection against reinfection. Little is known about the changes in gene expression as Ag-specific cells progress through these stages of development, i.e., naive to effector to memory. Using recombinant MHC class I tetramers, we isolated Ag-specific CD8(+) T cells from mice infected with lymphocytic choriomeningitis virus at various time points and performed semiquantitative RT-PCR. We examined expression of: 1) genes involved in cell cycle control, 2) effector and regulatory functions, and 3) susceptibility to apoptosis. We found that Ag-specific CD8(+) memory T cells contain high steady-state levels of Bcl-2, BAX:, IFN-gamma, and lung Kruppel-like factor (LKLF), and decreased levels of p21 and p27 mRNA. Moreover, the pattern of gene expression between naive and memory cells is distinct and suggests that these two cell types control susceptibility to apoptosis through different mechanisms.
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PMID:Gene expression in antigen-specific CD8+ T cells during viral infection. 1114 52

To elucidate potential roles of IL-15 in the maintenance of memory CD8+ T cells, we followed the fate of Ag-specific CD8+ T cells directly visualized with MHC class I tetramers coupled with listeriolysin O (LLO)(91-99) in IL-15 transgenic (Tg) mice after Listeria monocytogenes infection. The numbers of LLO(91-99)-positive memory CD8+ T cells were significantly higher at 3 and 6 wk after infection than those in non-Tg mice. The LLO(91-99)-positive CD8+ T cells produced IFN-gamma in response to LLO(91-99), and an adoptive transfer of CD8+ T cells from IL-15 Tg mice infected with L. monocytogenes conferred a higher level of resistance against L. monocytogenes in normal mice. The CD44+ CD8+ T cells from infected IL-15 Tg mice expressed the higher level of Bcl-2. Transferred CD44+ CD8+ T cells divided more vigorously in naive IL-15 Tg mice than in non-Tg mice. These results suggest that IL-15 plays an important role in long-term maintenance of Ag-specific memory CD8+ T cells following microbial exposure via promotion of cell survival and homeostatic proliferation.
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PMID:Overexpression of IL-15 in vivo increases antigen-driven memory CD8+ T cells following a microbe exposure. 1180 55

In clinical transplantation host CTL are major effectors of acute rejection, and graft endothelial cells (EC) are major targets of the CTL response. It is unclear what roles CTL will play in pig-into-human xenotransplantation. We compared the mechanisms of killing used by human CTL (huCTL) vs allogeneic and pig xenogeneic EC targets. Both responses show MHC class I restriction of target cell recognition. A granzyme B inhibitor peptide completely blocks anti-human and partially blocks anti-pig responses, while inhibitory Fas ligand Ab only blocks killing of porcine cells despite similar levels of Fas expression in both target cell types. Transduction of Bcl-2 completely protects human EC from huCTL, but has no effect on huCTL-mediated killing of porcine EC despite its efficacy vs drug-induced apoptosis. Bcl-2 effectively protects human EC rendered sensitive to Fas ligand by overexpressing Fas from huCTL, yet fails to protect porcine aortic endothelial cells from huCTL in the presence of anti-Fas ligand Ab. These data reveal differences in the susceptibility of human and porcine targets to huCTL.
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PMID:Porcine endothelial cells, unlike human endothelial cells, can be killed by human CTL via Fas ligand and cannot be protected by Bcl-2. 1247 Nov 17

Several distinct classes of surface receptors can, on ligand binding, transmit signals that modulate the survival, proliferation, and apoptosis of peripheral B, T, and natural killer (NK) cells. At the population level, dynamic changes in lymphocyte cell numbers are strictly regulated to maintain a steady state, a process referred to as homeostasis. Although several studies have investigated the signals that regulate B- and T-cell homeostasis, little is known about the mechanisms that control the survival and proliferation of peripheral NK cells. Using an adoptive transfer system, we have investigated the role of gammac-dependent cytokines, in particular interleukin 7 (IL-7) and IL-15, and major histocompatibility complex (MHC) class I molecules in peripheral NK-cell homeostasis. We observed that IL-15 plays a dominant role in the survival of peripheral NK cells, via maintenance of the antiapoptotic factor Bcl-2. IL-15 availability, however, also plays an important role because endogenous NK cells in the recipient mice influence the behavior of adoptively transferred NK cells. Finally, although NK cells bear functional inhibitory Ly49 receptors for MHC class I molecules, the presence or absence of specific ligands on host cells did not influence the survival or homeostatic expansion of donor NK cells.
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PMID:IL-15 is an essential mediator of peripheral NK-cell homeostasis. 1258 24

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth-promoting factor for myeloid-derived dendritic cells (DC) but not for lymphoid DC. The data about its effect on thymic DC (TDC), which are both of lymphoid and myeloid origin, are very scarce. Using an in vitro model, we demonstrated in this work that GM-CSF significantly increased the survival of rat TDC in culture by inhibiting their apoptosis and the effect correlated with up-regulation of Bcl-2 expression. GM-CSF also stimulated differentiation and maturation of TDC as judged by higher expression of MHC class I and II molecules, CD54, CD80 and CD86. These changes correlated with stronger stimulatory activity of GM-CSF-pulsed TDC in syngeneic thymocyte proliferation assay and MLR. The stimulatory potential of TDC was further increased when thymocytes were cultivated with an anti-alphabeta TCR (R73) monoclonal antibody (mAb). The influence of unstimulated TDC on proliferation of thymocytes was inhibited by anti-CD86 but not anti-CD80 mAb, whereas in cultures with GM-CSF-treated TDC both mAbs exerted an additive blocking effect. After separation of TDC on CD11b(+) and CD11b(-) we demonstrated that GM-CSF inhibited apoptosis and potentiated accessory activity of both TDC subsets independently of the myeloid marker expression. Cummulatively, our results suggest that GM-CSF is one of the regulatory cytokine involved in survival, maturation, differentiation and accessory function of TDC.
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PMID:Granulocyte-macrophage colony stimulating factor is an anti-apoptotic cytokine for thymic dendritic cells and a significant modulator of their accessory function. 1260 Jul 52

CD8(+) T cells are activated by the presentation of antigenic peptide through MHC class I molecules. Newly synthesized proteins formed as defective ribosomal products (DRiPs) can act as a major source of antigenic peptides for MHC class I presentation pathway. Majority of these peptides are generated from the intracellular degradation of self antigens. In the present study, we have shown that newly synthesized T cell receptor (TCR) beta chains formed as DRiPs in T cells are ubiquitinated and degraded by the proteasomes. These TCR-DRiPs are processed and presented by activated T cells to cognate anti-idiotypic CD8(+) T cells. Presentation of TCR idiopeptide (peptide derived from the variable region of idiotypic TCR) by activated T cells leads to Bcl-2 expression and cytokine secretion by anti-idiotypic CD8(+) T cells. Presentation of intracellular antigen by T cells may have important implications in immunoregulation, control of lymphotropic virus infection and autoimmune diseases.
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PMID:Idiotypic T cells specific for Morbillivirus nucleocapsid protein process and present their TCR to cognate anti-idiotypic CD8+ T cells. 1618 24

Naive T cells require costimulation for robust Ag-driven differentiation and survival. Members of the TNFR family have been shown to provide costimulatory signals conferring survival at distinct phases of the T cell response. In this study, we show that CD4 and CD8 T cells depend on TNFR type 2 (p75) for survival during clonal expansion, allowing larger accumulation of effector cells and conferring protection from apoptosis for a robust memory pool in vivo. We demonstrate using the MHC class I-restricted 2C TCR and MHC class II-restricted AND TCR transgenic systems that TNFR2 regulates the threshold for clonal expansion of CD4 and CD8 T cell subsets in response to cognate Ag. Using a novel recombinant Listeria monocytogenes (rLM) expressing a secreted form of the 2C agonist peptide (SIY) to investigate the role of TNFR2 for T cell immunity in vivo, we found that TNFR2 controls the survival and accumulation of effector cells during the primary response. TNFR2-/- CD8 T cells exhibit loss of protection from apoptosis that is correlated with diminished survivin and Bcl-2 expression. Null mutant mice were more susceptible to rLM-SIY challenge at high doses of primary infection, correlating with impaired LM-specific T cell response in the absence of TNFR2-mediated costimulation. Moreover, the resulting memory pools specific for SIY and listeriolysin O epitopes derived from rLM-SIY were diminished in TNFR2-/- mice. Thus, examination of Ag-driven T cell responses revealed a hitherto unknown costimulatory function for TNFR2 in regulating T cell survival during the differentiation program elicited by intracellular pathogen in vivo.
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PMID:TNF receptor type 2 (p75) functions as a costimulator for antigen-driven T cell responses in vivo. 1639 90

Allografts transplanted across ABO incompatibility or human leucocyte antigen (HLA)-sensitization undergoes antibody (Ab) mediated hyperacute rejection. Depleting anti-graft Ab from the recipient by plasmapheresis prior to transplantation can prevent this Ab-mediated rejection. Under these conditions, allografts have been shown to function even when the Ab rebound in the recipients. We have developed an in vitro model using human aortic endothelial cells (EC) and elucidated the ability of W6/32 HLA class I monoclonal Ab to provide signals following binding to MHC class I molecules. Using this model, we show that ECs undergo caspase 3-dependent cell death by apoptosis upon exposure to saturating concentrations of W6/32 and complement. In contrast, exposure of ECs to sub-saturating concentrations of W6/32 conferred resistance towards Ab/complement-mediated lysis that has been termed accommodation. Accommodated ECs exhibited a significant increase in the expression of anti-apoptotic genes Bcl-xL, Bcl-2 and Heme Oxygenase-1 and the induction of Phosphatidylinositol 3 kinase (PI3K) and cyclic adenosine monophosphate (cAMP) dependent protein kinase A activities that facilitate the phosphorylation of Bad at positions Ser(136) and Ser(112). In conclusion, exposure of sub-saturating concentrations of HLA class I Ab results in the induction of signals downstream that confers resistance to endothelial cells against Ab-complement mediated cell death. Together, the observations made in this study will provide the basis for delineating the molecular mechanisms involved in mediating accommodation and developing strategies to induce accommodation in grafts prior to transplantation in highly sensitized patients.
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PMID:HLA class I antibody mediated accommodation of endothelial cells via the activation of PI3K/cAMP dependent PKA pathway. 1643 Dec 85


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