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)

In this paper we compare survival characteristics of transgenic and polyclonal CD4 and CD8 T cells. Transgenic CD4 T cells have an intrinsically lower capacity for survival, reflected in their gradual disappearance in thymectomized hosts, their increased sensitivity to apoptosis in vitro, and fewer divisions during homeostatic proliferation upon transfer into syngeneic lymphopenic hosts compared with CD8 T cells. Homeostatic proliferation, however, does not generally result in phenotypic conversion of activation markers unless cognate or cross-reactive Ag is present. T cells from the A18 TCR transgenic strain normally selected into the CD4 lineage are fragile as CD4 T cells, yet display the typical robust survival pattern of CD8 T cells when diverted into the CD8 lineage in a CD4-deficient host. Polyclonal CD4 and CD8 T cells also show distinctive patterns of survival, emphasizing that survival signals are relayed differently in the two lymphocyte subpopulations. However, expression levels of Bcl-2 in either transgenic or polyclonal naive CD4 and CD8 T cells are similar, excluding a role for this molecule as a key factor in differential survival of CD4 vs CD8 T cells.
 ...
PMID:Differential survival of naive CD4 and CD8 T cells. 1103 73

The molecular events triggered by MHC recognition and how they lead to the emergence of mature CD4 and CD8 lineage thymocytes are not yet understood. To address these questions, we have examined what signals are necessary to drive the development of CD8 lineage thymocytes in TCRalpha(-) mice in which TCR/MHC engagement cannot occur. We find that the combination of constitutive Notch activity and constitutive Bcl-2 expression are necessary and sufficient to allow the appearance of mature CD8 lineage thymocytes in TCRalpha(-) mice. In addition, Notch activity alone in TCRalpha(-) mice can induce the up-regulation of HES1, suggesting that thymocytes are competent to respond to Notch signaling in the absence of MHC recognition. These data indicate that survival and lineage commitment represent distinct, parallel pathways that occur as a consequence of MHC recognition, both of which are necessary for the development of mature CD8 lineage T cells.
 ...
PMID:MHC recognition in thymic development: distinct, parallel pathways for survival and lineage commitment. 1112 Jul 88

Immature double-positive (DP) thymocytes mature into CD4(+)CD8(-) cells in response to coengagement of TCR with any of a variety of cell surface "coinducer" receptors, including CD2. In contrast, DP thymocytes are signaled to undergo apoptosis by coengagement of TCR with CD28 costimulatory receptors, but the molecular basis for DP thymocyte apoptosis by TCR plus CD28 coengagement is not known. In the present study, we report that TCR plus CD28 coengagement does not invariably induce DP thymocyte apoptosis but, depending on the intensity of CD28 costimulation, can induce DP thymocyte maturation. We demonstrate that distinct but interacting signal transduction pathways mediate DP thymocyte maturation signals and DP thymocyte apoptotic signals. Specifically, DP maturation signals are transduced by the extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and up-regulate expression of the antiapoptotic protein Bcl-2. In contrast, the apoptotic response stimulated by CD28 costimulatory signals is mediated by ERK/MAPK-independent pathways. Importantly, when TCR-activated thymocytes are simultaneously coengaged by both CD28 and CD2 receptors, CD28 signals can inhibit ERK/MAPK-dependent Bcl-2 protein up-regulation. Thus, there is cross-talk between the signal transduction pathways that transduce apoptotic and maturation responses, enabling CD28-initiated signal transduction pathways to both stimulate DP thymocyte apoptosis and also negatively regulate maturation responses initiated by TCR plus CD2 coengagement.
 ...
PMID:Maturation versus death of developing double-positive thymocytes reflects competing effects on Bcl-2 expression and can be regulated by the intensity of CD28 costimulation. 1120 5

Protein kinase C (PKC)-activating phorbol esters protect T cells from Fas-induced apoptosis. However, the mechanism of this protective effect and the identity of the relevant PKC isoform(s) are poorly understood. Here, we show that PKCtheta plays a selective and important role in this protection. Fas triggering led to a selective caspase-3-dependent cleavage of the enzyme and proteasome-mediated degradation and inactivation of its catalytic fragment. These events preceded the onset of apoptosis. Pharmacological inhibition of PKCtheta promoted Fas-mediated apoptosis in three different types of T cells. Conversely, constitutively active PKCtheta (and, to a lesser degree, PKCepsilon) selectively protected T cells from Fas-induced apoptosis. We provide evidence that the distant Bcl-2 family member, BAD, is a PKCtheta substrate, is phosphorylated by TCR stimulation, and can mediate at least in part the anti-apoptotic effect of PKCtheta.
 ...
PMID:Protein kinase C-theta mediates a selective T cell survival signal via phosphorylation of BAD. 1134 10

Mice lacking IFN-regulatory factor (IRF)-1 have reduced numbers of mature CD8+ T cells within the thymus and peripheral lymphoid organs, suggesting a critical role of IRF-1 in CD8(+) T cell differentiation. Here we show that endogenous Bcl-2 expression is substantially reduced in IRF-1(-/-)CD8+ thymocytes and that introduction of a human Bcl-2 transgene driven by Emu or lck promoter in IRF-1(-/-) mice restores the CD8(+) T cell development. Restored CD8+ T cells are functionally mature in terms of allogeneic MLR and cytokine production. In contrast to thymus-derived CD8+ T cells, other lymphocyte subsets including NK, NK T, and TCR-gammadelta(+) intestinal intraepithelial lymphocytes, which are also impaired in IRF-1(-/-) mice, are not rescued by expressing human Bcl-2. Our results indicate that IRF-1 differentially regulates the development of these lymphocyte subsets and that survival signals involving Bcl-2 are critical for the development of thymus-dependent CD8+ T cells.
 ...
PMID:Overexpression of Bcl-2 differentially restores development of thymus-derived CD4-8+ T cells and intestinal intraepithelial T cells in IFN-regulatory factor-1-deficient mice. 1135 1

We transferred naive alloreactive CD8 T cells from TCR transgenic mice to irradiated recipients expressing a partial (H-2Kbm8) or a full (H-2Kb) agonist alloantigen (alloAg). The consequences were strikingly distinct, resulting in acceleration of host lymphopoiesis in the former group, but in strong graft-vs-host reaction, preventing host lymphocyte reconstitution in the latter group. This was correlated, respectively, with long-term persistence and with rapid disappearance of the transferred CD8 T cells. Analysis of transferred T cells showed that initial T cell expansion and modulation of expression of activation markers CD44 and CD62L, as well as induction of cytotoxic function, were similar in both groups. However, IL-2 production and subsequent up-regulation of CD25, early perforin-independent cytolysis, and early down-regulation of Bcl-2 expression were detected only in T cells transferred in hosts expressing full agonist alloAg. Expansion of transferred CD8 T cells was not dependent on either IL-2 or CD25 expression. This expansion could lead to either accelerated host reconstitution or to strong graft-vs-host, depending on the nature of the alloAg. Thus, the extent of Ag stimulation may be a crucial parameter in protocols of alloreactive T cell immunotherapy.
 ...
PMID:Differential survival of transferred CD8 T cells and host reconstitution depending on TCR avidity for host-expressed alloantigen. 1139 Apr 68

IL-7 and IL-15 play important roles in gammadelta T cell development. These receptors transmit proliferation and/or survival signals in gammadelta T cells. In addition, the IL-7R promotes recombination and transcription in the TCR gamma locus. To clarify the role of the cytokine receptors in the development of epidermal gammadelta T cells, we introduced a Vgamma3/Vdelta1 TCR transgene, derived from Thy-1+ dendritic epidermal T cells (DETC), into IL-7Ralpha-deficient mice, and we found that they partly rescued gammadelta T cells in the adult thymus but not in the spleen. Introduction of an additional Bcl-2 transgene had a minimal effect on gammadelta T cells in the adult thymus of these mice. In contrast to the adult thymus, the introduction of the Vgamma3/Vdelta1 TCR transgene into IL-7Ralpha-/- mice completely restored Vgamma3+ T cells in the fetal thymus and DETC in the adult skin. On the contrary, the same Vgamma3/Vdelta1 TCR transgene failed to rescue DETC in the skin of IL-2Rbeta-deficient mice, even with the additional Bcl-2 transgene. These results suggest that the IL-2/IL-15R, rather than the IL-7R, plays an essential role in proliferation and survival of DETC in the fetal thymus and the skin. In contrast, the IL-7R is probably essential in the induction of V-J recombination of TCRgamma genes. Thus, this study proves that IL-7R and IL-2/IL-15R serve differential functions in epidermal gammadelta T cell development.
 ...
PMID:Differential roles of cytokine receptors in the development of epidermal gamma delta T cells. 1148 72

Mitochondria play a central role in many apoptotic reactions. Although mitochondrial apoptotic changes and caspase activation have been demonstrated in the apoptotic thymocytes, cell death signal through mitochondria in TCR-stimulated thymocytes has not been fully understood. In this study, we show that TCR stimulation induced disruption of mitochondrial transmembrane potential (Delta Psi(m)), the cytochrome c release from mitochondira, capase-3 activation, and the cell death of thymocytes. Bongkrekic acid, an inhibitor of Delta Psi(m) disruption, blocked the cytochrome c release from mitochondria and the following caspase-3-mediated cell death. Furthermore, a pro-apoptotic Bcl-2 family protein, Bax, but not Bad or Bid, was translocated from cytosol to mitochondria in TCR-stimulated thymocytes. This translocation and the following apoptotic changes were inhibited by SB203580, a p38 kinase inhibitor, in a specific manner. These results suggest that activated p38 kinase pathway by TCR stimulation induces translocation of Bax to mitochondria, causing Delta Psi(m) disruption, and the release of cytochrome c, which finally induces caspase-3-mediated apoptosis in thymocytes.
 ...
PMID:Differential involvement of p38 MAP kinase pathway and Bax translocation in the mitochondria-mediated cell death in TCR- and dexamethasone-stimulated thymocytes. 1153 68

Stromal cell-derived factor (SDF)-1 is a ligand for the chemokine receptor CXCR4 which is broadly expressed in lymphocytes, but the effects of SDF-1 on T cells are largely unknown. When examined using complementary DNA microarray, up-regulation of genes which are associated with DNA repair, detoxification, apoptosis, cell morphology, cell adhesion, and signal transduction was seen in CD4(+) T cells upon SDF-1 exposure. SDF-1 was shown to promote CD4(+) T cell survival through the phosphatidylinositol 3-kinase (PI3K)- and mitogen-activated protein kinase (MAPK)-cascades without cell cycle progression. The proapoptotic Bcl-2 antagonistic of cell death protein was also seen inactivated by the SDF-1-mediated activation of MAPK-extracellular signal-regulated kinases (MEK)-extracellular signal-regulated kinase-ribosomal S6 kinases- and PI3K-pathways. Moreover, the genes known to be associated with cell survival were up-regulated upon SDF-1 exposure and were linked to the MAPK-MEK and PI3K-pathways. Thus, SDF-1 promotes cell survival by two mechanisms: posttranslational inactivation of the cell death machinery and an increased transcription of cell survival-related genes. SDF-1 also primed resting CD4(+) T cells for cytokine- and TCR-mediated stimuli. These data suggest that the SDF-1-mediated cell survival combined with its priming function would set T cells to respond to immunologic challenges.
 ...
PMID:Diverse transcriptional response of CD4+ T cells to stromal cell-derived factor SDF-1: cell survival promotion and priming effects of SDF-1 on CD4+ T cells. 1154 90

The ability of CD8+ cytotoxic T lymphocytes (CTL) to clear viral infections may be limited when high avidity CTL encounter supra-optimal antigen density on antigen-presenting cells (APC) and undergo antigen-dependent apoptosis of CTL (ADAC). Previously, we have shown ADAC in CD8+ populations to be Fas independent, TNF-alpha receptor 2 (TNFR2) mediated, caspase dependent, and accompanied by a decrease in Bcl-2. We now employ flow cytometry to follow ADAC within individual CD8+ cells to demonstrate that the intense TCR signal induced in high avidity CTL by supra-optimal antigen density results 8 - 16 h later in a caspase-independent TNFR2 down-modulation that is directly related to the stimulating APC antigen density and concludes in a rapid onset of apoptosis by 18 - 24 h. Individual CTL undergoing apoptosis exhibit a dramatic and concurrent: (1) positive staining with Annexin V and propidium iodide; (2) transformation to a smaller cell size characteristic of apoptosis; and (3) a nearly complete loss of Bcl-2, c-IAP1, and TRAF2. We conclude that the antigen-dependent apoptosis of CD8+ CTL occurs when a tandem TCR/TNFR2 signal initiates an abrupt and concordant onset of multiple apoptotic events.
 ...
PMID:An abrupt and concordant initiation of apoptosis: antigen-dependent death of CD8+ CTL. 1159 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>