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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptotic cell death is induced in mature cycling T cells upon ligation of the Ag-specific TCR. This process is essential for the maintenance of homeostasis in the immune system, as it is capable of down-regulating ongoing immune responses. The analysis of the mechanism underlying TCR-induced programmed cell death has focused the attention of many scientists recently. In this regard, several recent reports have implicated Fas/Fas-ligand molecules as the final mediators of this process. Several other gene products have been implicated in the control of apoptosis (as Bcl-2, p53, and c-Myc); however, no information was available in the early signaling molecules that trigger this phenomena. The results presented in this work indicate that pp56(lck) src family kinase is actually required for the TCR to trigger cell death in mature cycling T cells. In fact, while inhibition of pp56(lck) expression with antisense oligonucleotides blocked TCR-induced apoptosis, pharmacologic inhibition of phosphatidylinositol 3-kinase activity had no effect. Accordingly, ligation of the Ag receptor in a cell line defective for pp56(lck) expression was unable to induce apoptosis, although it induced cellular stimulation, as measured by the expression of CD69. In addition, we show in this work that expression of constitutively active pp56(lck) mutants, but not pp59(fyn) mutants, in the absence of any other TCR-derived signal, is sufficient to induce apoptosis not only in transformed, but also in normal cycling T cells. Finally, evidence is presented indicating that a mechanism through which pp56(lck) regulates TCR-induced apoptosis in mature cycling T cells is by controlling Fas-ligand expression.
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PMID:Lck is necessary and sufficient for Fas-ligand expression and apoptotic cell death in mature cycling T cells. 912 69

TCR-mediated activation of T cell hybridomas induces programmed cell death by a Fas-dependent pathway. We now show that costimulation of 2B4 cells, in the absence or presence of transgenic Bcl-2, with anti-CD3 epsilon and forskolin, an activator of cAMP signaling, resulted in antagonism of Fas-dependent activation-induced cell death that was always accompanied by selective downregulation of the nuclear levels of NF-kappa B p65-p50 (RelA-p50) transcription factor. Forskolin not only inhibited activation-induced cell death and NF-kappa B activation, but also suppressed expression of Fas and Fas ligand (Fas-L). Furthermore, NF-kappa B p65 antisense oligonucleotide down-regulated nuclear levels of NF-kappa B, inhibited cell surface expression of Fas-L and apoptosis of 2B4. Collectively, these finding demonstrate a potential role of NF-kappa B in the regulation of activation-induced apoptosis in T lymphocytes.
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PMID:Regulation of Fas-dependent activation-induced T cell apoptosis by cAMP signaling: a potential role for transcription factor NF-kappa B. 918 60

Signals from cytokine and antigen receptors play crucial roles during lymphocyte development. Mice lacking interleukin-7 receptor are lymphopenic, due to a defect in cell expansion at an early stage of differentiation, and the few mature T cells that develop in IL-7R-/- animals are functionally impaired. Both defects were rescued completely by overexpression of the anti-apoptosis protein Bcl-2. T cell progenitors lacking antigen receptor molecules are also blocked in differentiation and die, presumably because they fail to receive a positive signal via their pre-T cell receptor. Surprisingly, Bcl-2 did not promote survival or differentiation of T cells in rag-1-/- mice. These results provide evidence that blocking apoptosis is the essential function of IL-7R during differentiation and activation of T lymphocytes and that pre-TCR signaling blocks a pathway to apoptosis that is insensitive to Bcl-2.
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PMID:Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1-/- mice. 921 24

Administration of glucocorticoids or exposure to ionizing radiation in vivo results in a rapid cell death of thymocytes. We report that murine small intestinal intraepithelial lymphocytes (IEL) are resistant to both steroid- and radiation-induced deletion. This is due to resistance to apoptosis, as evidenced by the absence of detectable apoptotic IEL nuclei in situ after in vivo glucocorticoid treatment. IEL express normal levels of glucocorticoid receptors and these receptors bind [3H]dexamethasone to equivalent levels as other lymphocyte populations. Thus, their survival is due to post-receptor signaling mechanisms. Many IEL express high levels of Bcl-2 and that of these Bcl-2high IEL are largely TCR gamma delta +. Those IEL that do express high levels of Bcl-2 are CD8 alpha + beta - CD4-. In addition, IEL express Bcl-x, another protein shown to be involved in the protection of cells from apoptotic signals. IEL represent the first lymphocyte population in vivo shown to have high levels of expression of both molecules, that otherwise occur only in activated lymphocytes in vitro. These data suggest that the Bcl-2+Bcl-x+ IEL are activated cells and not an effete population of cells necessarily destined to die. Also, the high levels of Bcl-2 and Bcl-x in this in vivo activated population supports the in vitro correlate of protection from activation-induced cell death.
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PMID:Elevated expression of Bcl-2 and Bcl-x by intestinal intraepithelial lymphocytes: resistance to apoptosis by glucocorticoids and irradiation. 923 3

In the peripheral immune system, apoptosis is involved in the down-regulation of immune reactions, acting as a homeostatic mechanism to limit the expansion of activated lymphocytes, for example in viral diseases. We previously reported that uninfected T lymphocytes from HIV-infected persons were highly prone to in vitro spontaneous apoptosis which was increased following TCR-dependent or independent activation. The present report reviews recent data suggesting that the chronic stimulation of the immune system in HIV infection induces a dysregulation in the expression of molecules involved in cell survival (Bcl-2) or cell death (Fas), promoting an exacerbated peripheral cell death in blood and lymph nodes, possibly contributing to the loss of both functional cytotoxic and helper T lymphocytes in AIDS.
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PMID:Programmed cell death in HIV infection: dysregulation of BCL-2 and Fas pathways and contribution to AIDS pathogenesis. 926 45

Proliferative expansion and apoptotic cell death play prominent roles in T cell development. The molecular control of cell cycle progression and apoptosis appear to be inter-connected since the Bcl-2 protein can inhibit apoptosis and slow cell cycle progression in cortical thymocytes and mature T cells, particularly during the transition from the quiescent state into the cell cycle. Here the impact of bcl-2 transgene expression on CD3-CD4-CD8- T cell progenitors was assessed. Bcl-2 enhanced the survival of these progenitors at all of the four major differentiation stages, CD25- CD44+ (pro-T1), CD25 + CD44+ (pro-T2), CD25 + CD44- (pro-T3) and CD25-CD44- (pro-T4). However, it reduced cell cycling and slowed turnover only in the pro-T4 subset. From an analysis of bcl-2 transgenic mice expressing a TCR transgene or bearing a mutation in the scid or rag-1 gene we conclude that Bcl-2 inhibits proliferation only of T cell progenitors that are activated via the pre-TCR, not those stimulated via c-Kit and the IL-7 receptor.
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PMID:bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8- T cell progenitors. 931 Aug 32

Mice lacking the common cytokine receptor gamma-chain (gamma c) exhibit severely compromised lymphoid development. T cells that develop in these mice exhibit decreased Bcl-2 levels and accelerated apoptosis; nevertheless, these mice exhibit an age-dependent accumulation of activated CD4+ T cells. To investigate the basis for this accumulation, we analyzed both thymic and peripheral deletion in these mice. Gamma c-deficient mice had increased numbers of V beta 11+ T cells, consistent with a possible defect in Mtv-9-induced deletion; however, the deletion of V beta 5+ T cells by Mtv-9 and that of V beta 6+ T cells by Mls-1a were normal. Moreover, antigenic peptide could induce wild-type levels of deletion of CD4+ CD8+ thymocytes in TCR-transgenic gamma c-deficient mice. In contrast to this relatively normal deletion of thymocytes, bacterial superantigen (staphylococcal enterotoxin B)-induced elimination of peripheral T cells was greatly impaired, suggesting that defective peripheral deletion contributed to the accumulation of activated T cells. Interestingly, despite CD4+ T cell accumulation, these cells exhibited increased sensitivity to Fas-mediated death in vitro. Correction of the defect in Bcl-2 expression by mating to Bcl-2 transgenic mice augmented the splenic T cell accumulation and substantially enhanced the survival of gamma c-deficient T cells; however, these cells still exhibited significant Fas-mediated death, indicating that the increased Fas-mediated death was not simply due to diminished Bcl-2 expression. Moreover, these T cells exhibit decreased expression of Fas ligand, suggesting that Fas-bearing cells cannot be effectively eliminated in vivo in gamma c-deficient mice. Thus, gamma c-dependent signals play a role in peripheral T cell deletion, presumably by inducing Fas ligand on activated T cells.
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PMID:Impaired peripheral deletion of activated T cells in mice lacking the common cytokine receptor gamma-chain: defective Fas ligand expression in gamma-chain-deficient mice. 936 97

Ligation of the protein tyrosine phosphatase CD45 on both mature and immature T cells modulates the amplitude of TCR-mediated signals. In this work, we have evaluated the consequences of CD45 ligation on immature T cells, in the absence of TCR engagement. Cross-linking of CD45 on thymocytes by mAbs led to the induction of cellular death, characterized by a reduction in mitochondrial membrane potential (delta psi(m)), production of reactive oxygen species, loss in membrane asymmetry, exposure of phosphatidylserine residues, and incorporation of vital dyes. In sharp contrast to most stimuli causing thymocyte death, CD45 cross-linking did not lead to DNA degradation. Cell death was not blocked by Bcl-2 overexpression or treatment with caspase inhibitor. However, death was inhibited by the addition of scavengers of reactive oxygen species. We also established that susceptibility to CD45-mediated death is acquired during the transition of early CD4- CD8- TCR- T cell precursors into CD4+ CD8+ TCR- thymocytes and is increased with further acquisition of surface TCR on these cells. Moreover, mature thymocytes were much less sensitive to CD45 cross-linking than CD4+ CD8+ cells. We propose that during T cell development, CD45 ligation could induce the death of those immature thymocytes that do not fulfill the requirements for positive selection.
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PMID:CD4+ CD8+ thymocytes are preferentially induced to die following CD45 cross-linking, through a novel apoptotic pathway. 936

Memory T cells are considered to be less dependent on costimulation and to respond more vigorously to TCR triggering compared to their naive counterparts. We and others, however, observed that memory CD4 T cells display nonresponsiveness to a variety of stimuli, including superantigens and soluble anti-CD3. We now report that CD28-derived costimulation can revert the nonresponsive state of antigen-exposed CD4 T cells. Interestingly, the rescuing effect of CD28 can be completely negated by CTLA-4 engagement. The malfunction of memory T cells is related to increased cell death; the viability can be restored by CD28 engagement and is negatively regulated by CTLA-4 engagement. Importantly, it has been reported that antigen-exposed T cells express lower levels of the anti-apoptotic mediator Bcl-2. In addition, CD28 costimulation was reported to upregulate the expression levels of Bcl-xL. We therefore examined the possible role of Bcl-2 family proteins in the nonresponsiveness of antigen-exposed CD4 T cells, and determined whether CTLA-4, in analogy to CD28, mediates its negative regulatory effects via the Bcl-2 family of apoptotic mediators. Our data indicate that neither the nonresponsiveness nor the susceptibility to CTLA-4 of antigen-experienced CD4 T cells are related to the expression levels of Bcl-2 or Bax. The rescuing effects of CD28, however, may be related to increased Bcl-xL levels. Addition of IL-2 normalizes the nonresponsiveness of memory CD4 T cells and renders these cells resistant to the negative effects of CTLA-4 engagement. Impaired IL-2 production is therefore likely to be the cause of the malfunction and CTLA-4 susceptibility of memory CD4 T cells.
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PMID:Nonresponsiveness and susceptibility to CTLA-4 of antigen-exposed CD4 T cells are not regulated by the Bcl-2 family of apoptotic mediators, but can be restored by IL-2. 949 88

Apoptotic cell death is an important mechanism for maintaining homeostasis in the immune system and for regulating the fates of lymphocytes following encounters with self and foreign Ags. To study the physiologic roles of the proapoptotic Fas pathway and the antiapoptotic protein, Bcl-2, in T cell maturation and homeostasis, a TCR transgene has been bred into mice lacking functional Fas and mice that express Bcl-2 constitutively. In vitro, Fas-deficient T cells are resistant to activation-induced cell death, whereas Bcl-2-overexpressing T cells are resistant to death induced by withdrawal of growth factors. In vivo, Bcl-2-overexpressing mice accumulate T cells in the thymus and peripheral lymphoid tissues in the absence of Ag, but these cells are deleted normally after Ag administration. In contrast, Fas-deficient mature T cells are present in normal numbers in the absence of Ag, but are resistant to Ag-induced deletion. Both Fas-deficient and Bcl-2 overexpressing thymocytes are deleted when exposed to transgene-encoded circulating self Ag, indicating that the pathways of apoptosis controlled by these proteins are not critical for negative selection of developing thymocytes. Moreover, deficiency of Fas, but not Bcl-2 overexpression, results in the accumulation of autoreactive T cells in peripheral lymphoid tissues. These results demonstrate that Fas and Bcl-2 regulate different pathways of apoptosis that may serve distinct functions in lymphocyte homeostasis and in the maintenance of T cell tolerance.
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PMID:Functional roles of Fas and Bcl-2-regulated apoptosis of T lymphocytes. 949 42


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