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)

This report examines the mechanisms involved in the down-regulation of the immune response in acute viral infection and documents the presence of apoptotic lymphocytes in situ in the spleens of mice during the resolution of the immune response to acute lymphocytic choriomeningitis virus infection. Apoptotic cells were detected by an in situ nucleotidyl transferase assay. Both T and B lymphocytes were shown to be dying in vivo, the latter in clusters. A biphasic occurrence of apoptosis during the course of the acute infection was observed, with elevated levels occurring at day 3 after infection and a second more pronounced peak at day 11 after infection, coincident with the decline of the cytotoxic T lymphocyte response and with the decrease in total splenic leukocyte number. Apoptosis in vivo was detected in lpr mice, suggesting that Fas expression is not imperative for lymphocyte apoptosis in the context of an acute viral infection. Apoptosis in situ and the decline of the T lymphocyte response to acute lymphocytic choriomeningitis virus infection was unaffected by the enforced lymphocyte-directed expression of Bcl-2, a protein that blocks growth factor deprivation-induced apoptosis of lymphocytes in vitro. These results argue that the silencing of the T cell response to acute infection may not be a result simply of growth factor deprivation. The susceptibility of activated T cells to apoptotic death, which has previously been associated with virus-induced immune deficiency, may therefore also explain the en masse elimination of the expanded lymphocyte pool subsequent to an acute viral infection.
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PMID:Lymphocyte apoptosis during the silencing of the immune response to acute viral infections in normal, lpr, and Bcl-2-transgenic mice. 760 87

We examined the CD8+ T cell response to lymphocytic choriomeningitis virus (LCMV) in mice doubly transgenic for an LCMV-specific TCR and for either bcl-xL or bcl-2. Clonal down-sizing of the anti-viral CD8+ T cell response and the generation of T cell memory was not influenced by constitutive expression of these anti-apoptotic proteins in T cells. Expression of Bcl-xL or Bcl-2 did, however, prevent LCMV peptide-induced peripheral deletion of mature CD8+ T cells in vivo and apoptosis of activated LCMV-specific effector T cells in vitro. The CD8+ T cells "rescued" by Bcl-xL or Bcl-2 from peptide antigen-induced cell death were anergic and this could not be reversed by addition of IL-2 in vitro or by adoptive transfer into antigen-free recipient mice followed by LCMV infection in vivo. Taken together, we show here that 1) Bcl-xL or Bcl-2 are functionally equivalent in their ability to modulate CD8+ T cell survival in vivo, 2) distinct apoptosis signaling pathways exist in CD8+ T cells, one that can be inhibited by Bcl-2 or Bcl-xL and one that cannot be blocked, and 3) apoptosis of CD8+ effector T cells during the declining phase of an immune response is not prevented by constitutive expression of the anti-apoptotic proteins Bcl-xL and Bcl-2.
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PMID:Constitutive expression of Bcl-xL or Bcl-2 prevents peptide antigen-induced T cell deletion but does not influence T cell homeostasis after a viral infection. 952 Oct 66

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

Viral persistence following infection with invasive strains of lymphocytic choriomeningitis virus (LCMV) can be achieved by selective down-regulation of virus-specific T lymphocytes. High viral burden in the onset of infection drives responding cells into functional unresponsiveness (anergy) that can be followed by their physical elimination. In this report, we studied down-regulation of the virus-specific CD8(+)-T-cell response during persistent infection of adult mice with LCMV, with emphasis on the role of perforin-, Fas/FasL-, or tumor necrosis factor receptor 1 (TNFR1)-mediated cytolysis in regulating T-cell homeostasis. The results reveal that the absence of perforin, Fas-ligand, or TNFR1 has no significant effect on the kinetics of proliferation and functional inactivation of virus-specific CD8(+) T cells in the onset of chronic LCMV infection. However, these molecules play a critical role in the homeostatic regulation of T cells, influencing the longevity of the virus-specific CD8(+)-T-cell population once it has become anergic. Thus, CD8(+) T cells specific to the dominant LCMV NP(396-404) epitope persist in an anergic state for at least 70 days in perforin-, FasL-, or TNFR1-deficient mice, but they were eliminated by day 30 in C57BL/6 controls. These effects were additive as shown by a deficit of apoptotic death of NP(396-404) peptide-specific CD8(+) T cells in mice lacking both perforin and TNFR1. This suggests a role for perforin-, FasL-, and TNFR1-mediated pathways in down-regulation of the antiviral T cell response during persistent viral infection by determining the fate of antigen-specific T cells. Moreover, virus-specific anergic CD8(+) T cells in persistently infected C57BL/6 mice contain higher levels of Bcl-2 and Bcl-XL than functionally intact T cells generated during acute LCMV infection. In the case of proapoptotic factors, Bax expression did not differ between T-cell populations and Bad was below the limit of detection in all samples. As expression of the Bcl-2 family members controls susceptibility to apoptosis, this finding may provide a molecular basis for the survival of anergic cells under conditions of prolonged antigen stimulation.
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PMID:Critical role for perforin-, Fas/FasL-, and TNFR1-mediated cytotoxic pathways in down-regulation of antigen-specific T cells during persistent viral infection. 1175 72

While the precise function of CD8alphaalpha homodimer expression on peripheral T cells is uncertain, recent evidence indicates that it facilitates survival and differentiation of lymphocytic choriomeningitis virus (LCMV)-specific memory CD8alphabeta T cell precursors in vivo. Here, we show that the CD8alphaalpha homodimer is also transiently up-regulated on influenza A virus-specific CD8alphabeta T cells after infection in vivo, temporally correlating with increased levels of the memory T cell development- and survival-related molecules IL-7Ralpha and Bcl-2, respectively. Unlike with LCMV, however, deletion of the CD8alphaalpha enhancer I does not abrogate CD8alphaalpha homodimer expression or manifest a significant impact on the generation of virus-specific, functional effector and central memory T cells in influenza A virus infection. These results demonstrate that the role of CD8alphaalpha in the generation of antiviral CD8 T cell memory is complex, presumably because various viral stimuli differentially regulate CD8alphaalpha expression. Further studies are needed to define those ligands that induce CD8alphaalpha on T cells during acute viral infections, and the general relevance of this process to memory T cell formation.
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PMID:CD8 alpha alpha homodimer expression and role in CD8 T cell memory generation during influenza virus A infection in mice. 1627 80

Following an acute T cell response, most activated effector cells die, while some survive and become memory cells. The pro-apoptotic Bcl-2 family member, Bcl-2 interacting mediator of death (Bim) is critical for eliminating most effector T cells, while expression of CD127 (IL-7Ralpha) has been proposed to mark effector cells destined to become memory cells. Here, we examined the effects of Bim on the death of effector T cells in relationship to CD127 expression and on development of T cell memory following lymphocytic choriomeningitis virus (LCMV) infection. We found that large numbers of CD127(lo) LCMV-specific CD4(+) and CD8(+) T cells were lost in wild-type mice, but were spared in Bim(-/-) mice. Further, while the numbers of CD127(hi) T cells declined only slightly during contraction of the response in wild-type mice, they increased significantly in Bim(-/-) mice due to re-expression of CD127 on CD127(lo) T cells that had avoided apoptosis. Functional memory T cells were significantly increased in Bim(-/-) mice; however, they underwent a slow attrition due to decreased proliferative renewal. Taken together, these data suggest that the absence of Bim-mediated death of LCMV-specific CD4(+) and CD8(+) T cells in vivo can increase T cell memory, but other homeostatic mechanisms control the long-term maintenance of memory cells.
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PMID:Bim mediates apoptosis of CD127(lo) effector T cells and limits T cell memory. 1676 15

Apoptosis is critical for the development and maintenance of the immune system. The proapoptotic Bcl-2 family member Bim is important for normal immune system homeostasis. Although previous experiments have shown that Bim is critical for the apoptosis of antigen-specific CD8(+) T cells during acute viral infection, the role of Bim during chronic viral infection is unclear. Using lymphocytic choriomeningitis virus clone 13 infection of mice, we demonstrate a role for Bim in CD8(+) T-cell apoptosis during chronic viral infection. Enumeration of antigen-specific CD8(+) T cells by major histocompatibility complex class I tetramer staining revealed that CD8(+) D(b)NP396-404(+) T cells, which undergo extensive deletion in wild-type mice, exhibited almost no decrease in Bim mutant mice. This contrasts with CD8(+) D(b)GP33-41(+) and CD8(+) D(b)GP276-286(+) T cells that underwent similar decreases in numbers in both Bim mutant and wild-type mice. Increased numbers of CD8(+) D(b)NP396-404(+) T cells in Bim mutant mice were due to lack of apoptosis and could not be explained by altered proliferation, differential homing to tissues, or increased help from CD4(+) T cells. When viral titers were examined, high levels were initially observed in both groups, but in Bim mutant mice, clearance from the spleen and sera was slightly accelerated. These experiments demonstrate the critical role of Bim during chronic viral infection to down-regulate CD8(+) T-cell responses and have implications for designing strategies for optimizing immunotherapies during situations where antigen persists, such as chronic infection, autoimmune syndromes, and cancer.
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PMID:Role of Bim in regulating CD8+ T-cell responses during chronic viral infection. 1691 11

CD8+ T-cell apoptosis is essential for the contraction phase of the immune response, yet the initiating signals and precise pathways involved are unresolved. The ST3Gal-I sialyltransferase is a candidate mechanistic component and catalyzes sialic acid addition to core 1 O-glycans during protein O glycosylation. ST3Gal-I inactivation or enzymatic removal of its product renders CD8+ T cells, but not CD4+ T cells, susceptible to apoptosis by differential cross-linking of O-glycoproteins in the absence of interleukin-2 and T-cell receptor (TCR) signaling. This results in caspase activation, DNA fragmentation, and phosphatidylserine externalization prior to cell death. We further show that ST3Gal-I function is regulated by a posttranscriptional mechanism operating distal to Golgi core 2 O glycosylation and is invariably linked to CD8+ T-cell contraction following viral (lymphocytic choriomeningitis virus) infection and bacterial (staphylococcal enterotoxin B) antigen immunization. The mechanism does not involve the ST3Gal-I substrate CD43 or core 2 O-glycan induction and overcomes the ability of Bcl-2 to inhibit the contraction phase in vivo. Loss of ST3Gal-I function further reduces Bim-deficient CD8+ T-cell accumulation without diminishing apoptotic sensitivity. We propose that an endogenous lectin activates an apoptotic pathway constructed in CD8+ T cells following TCR stimulation and enables contraction upon attenuation of immune signaling.
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PMID:Structural and mechanistic features of protein O glycosylation linked to CD8+ T-cell apoptosis. 1710 70

We examined the role of the antiapoptotic molecule Bcl-2 in combating the proapoptotic molecule Bim in control of naive and memory T cell homeostasis using Bcl-2(-/-) mice that were additionally deficient in one or both alleles of Bim. Naive T cells were significantly decreased in Bim(+/-)Bcl-2(-/-) mice, but were largely restored in Bim(-/-)Bcl-2(-/-) mice. Similarly, a synthetic Bcl-2 inhibitor killed wild-type, but not Bim(-/-), T cells. Further, T cells from Bim(+/-)Bcl-2(-/-) mice died rapidly ex vivo and were refractory to cytokine-driven survival in vitro. In vivo, naive CD8(+) T cells required Bcl-2 to combat Bim to maintain peripheral survival, whereas naive CD4(+) T cells did not. In contrast, Bim(+/-)Bcl-2(-/-) mice generated relatively normal numbers of memory T cells after lymphocytic choriomeningitis virus infection. Accumulation of memory T cells in Bim(+/-)Bcl-2(-/-) mice was likely caused by their increased proliferative renewal because of the lymphopenic environment of the mice. Collectively, these data demonstrate a critical role for a balance between Bim and Bcl-2 in controlling homeostasis of naive and memory T cells.
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PMID:Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis. 1759 57


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