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)

In this study, we document the development of stable, antigen-independent CD8+ T cell memory after drug-induced cure of a chronic infection. By establishing a system for drug cure of chronic Trypanosoma cruzi infection, we present the first extensively documented case of total parasite clearance after drug treatment of this infection. Cure resulted in the emergence of a stable, parasite-specific CD8+ T cell population with the characteristics of central memory cells, based upon expression of CD62L, CCR7, CD127, CD122, Bcl-2 and a reduced immediate in vivo CTL function. CD8+ T cells from treated and cured mice also expanded more rapidly and provided greater protection following challenge than those from chronically infected mice. These results show that complete pathogen clearance results in stable, antigen-independent and protective T cell memory, despite the potentially exhausting effects of prior long-term exposure to antigen in this chronic infection.
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PMID:Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease. 1842 31

The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-alpha) antiviral therapy achieves the highest rate of success when IFN-alpha is administered early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCV-specific T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-gamma- and IL-2-producing and CD107a(+)) virus-specific CD8(+) T cells. These polyfunctional T cells are distinguished by the expression of CD127 and Bcl-2 and represent a transitional memory T-cell subset that exhibits the phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific CD8(+) T cells in acute infections evolving to chronicity expressed low levels of CD127 and Bcl-2, exhibited diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN-alpha rescued polyfunctional memory T cells expressing high levels of CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory T cells.
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PMID:Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells. 1866 16

Expression of IL-7 receptor alpha (CD127) is associated with naive and memory (i.e. non-effector) CD8+ T cell phenotypes. Effector CD8+ T cells are predominantly CD127- and most die by apoptosis. Therefore, CD127 appears to be a marker for CD8+ T cell differentiation, yet its role in CD8+ T cell survival and memory development is unclear. To address this, we investigated the cell death and cell division of isolated CD8+CD127+ and CD8+CD127- T cells in response to common IL-2 receptor gamma chain (gamma(C)) cytokines other than IL-7. We show here that (i) memory cells (CD127+CD45RA-) divide frequently in response to either IL-2, -4 or -15; (ii) IL-2 and -15 enhance cell division in effector-memory-like cells (CD127-CD45RA+) while IL-4 enhances the cell division of effector cells (CD127-CD45RA-); (iii) CD8+CD127+ T cells are more sensitive to the anti-apoptotic effects of IL-2 or IL-15 than CD8+CD127- T cells and (iv) CD8+CD127+ T cell produce more Bcl-2 in response to IL-2 or IL-15 compared with CD8+CD127- T cells. Therefore, CD8+CD127+ and CD8+CD127- T cells differ in their responsiveness to cell division and anti-apoptotic signals from IL-2, -4 and -15. This suggests a role for gamma(C) cytokines in the pathogenesis of diseases in which CD127 expression is altered on CD8+ T cells such as in progressive viral infections and cancer.
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PMID:IL-2 receptor gamma chain cytokines differentially regulate human CD8+CD127+ and CD8+CD127- T cell division and susceptibility to apoptosis. 1901 Nov 58

The role of IL-15 in T cell survival was examined during chronic CNS coronavirus infection. Similar numbers of virus-specific CD8(+) T cells were retained in the CNS of IL-15(-/-) and wt mice, consistent with loss of IL-2/15 receptor (CD122) expression. IL-15 deficiency also had no affect on IL-7 receptor (CD127) expression, Bcl-2 upregulation, granzyme B expression, or IFN-gamma secretion in CNS persisting CD8(+) T cells. Furthermore, CD8(+) T cell division in the CNS was reduced compared to spleen. CD8(+) T cells in the persistently infected CNS are thus characterized by IL-15 independent, low level proliferation and an activated/memory phenotype.
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PMID:IL-15 independent maintenance of virus-specific CD8(+) T cells in the CNS during chronic infection. 1910 6

IL-7 signaling is essential for optimal CD8 T cell function, homeostasis and establishment of memory. We have previously shown decreased expression of the IL-7 receptor alpha-chain (CD127) on CD8 T cells from HIV-infected patients with active viral replication. We have also shown that soluble HIV Tat protein specifically down-regulates CD127 on the surface of CD8 T cells and impairs cell proliferation and cytolytic potential following stimulation with IL-7 in vitro. We now show that soluble HIV Tat protein and IL-7 at near physiologic concentrations act synergistically to suppress CD127 expression. While soluble HIV Tat protein and IL-7 both independently reduce CD127 expression on the surface of CD8 T cells, Tat concentrations of 10 microg ml(-1) and IL-7 concentrations of 500 pg ml(-1) are required in vitro to have an appreciable effect. However, where 0.5 microg ml(-1) of Tat has no effect on CD127 expression and 200 pg ml(-1) of IL-7 decreases CD127 by only 14%, these two together at these same concentrations induce a 35% reduction in CD127 expression after 24 h. Inhibition of Janus kinase (JAK) completely blocks IL-7's ability to down-regulate CD127 on the surface of CD8 T cells and also abolishes synergy with Tat. Interestingly, while Tat acts synergistically with IL-7 to reduce CD127 expression, it antagonizes IL-7-induced cell proliferation and Ki-67 expression and has no effect on IL-7-mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation or expression of the anti-apoptotic gene Bcl-2. Thus, by affecting different IL-7 signal transduction pathways, HIV Tat protein is able to impair both CD8 T cell activation and proliferation without inducing apoptosis.
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PMID:IL-7 and the HIV Tat protein act synergistically to down-regulate CD127 expression on CD8 T cells. 1914 39

TNF receptor-2 (TNFR2) plays a critical role in promoting the activation and survival of naive T cells during the primary response. Interestingly, anti-CD3 plus IL-2 activated TNFR2(-/-) CD8 T cells are highly resistant to activation-induced cell death (AICD), which correlates with high expression levels of prosurvival molecules such as Bcl-2, survivin, and CD127 (IL-7Ralpha). We determined whether the resistance of activated TNFR2(-/-) CD8 T cells to AICD contributes to more effective protection against tumor cell growth. We found that during a primary tumor challenge, despite initial inferiority in controlling tumor cell growth, TNFR2(-/-) mice were able to more effectively control tumor burden over time compared with wild-type (WT) mice. Furthermore, vaccination of TNFR2(-/-) mice with recombinant Listeria monocytogenes that express OVA confers better protection against the growth of OVA-expressing E.G7 tumor cells relative to similarly vaccinated WT mice. The enhanced protection against tumor cell growth was not due to more effective activation of OVA-specific memory CD8 T cells in vaccinated TNFR2(-/-) mice. In vitro studies indicate that optimally activated OVA-specific TNFR2(-/-) CD8 T cells proliferated to the same extent and possess similar cytotoxicity against E.G7 tumor cells as WT CD8 T cells. However, relative to WT cells, activated OVA-specific TNFR2(-/-) CD8 T cells were highly resistant to AICD. Thus, the enhanced protection against E.G7 in TNFR2(-/-) mice is likely due to the recruitment and activation of OVA-specific memory TNFR2(-/-) CD8 T cells and their prolonged survival at the tumor site.
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PMID:TNFR2-deficient memory CD8 T cells provide superior protection against tumor cell growth. 1984 Nov 76

Interleukin-7 (IL-7) plays a central role in controlling the homeostasis of both naive and long-term-memory CD4(+) T cells. To better understand how human immunodeficiency virus (HIV) perturbs CD4(+) T-cell homeostasis, we performed a detailed analysis of IL-7R expression, IL-7 binding, and IL-7-dependent early and late signaling events in CD4(+) T-cell subsets from viremic and efficiently treated patients. HIV infection differentially affected the expression of IL-7 receptor (IL-7R) chains, with decreases in IL-7Ralpha/CD127 expression in the memory subset and increases in gammac/CD132 expression in all CD4(+) T cells. This resulted in preserved IL-7 binding in the naive compartment and decreased IL-7 binding in the memory compartment of viremic patients. Accordingly, the percentages of cells signaling in response to IL-7, as measured by pSTAT5 induction, were decreased in memory subsets, including conventional CD4(+) T cells and regulatory T cells. However, the levels of pSTAT5 induction per responding cell, as measured by pSTAT5 fluorescence intensity, were increased within all naive and memory CD4(+) T-cell subsets of viremic patients. The basal level of pSTAT5 was also increased, indicating a constitutive activation of the JAK/STAT5 pathway. IL-7 functional responses, as measured by Bcl-2, CD25, and Foxp3 induction, were impaired in viremic patient CD4(+) T cells, suggesting that chronic activation led to downstream defects in the STAT5 signaling pathway. Thus, HIV infection perturbs IL-7 responses at both receptor binding and signaling steps, which likely compromises the regenerative capacity of the CD4(+) T-cell pool and may contribute to CD4(+) T-cell depletion.
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PMID:Dual mechanism of impairment of interleukin-7 (IL-7) responses in human immunodeficiency virus infection: decreased IL-7 binding and abnormal activation of the JAK/STAT5 pathway. 1986 82

The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8(+) T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8(+) T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8(+) T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8(+) T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8(+) T cells appear to pass through an effector phase and then gradually down-regulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-gamma, TNF-alpha, IL-2, and MIP-1beta. 4) The YF-17D-specific memory CD8(+) T cells had a phenotype (CCR7(-)CD45RA(+)) that is typically associated with terminally differentiated cells with limited proliferative capacity (T(EMRA)). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8(+) T cells generated after acute viral infections.
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PMID:The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. 1993 69

The interleukin (IL)-7 receptor (IL-7R) is expressed on human pre-B but not mature B-cells. We hypothesised that aberrant expression of IL-7R contributes to B-cell oncogenesis. Surface expression of IL-7R components CD127 and CD132, and intracellular Ki-67 and Bcl-2 were examined by flow cytometry on peripheral blood or bone marrow mononuclear cells (PBMC; BMMC) from patients with B-cell derived neoplasms, chronic human immunodeficiency virus type-1 (HIV-1) infection alone, or healthy volunteers. Plasma IL-7, IL-2, IL-4, IL-6, IL-10, IL-21, TNF-alpha, IFN-gamma and BAFF were measured by enzyme-linked immuno-sorbent assay or bead array. The effects of exogenous IL-7 on PBMC and BMMC were examined. CD127 expression was elevated in pre-B-cell acute lymphoblastic leukemia (pre-B-ALL) and in some cases of Non-Hodgkin's Lymphoma (B-NHL). Plasma IL-7 levels were higher in pre-B-ALL, B-cell chronic lymphocytic leukemia (B-CLL) and HIV-1 associated B-NHL (HIV-B-NHL) compared with control groups. CD127+ pre-B-ALL cells had higher expression of Ki-67, Bcl-2 and CD132 than CD127- counterparts. Unlike T-lineage cells, CD127+ pre-B-ALL cells did not down-regulate CD127 in response to exogenous IL-7. Patients with B-cell derived neoplasms had elevated circulating IL-10 and decreased BAFF. These findings support a role for the IL-7/IL-7R system in B-cell oncogenesis.
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PMID:IL-7 receptor is expressed on adult pre-B-cell acute lymphoblastic leukemia and other B-cell derived neoplasms and correlates with expression of proliferation and survival markers. 2006 Jul 40

Interleukin (IL)-7 is a factor essential for mouse and human thymopoiesis. Mouse thymocytes have altered sensitivities to IL-7 at different developmental stages. CD4/CD8 double positive (DP) mouse thymocytes are shielded from the influence of IL-7 because of loss of CD127 (IL-7Ralpha). In this study, we assessed IL-7 receptor expression and IL-7 signaling in human thymocytes. We found human DP cells to be severely limited in their ability to phosphorylate STAT-5 in response to IL-7. The relative expression levels of the IL-7-inducible proteins Bcl-2 and Mcl-1 were also lower in human DP cells, consistent with a stage-specific decrease in IL-7 responsiveness. IL-7 responses were restored in a subset of cells that matured past the DP stage. Unlike the regulation of IL-7 signaling in mouse thymocytes, loss of IL-7 signaling in human DP cells was not due to absence of CD127, but instead correlated with downregulation of CD132 (common gamma chain).
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PMID:Differential IL-7 responses in developing human thymocytes. 2007 4


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