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)

Allogeneic hematopoietic stem cell transplantation (AHSCT) leads to a prolonged state of immunodeficiency characterized by low peripheral naive T-cell counts. To identify the mechanisms leading to this defect we quantitatively and qualitatively analyzed thymic function through quantification of T-cell receptor excision circle (TREC) frequencies (both the signal-joint TREC [sjTREC] and 6 different DbetaJbeta TRECs, by-products of T-cell receptor [TCR] alpha and beta gene rearrangement, respectively), in conjunction with immunophenotype and spectratype analyses in a cohort of patients sampled from 1 to 10 years following AHSCT. In this cohort, reduced thymic function was associated only with ongoing clinical chronic graft-versus-host disease (cGVHD). Nonetheless, the diversity of thymic production remained unchanged irrespective of the patient's cGVHD status. Interestingly, increased homeostatic proliferation was found in the naive T-cell compartment of cGVHD- patients who underwent transplantation. However, reduced expression of both the interleukin-7 receptor alpha (IL-7Ralpha) (CD127) chain and the antiapoptotic protein Bcl-2 was observed. Taken together, these data indicate that the inability to reconstitute the naive T-cell compartment for several years after AHSCT, in the absence of cGVHD, is a consequence of impaired naive T-cell survival rather than thymic dysfunction.
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PMID:Evidence for adequate thymic function but impaired naive T-cell survival following allogeneic hematopoietic stem cell transplantation in the absence of chronic graft-versus-host disease. 1293 79

An important prerequisite in using regulatory T cells for immunotherapy is their ex vivo expansion without loss of suppressor function. Human anergic regulatory T cells are expandable by Ag-specific stimulation in the presence of IL-2. IL-15, like IL-2, is a T cell growth factor that, in contrast to IL-2, stimulates survival of T cells. In this study, we examined whether IL-15 could be exploited as a superior growth factor of human CD4(+) anergic regulatory T cells that were generated by costimulation blockade. Next, IL-15, as compared with IL-2, was investigated with respect to expansion and function of these regulatory T cells. Optimal expansion required cognate allogeneic stimulation in the presence of exogenous IL-15. IL-15 resulted in enhanced survival that was paralleled by an increased number of Bcl-2-expressing cells. Moreover, IL-15 induced a distinct type of anergy characterized by hyperreactivity to IL-15, resulting in improved expansion. This is likely attributed to increased propensity of these cells to up-regulate both alpha- and gamma-chains of the IL-2 and IL-15 receptor. Notably, IL-15-expanded regulatory CD4(+) T cells suppressed both naive and memory T cells in a superior way. Immunosuppression required alloantigen-specific stimulation and appeared gamma-irradiation resistant and independent of IL-10, TGFbeta, or CTLA-4 interactions. These regulatory T cells were stable suppressors, mediating bystander suppression upon TCR stimulation, but leaving recall responses unaffected in the absence of cognate Ag. Finally, human naturally occurring regulatory CD4(+)CD25(+) T cells appeared important in generating regulatory T cells by costimulation blockade. In conclusion, IL-15-expanded, de novo-induced human anergic regulatory CD4(+) T cells are of interest in Ag-specific immunotherapy.
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PMID:IL-15 and cognate antigen successfully expand de novo-induced human antigen-specific regulatory CD4+ T cells that require antigen-specific activation for suppression. 1466 42

E2A proteins regulate multiple stages of thymocyte development and suppress T-cell lymphoma. The activity of E2A proteins throughout thymocyte development is modulated by signals emanating from the pre-TCR and TCR. Here we demonstrate that E2A is required for the complete arrest in both differentiation and proliferation observed in thymocytes with defects in proteins that mediate pre-TCR signaling, including LAT, Lck and Fyn. We show that E2A proteins are required to prevent the accumulation of TCRbeta negative cells beyond the pre-TCR checkpoint. E2A-deficient thymocytes also exhibit abnormal cell-cycle progression prior to pre-TCR expression. Furthermore, we demonstrate that E47 can act in concert with Bcl-2 to induce cell-cycle arrest in vitro. These observations indicate that E2A proteins function during early thymocyte development to block cell-cycle progression prior to the expression of TCRbeta. In addition, these data provide further insight into how deficiencies in E2A lead to T lymphoma.
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PMID:E2A proteins enforce a proliferation checkpoint in developing thymocytes. 1468 78

CD24, also referred to as the heat-stable Ag, is a T cell differentiation Ag that is highly expressed on both CD4-CD8- double negative and CD4+CD8+ double positive thymocytes. Here, we report that CD24 ligation by a new anti-CD24 Ab, mT-20, induced the apoptosis of both double negative and double positive thymocytes, as well as the Scid.adh thymic lymphoma cell line, in the absence of TCR/CD3 engagement. CD24-mediated apoptosis of mouse thymocytes and its signaling pathway appeared not to be associated with p53, CD95, TNFR, or caspases. Furthermore, we found that cell death was blocked by the addition of scavengers of reactive oxygen species or by Bcl-2 overexpression, implying the role of CD24 signaling in the mitochondrial regulation. In this study, we suggest that CD24 ligation induced the apoptosis of immature thymocytes independently of both caspase and TCR.
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PMID:TCR-independent and caspase-independent apoptosis of murine thymocytes by CD24 cross-linking. 1470 49

To evaluate the in vivo effect of immunosuppressive glucocorticoids on CD4+CD25+ T regulatory cells, we injected dexamethasone (Dex) into BALB/c mice. Administration of Dex enhanced the proportion of CD4+CD25+ cells and the ratio of CD4+CD25+ cells to CD4+CD25- cells in the lymphoid organs, especially in the thymus. This correlates with our in vitro observation that CD4+CD25+ T cells express higher levels of glucocorticoid receptor and Bcl-2, and are therefore more resistant to Dex-mediated cell death than CD4+CD25- T cells. Furthermore, IL-2 selectively protected CD4+CD25+ T cells from Dex-induced cell death, while IL-7 and IL-15 did not exert preferential protective effects. Dex-treated CD4+CD25+ T cells expressed higher levels of intracellular CTLA-4 and surface glucocorticoid-induced TNF receptor than fresh CD4+CD25+ T cells, but still failed to respond to TCR stimulation and inhibited proliferation of CD4+CD25- T cells. These results suggest that, in addition to suppressing cytokine transcription, Dex treatment is permissive for the survival of functional CD4+CD25+ T regulatory cells, and this property may contribute to the anti-inflammatory and immunosuppressive efficacy of glucocorticoids. Our data also suggest that selective protection of CD4+CD25+ T cell from apoptosis may constitute a role in immune tolerance for IL-2.
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PMID:Differential response of murine CD4+CD25+ and CD4+CD25- T cells to dexamethasone-induced cell death. 1499 16

The factors affecting T cell viability vary depending on the type and status of the T cell involved. Naive T cells die via a Bcl-2/Bim dependent route. Their deaths are prevented in animals by IL-7 and contact with MHC. Activated T cells die in many different ways. Among these is a pathway involving signals that come from outside the T cell and affect it via surface receptors such as Fas. Activated T cells also die through a pathway driven by signals generated within the T cell itself, a cell autonomous route. This pathway involves members of the Bcl-2 family, in particular Bcl-2, Bcl-xl, Bim, and probably Bak. The viability of CD8+ and CD4+ memory T cells is controlled in different ways. CD8+ memory T cells are maintained by IL-15 and IL-7. The control of CD4+ memory T cells is more mysterious, with roles reported for IL-7 and/or contact via the TCR.
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PMID:Control of T cell viability. 1503 96

A CD4(+)CD8(+) double-positive thymocyte cell line, 257-20-109 was established from BALB/c mice thymocytes and used to analyze the requirements to induce CD4 or CD8 single-positive (SP) T cells. CD4SP cells were induced from 257-20-109 cells by anti-CD3 stimulation in the presence of the FcR-positive macrophage cell line, P388D1. During stimulation, maturation events, such as the down-regulation of CD24 and the up-regulation of CD69, H-2D(d), CD5, and Bcl-2, were recognized. Furthermore, these CD4SP cells appeared to be functional because the cells produced IL-2 and IL-4 when activated with phorbol ester and calcium ionophore. In contrast, CD8SP cells could be induced by stimulation with fixed anti-CD3 after removal of stimulation. To investigate the extent of signals required for CD4SP and CD8SP, the cells stimulated under either condition for 2 days were sorted and transferred to different culture conditions. These results suggested that the fate of lineage commitment was determined within 2 days, and that CD4 lineage commitment required longer activation. Furthermore, the experiments with subclones of 257-20-109 demonstrated that the lower density of CD3 did not shift the cells from CD4SP to CD8SP, but only reduced the amount of CD4SP cells. In contrast, when the 257-20-109 cells were stimulated by the combination of fixed anti-CD3 and anti-CD28, the majority of the cells shifted to CD4SP, with an enhancement of extracellular signal-regulated kinase 1 phosphorylation. Our results indicate that the signals via TCR/CD3 alone shifted the double-positive cells to CD8SP cells, but the reinforced signals via TCR/CD3 and costimulator could commit the cells to CD4SP.
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PMID:The novel murine CD4+CD8+ thymocyte cell line exhibits lineage commitment into both CD4+ and CD8+ T cells by altering the intensity and the duration of anti-CD3 stimulation in vitro. 1515 78

Type I IFNs (IFN-alphabeta) enhance immune responses, notably T cell-mediated responses, in part by promoting the functional activities of dendritic cells. In this study, we analyzed the direct impact of IFN-alpha on proliferative and apoptotic signals upon in vitro activation of human naive CD4+ T lymphocytes. We demonstrate that IFN-alpha protects T cells from the intrinsic mitochondrial-dependent apoptosis early upon TCR/CD28 activation. IFN-alpha acts by delaying entry of cells into the G1 phase of the cell cycle, as well as by increasing Bcl-2 and limiting Bax activation. Later, upon activation, T cells that were exposed to IFN-alpha showed increased levels of surface Fas associated with partially processed caspase-8, a key component of the extrinsic apoptotic pathway. Caspase-8 processing was augmented furthermore by Fas ligation. Overall, these findings support a model whereby IFN-alpha favors an enhanced clonal expansion, yet it sensitizes cells to the Ag-induced cell death occurring at the end of an immune response. These observations point to a complex role of type I IFN in regulating the magnitude of proliferation and survival of naive CD4+ T cells during primary response and underline how crucial could be the timing of exposure to this cytokine.
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PMID:A dual role of IFN-alpha in the balance between proliferation and death of human CD4+ T lymphocytes during primary response. 1535 20

In the thymus, during T-cell differentiation, the expression of the peripheral benzodiazepine receptor (PBR) modulates. The protein level decreases between the double negative and double positive stages, and then increases when thymocytes become single positive. We addressed the role played by PBR in T-cell maturation. To this aim, we used Jurkat cells, which are immature T lymphocytes derived from an acute lymphoblastic leukemia. These cells are PBR negative and were stably transfected to achieve PBR levels similar to that in mature T cells. Using the DNA chip technology, we analyzed the PBR expression-dependent gene changes and evidenced that PBR-expressing cells exhibited more mature features than mock-transfected ones. A majority of the modulated genes encode proteins playing direct or indirect roles during the lymphocyte maturation process. In particular, PBR expression induced several differentiation markers (such as CD1, CD6), or key regulating elements (e.g., RAG1, RAG2, CD99, TCR). By contrast, some regulators of TCR signaling were reduced. PBR expression also affected the expression of critical apoptosis regulators: the proapoptotic lipocortin I, galectin-1, and galectin-9 were reduced while the antiapoptotic Bcl-2 was induced. Altogether our results supported the hypothesis that PBR controls T-cell maturation and suggested mechanisms through which PBR may regulate thymocyte-positive selection.
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PMID:Expression of the peripheral benzodiazepine receptor triggers thymocyte differentiation. 1547 57

NOD mice exhibit defects in T cell functions that have been postulated to contribute to diabetes susceptibility in this strain. However, early T cell development in NOD mice has been largely unexplored. NOD mice with the scid mutation and Rag1 deficiency were analyzed for pre-T cell development in the NOD genetic background. These strains reveal an age-dependent, programmed breakdown in beta selection checkpoint enforcement. At 5-8 wk of age, even in the absence of TCRbeta expression, CD4+ and CD4+CD8+ blasts appear spontaneously. However, these breakthrough cells fail to restore normal thymic cellularity. The breakthrough phenotype is recessive in hybrid (NODxB6)F1-scid and -Rag1null mice. The breakthrough cells show a mosaic phenotype with respect to components of the beta selection program. They mimic normal beta selection by up-regulating germline TCR-Calpha transcripts, CD2, and Bcl-xL and down-regulating Bcl-2. However, they fail to down-regulate transcription factors HEB-alt and Hes1 and initially express aberrantly high levels of Spi-B, c-kit (CD117), and IL-7Ralpha. Other genes examined distinguish this form of breakthrough from previously reported models. Some of the abnormalities appear first in a cohort of postnatal thymocytes as early as the double-negative 2/double-negative 3 transitional stage. Thus, our results reveal an NOD genetic defect in T cell developmental programming and checkpoint control that permits a subset of the normal outcomes of pre-TCR signaling to proceed even in the absence of TCRbeta rearrangement. Furthermore, this breakthrough may initiate thymic lymphomagenesis that occurs with high frequency in both NOD-scid and -Rag1null mice.
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PMID:Deranged early T cell development in immunodeficient strains of nonobese diabetic mice. 1549 84


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