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)

During acute infection, latent and lytic Epstein-Barr virus (EBV) epitope-specific CD8(+) T cells have a CD45RO(+) CD45RA(-) phenotype. However, after resolution of the infection, a large proportion of these cells, particularly those specific for lytic viral epitopes, re-express the CD45RA molecule. The role of CD8(+) CD45RA(+) T cells in ongoing immunity to EBV and other viruses is unknown. We now demonstrate that, relative to their CD45RO(+) counterparts, the EBV-specific CD8(+) T cells that revert to CD45RA expression after acute infectious mononucleosis are not in cell cycle, have longer telomeres, and are more resistant to apoptosis partly because of increased Bcl-2 expression. However, the EBV-specific CD8(+) CD45RA(+) T cells have shorter telomeres than the total CD8(+) CD45RA(+) T-cell pool and predominantly express low levels of the CCR7 chemokine receptor, indicating that they are not naive cells. In addition, EBV-specific CD8(+) CD45RA(+) T cells can be induced to proliferate and exhibit potent cytotoxic activity against target cells loaded with specific peptide. Our results strongly suggest, therefore, that EBV-specific CD8(+) CD45RA(+) T cells represent a stabilized virus-specific memory pool and not terminally differentiated effector cells. The identification of mechanisms that enable stable virus-specific CD8(+) T cells to persist after acute infection may lead to the enhancement of antiviral immunity in immunocompromised and elderly persons.
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PMID:Epstein-Barr virus-specific CD8(+) T cells that re-express CD45RA are apoptosis-resistant memory cells that retain replicative potential. 1213 May 5

Differential gene expression analysis, using high-density microarray chips, demonstrated 300-400 genes to be deregulated in mantle cell lymphomas (MCLs) compared with normal B-cell populations. To investigate the significance of this genetic signature in lymphoma etiology and diagnostics, we selected 90 annotated genes involved in a number of cellular functions for further analysis. Our findings demonstrated a normal gene expression of CCR7, which indicated a normal homing to primary follicles, which was in contrast to other receptors for B-cell trafficking, such as a significant down-regulation for CXCR5 and CCR6, as well as down-regulation of IL4R involved in differentiation. This indicated that the malignant transformation of a normal B cell could have appeared during the transition of a primary follicle to a germinal center, i.e., after an initial B-cell activation. Genes involved in blockage of antiproliferative signals in normal cells were also deregulated, e.g., gene expression of TGF beta 2 and Smad3 was suppressed in MCLs. Furthermore, lymphoproliferative signal pathways were active in MCLs compared with normal B cells, because genes encoding, e.g., IL10R alpha and IL18 were up-regulated, as were oncogenes like Bcl-2 and MERTK. Genes encoding receptors for different neurotransmitters mediating B-cell stimulation, such as norepinephrine and cannabinoids were also up-regulated, again illustrating deregulation of a complex network of genes involved in growth and differentiation. Furthermore, hierarchical cluster analysis revealed two subpopulations of MCLs, which indicates that despite the homogeneous and strong overexpression of cyclin D1, further subtyping might be possible.
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PMID:Mantle cell lymphomas express a distinct genetic signature affecting lymphocyte trafficking and growth regulation as compared with subpopulations of normal human B cells. 1215 46

Four human CD8+ T-cell subsets, naive (CCR7+CD45RA+), central memory (TCM, CCR7+CD45RA-), effector memory (TEM, CCR7-CD45RA-), and CD45RA+ effector memory cells (TEMRA, CCR7-CD45RA+) were compared for their capacity to proliferate and differentiate in response to antigen or homeostatic cytokines. Cytokine responsiveness and interleukin-15 receptor expression were low in naive T cells and progressively increased from TCM to TEM and TEMRA. In contrast, the capacity to accumulate in response to T-cell receptor (TCR) or cytokine stimulation showed a reciprocal pattern and was associated with resistance to cell death and Bcl-2 expression. Whereas all TCR-stimulated cells acquired a CD45RA-CCR7- phenotype, cytokine-stimulated cells maintained their phenotype with the exception of TCM cells, which expressed CCR7, CD45RA, and perforin in various combinations. Single CD8+ TCM cells, but not TEM cells, could be expanded with cytokines, and the obtained clones displayed several distinct phenotypes, suggesting that TCM cells are heterogeneous. Consistently, CCR4 expression in the CD8+ TCM pool discriminated CCR4+ type 2 polarized cells (Tc2) and CCR4-CTL precursors. Finally, ex vivo bromodeoxyuridine (BrdU) incorporation experiments revealed that memory subsets have different in vivo proliferation rates, with CCR4-TCM having the highest turnover and TEMRA the lowest. These results show that human CD8+ memory T-cell subsets have different proliferation and differentiation potentials in vitro and in vivo. Furthermore, they suggest that TEMRA cells are generated from a TCM subset upon homeostatic proliferation in the absence of antigen.
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PMID:Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. 1257 17

Tuberculous pleuritis is a good model for the study of specific cells at the site of active Mycobacterium tuberculosis (Mtb) infection. We investigated the frequency and phenotype of NK cells in paired samples of peripheral blood and pleural fluid (PF) from patients with tuberculosis (TB) or parapneumonic infection. We demonstrated for the first time a reduction of NK cells in PF from TB with an enrichment in the CD56brightCD16- subset. In agreement, in PF NK cells we observed an increased expression of CD94, NKG2A, CD62L, and CCR7 molecules and lower expression of Bcl-2 and perforin. The activation markers CD69 and HLA-DR were also increased. The enrichment in the CD56bright subset was due to an increased susceptibility to apoptosis of CD56+CD16+ NK cells mediated by heat-labile and stable soluble factors present in tuberculous effusions and not in PF from other etiologies. Furthermore, in TB patients, Mtb-induced IFN-gamma production by PF NK cells was not dependent on the presence of CD3+, CD19+, and CD14+ cells, suggesting a direct interaction of CD56bright cells with Mtb and/or the involvement of other accessory cells present at the site of Mtb infection.
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PMID:Increased susceptibility to apoptosis of CD56dimCD16+ NK cells induces the enrichment of IFN-gamma-producing CD56bright cells in tuberculous pleurisy. 1627 43

The formation of immunological memory is a hallmark of adaptive immunity and the goal of vaccination. For CD8(+ )T cells, successful generation of memory cells has been linked to IL-7 receptor alpha (IL-7Ralpha) expression, suggesting a role for IL-7 signaling, which in turn is important for preventing T cell apoptosis. We thus investigated the kinetics and changes of IL-7Ralpha and anti-apoptotic protein Bcl-2 expression levels in tetanus toxoid (TT)-specific CD4(+ )T cells at different time points prior and after TT re-immunization of TT-immune individuals. Prior to re-immunization, most TT-specific CD4(+ )T cells were high IL-2 producers, CD45RA(-)CCR7(+), IL-7Ralpha(high)Bcl-2(high) cells, resembling typical long-lived central memory cells. Already 5 days, and more importantly at the peak of the response, after TT re-immunization, a substantial fraction of these cells secreted also IFN-gamma, down-regulated CCR7, IL-7Ralpha and Bcl-2 and became Ki67 positive, resembling effector memory cells. In contrast, TT-specific CD4(+ )T cells found 60 days or later after re-immunization were again as baseline. Interestingly, a significant fraction of IL-7Ralpha(high)Bcl-2(high) TT-specific CD4(+ )T cells, i.e. the proposed memory cell precursors, remained stable at any time point upon re-immunization. Together, these results suggest that IL-7Ralpha expression levels might be a useful marker for identifying long-lived Ag-specific CD4(+ )T cells in memory T cells.
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PMID:Functional and phenotypic characterization of tetanus toxoid-specific human CD4+ T cells following re-immunization. 1737 91

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

Chemokine CCL21 can effectively attract CCR7(+) dendritic cells (DCs), however its role in this event is poorly understood. In this report, we investigated the effect of exogenous CCL21 expressed in breast cancer MCF-7 on human monocyte-derived DCs. CCL21-transfected MCF-7 stimulation prompted DC functions: migration, antigen-uptake and presentation. The stimulated DCs facilitated Th1 type cytokines production, perforin-forming CD8(+) T cell transformation and final T cell-associated clearance of MCF-7. Moreover, the MCF-7-resourced CCL21 protected DCs from apoptosis significantly, involving up-regulations of Bcl-2 expression and NF-kappaB activity, and reduction of caspase-3. This study provides evidence that tumor-derived CCL21 increases the presentation and apoptosis resistance of DCs, suggesting such a mechanism may be useful for the improvement of tumor cell immunogenicity and anti-tumor response.
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PMID:Tumor transfected with CCL21 enhanced reactivity and apoptosis resistance of human monocyte-derived dendritic cells. 1847 50

IL-21 is a key T-cell growth factor (TCGF) involved in innate and adaptive immune response. It contributes to the proliferation of naive, but not memory T lymphocytes. However, the full spectrum of IL-21 activity on T cells remains unclear. Here, we demonstrate that IL-21 primarily maintains the expression of specific naive cell surface markers such as CD45RA, CD27, CD62L and CCR7 on human CD4(+) T lymphocytes and that the expression of CCR7 induces cell migration by means of CCL21 chemoattraction. These effects contrast with those of IL-2 which induced the marked proliferation of CD4(+) T lymphocytes, leading to an activated-memory phenotype. Nevertheless, IL-21 maintained cell cycle activation and expression of proliferation markers, including proliferating cell nuclear antigen and Ki-67, and triggered T-cell proliferation via TCR and co-stimulation pathways. Unlike IL-2, IL-21 decreased the expression of the anti-apoptotic Bcl-2 protein, which correlated with the absence of activation of the phosphatidylinositol 3'-kinase/Akt signaling pathway. Thus, IL-21 is a TCGF whose function is the preservation of a pool of CD4(+) T lymphocytes in a naive phenotype, with a low proliferation rate but with the persistence of cell cycling proteins and cell surface expression of CCR7. These findings strongly suggest that IL-21 plays a part in innate and adaptive immune response owing to homeostasis of T cells and their homing to secondary lymphoid organs.
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PMID:IL-21 promotes survival and maintains a naive phenotype in human CD4+ T lymphocytes. 1855 71

4-1BB (CD137) is expressed on dendritic cells (DCs) and its biological function has remained largely unresolved. By comparing 4-1BB-intact (4-1BB(+/+)) and 4-1BB-deficient (4-1BB(-/-)) DCs, we found that 4-1BB was strongly induced on DCs during the maturation and that DC maturation was normal in the absence of 4-1BB. However, DC survival rate was low in the absence of 4-1BB, which was due to the decreased Bcl-2 and Bcl-x(L) in 4-1BB(-/-) DCs compared with 4-1BB(+/+) DCs after DC maturation. Consistent with these results, 4-1BB(-/-) DCs showed an increased turnover rate in steady state and more severely decreased in spleen by injecting LPS compared with 4-1BB(+/+) DCs. When OVA-pulsed DCs were adoptively transferred to recipient mice along with OVA-specific CD4(+) T cells, 4-1BB(-/-) DCs did not properly migrate to the T cell zone in lymph nodes and poorly induced proliferation of CD4(+) T cells, although both DCs comparably expressed functional CCR7. Eventually, 4-1BB(-/-) DCs generated a reduced number of OVA-specific memory CD4(+) T cells compared with 4-1BB(+/+) DCs. To further assess the role of 4-1BB on DC longevity in vivo, 4-1BB(+/+) and 4-1BB(-/-) C57BL/6 were administrated with Propionibacterium acnes that develop liver granuloma by recruiting DCs. Number and size of granuloma were reduced in the absence of 4-1BB, but the inflammatory cytokine level was comparable between the mice, which implied that the granuloma might be reduced due to the decreased longevity of DCs. These results demonstrate that 4-1BB on DCs controls the duration, DC-T interaction, and, therefore, immunogenicity.
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PMID:4-1BB functions as a survival factor in dendritic cells. 1929 8

Regulatory T cells (Treg) play crucial roles in regulating autoimmune responses and immunity to tumors and infectious diseases. However, numerous subpopulations of Treg are now being described and the utility of various Treg markers is being reassessed. Here we report the results of a detailed phenotypic comparison of two supposedly regulatory human T-cell populations, namely CD4+FOXP3+ T cells and CD4+CD25hi T cells. We find that CD4+FOXP3+ cells are extremely heterogeneous with respect to CD25 expression and that FOXP3+ and CD25hi CD4+ T cells differ in their expression of chemokine receptors (CCR), CD95 and Bcl-2, suggestive of distinct migration characteristics and susceptibility to apoptosis. Further, we propose that CD25 expression should be regarded as an activation marker rather than as a defining marker of Treg. Lastly, CD4+FOXP3+ T cells activated in vitro with malaria antigen expressed the highest levels of CCR4 and CD95, and the lowest levels of CCR7, indicating that they are most likely generated from effector memory cells during an immune response and rapidly succumb to apoptosis at the end of the response.
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PMID:Phenotypic analysis of human peripheral blood regulatory T cells (CD4+FOXP3+CD127lo/-) ex vivo and after in vitro restimulation with malaria antigens. 1987 16


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