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GALIG gene expression induces apoptosis in cultured cells through a pathway still under investigation. It is highly expressed in leukocytes but weakly detectable in bone marrow, suggesting a role in the myeloid lineage homeostasis. We show here that GALIG-induced cell death is counteracted by the overexpression of MCL-1, a pro-survival member of the Bcl2 family. Moreover, during spontaneous neutrophil apoptosis, a substantial increase in GALIG gene expression is observed : GALIG still opposes MCL-1. Finally, in bone marrow and peripheral blood cells from patients with Acute Myeloid Leukemia type 2, the level of GALIG transcripts is massively down-regulated when compared to their normal counterparts, while MCL-1 is expressed to the same extent. These data suggest that GALIG could be a key player in the cell death pathway involved in leukocytes homeostasis and myeloid malignancies.
Galig, a gene embedded within the galectin-3 gene, induces cell death when transfected in human cells. This death is associated with cell shrinkage, nuclei condensation, and aggregation of mitochondria. Galig contains two different overlapping open reading frames encoding two unrelated proteins. Previous observations have shown that one of these proteins, named mitogaligin, binds to mitochondria and promotes the release of cytochrome c. However, the mechanism of action of this cytotoxic protein remains still obscure.
Live attenuated RNA viruses make highly efficient vaccines. Among them, measles virus (MV) vaccine has been given to a very large number of children and shown to be highly effective and safe. MV vaccine induces a life-long immunity after a single or two low-dose injections. It is easily produced on a large scale in most countries and can be distributed at low cost. Reversion to pathogenicity has never been observed with this vaccine. Because of all these characteristics, MV vaccine might be a very promising vector to immunise children against both measles and other infectious agents, such as HIV or flaviviruses, in the developing world. In this article, we describe recent data that we obtained showing the capacity of recombinant Schwarz MVs to express proteins from human immunodeficiency or West Nile viruses, and to induce specific immune responses able, in the case of West Nile virus, to protect from an experimental challenge.
Live attenuated RNA viruses make highly efficient vaccines. Among them, measles virus (W) vaccine has been given to a very large number of children and has been shown to be highly efficacious and safe. Therefore, this vaccine might be a very promising vector to immunize children against both measles and other infectious agents, such as human immunodeficiency virus. A vector was previously derived from the Edmonston B strain of MV, a vaccine strain abandoned 25 years ago. Sequence analysis revealed that the genome of this vector diverges from Edmonston B by 10 amino acid substitutions not related to any Edmonston subgroup. Here we describe an infectious cDNA for the Schwarz/Moraten strain, a widely used MV vaccine.
The influence of HIV burden variations on the frequencies of Ag-specific CD8(+) T cell responses was evaluated before and during highly active antiretroviral therapy by analyzing the number, diversity, and function of these cells. The frequencies of HLA-A2-restricted CD8+ PBL binding HLA-A2/HIV-epitope tetramers or producing IFN-gamma were below 1%, A panel of 16 CTL epitopes covering 15 HLA class I molecules in 14 patients allowed us to test 3.8 epitopes/patient and to detect 2.2 +/- 1.8 HIV epitope-specific CD8(+) subsets per patient with a median frequency of 0.24% (0.11-4.79%).
Leukemic T-LGL (large granular lymphocyte) composed of clonal CD3(+)TCR alpha beta(+)CD8(+)CD57(+) cells were compared with oligoclonally CD3(+)CD8(+)CD57(-) lymphocytes expanded after BMT. Leukemic CD3(+)CD8(hl+)CD57(+) LGL showed several phenotypic differences such as an upregulation of CD16 and adhesion molecules (mainly CD11c, CD58 and CD54), activation markers and an exclusive CD45RA isoform expression. Unstimulated CD3(+)CD8(+)CD57(+) LGL from both leukemic and BMT donors spontaneously developed an ex vivo CTL-like CD3-redirected cytotoxicity but no NK cell activity. Different stimuli (PHA, PMA or rhlL-2) induced similar cytotoxic profiles after a 6-day culture involving a CD3-redirected lysis predominating over a low NK cell activity.
Based on the previous observation that RANTES mediates the cytotoxic activity of human HIV-specific CD8(+) T cells via the chemokine receptor CCR3, we studied the effect of this chemokine on different effector CD8(+) cytolytic cells requiring Fas/Fas ligand (FasL) or perforin-dependent pathway,In CTLs derived from PBMCs of HIV-infected patients, both the spontaneous and the RANTES-induced cytotoxicity were inhibited by anti-FasL, neutralizing Abs, In contrast, allogeneic CTLs or NK cells killing through perforin were not affected by RANTES and anti-Fast Ab, Accordingly, RANTES enhanced the expression of Fast in a concentration- and time-dependent manner in HIV-specific CTLs, whereas anti-RANTES Ab decreased markedly Fast expression. Finally, cell surface expression of Fast protein in HIV-specific CTLs was also upregulated by eotaxin, a selective ligand for CCR3, Our observations show that the action of RANTES via CCR3 is necessary to regulate Fast expression on HIV-specific CD8(+) T cells that kill through the Fas/FasL, pathway.
Major expansions of CD8(hi+)CD57(+) T lymphocytes frequently occur during human immunodeficiency virus (HIV) infection and after transplantation. To investigate mechanisms of such cell expansion, we compared the activation and functional status of CD8(hi+)CD57(+) and CD57(-) peripheral blood lymphocytes (PBL) from normal, bone marrow transplantation (BMT) and HIV+ donors, The CD8(hi+)CD57(+) PBL from BMT and HIV+ donors preferentially displayed CD38 and HLA-DR activation markers without correlation between CD8(hi+)CD57(+) percentages and HIV load, the CD45RA(+) isoform in all ex vivo conditions but acquired CD45RO after in vitro expansion, CD11b and CD11c in BMT and HIV+ donors but decreased expression of CD62-L, VLA-2 and VLA-6.
An inhibitor of the cytotoxic functions (ICF) mediated by human immunodeficiency virus (HIV)- or HLA-specific cytotoxic T lymphocytes, natural killer and lymphokine-activated killer (LAK) cells is secreted by CD8(+)CD57(+) T lymphocytes, a subset expanded during infection with HIV and after bone marrow transplantation. We previously showed an apparent molecular mass of 20-30 kDa for this soluble glycosylated concanavalin A-binding inhibitor which is distinct from known cytokines. Here, we report a characterization of the mechanism of action of this CD8(+)CD57(+) ICF. We show that the ICF-induced inhibition of LAK cell cytolytic activity is transient, with a spontaneous recovery of cytolytic potential after 18 h.
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