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Biomedical subjects

E Vivier

Publications and source records attributed to E Vivier.

At least 19 recordsLinked to original sources
PubMed1992

Infection of human natural killer (NK) cells with replication-defective human T cell leukemia virus type I provirus. Increased proliferative capacity and prolonged survival of functionally competent NK cells.

Human T-cell leukemia virus type I (HTLV-I) can infect a variety of human cell types, but only T lymphocytes are efficiently immortalized after HTLV-I infection. This study reports an attempt to infect and to immortalize NK cells with HTLV-I. Co-cultivation of freshly isolated NK cells with a HTLV-I-producing T cell line did not result in NK cell infection. However, NK cells activated with an anti-CD16 mAb and co-cultivated with a HTLV-I-producing T cell line were reproducibly infected by HTLV-I. HTLV-I infection was documented in NK cell lines and clones by the detection of defective integrated provirus by both Southern blot and polymerase chain reaction analysis. Although HTLV-I-infected NK cells produced viral proteins, they did not produce infectious viral particles. HTLV-I-infected NK cells were phenotypically indistinguishable from their uninfected counterparts (CD16+, CD2+, CD56+, CD3-). They also retained the ability to mediate both natural and antibody-dependent cell cytotoxicity. The IL-2-dependent proliferation of HTLV-I-infected NK cells was significantly greater than that of uninfected NK cells. The doubling time of this infected population was reduced from 9 days to 3 days, and the overall survival of the culture in the absence of restimulation was extended from 5 wk to 18 wk. Unlike T lymphocytes, HTLV-I-infected NK cells were not immortal, implying a fundamental difference between these two lymphocyte populations.

Base Sequence↗
PubMed1992

CD2 triggering stimulates the formation of platelet-activating factor-acether from alkyl-arachidonoyl-glycerophosphocholine in a human CD4+ T lymphocyte clone.

A human CD4+ T lymphocyte clone synthesized platelet-activating factor (PAF) acether when stimulated via the CD2 pathway. PAF-acether was characterized by biochemical and biophysical properties and precursor-product relationships (alkyl-acyl-sn-glycero-3-phosphocholine (GPC)----alkyl-lyso-GPC (lyso-PAF)----PAF-acether) were demonstrated. The clone contained substantial amounts of alkyl-acyl-GPC. i) Hydrolysis of alkyl-acyl-GPC upon CD2 stimulation was evidenced: [3H]alkyl-lyso-GPC was formed from [3H]alkyl-acyl-GPC in [3H] alkyl-labeled cells; alkyl-lyso-GPC production was also bioassayed after CD2 triggering. ii) The rate of arachidonate transfer from diacyl-GPC to alkyl-acyl-GPC increased after CD2 stimulation of the [3H]arachidonate-labeled P28D T cells, demonstrating alkyl-lyso-GPC formation. iii) Comparison of the molecular species of the produced PAF-acether with those of arachidonate-containing alkyl-acyl-GPC raises the possibility that the produced PAF-acether is related to alkyl-arachidonoyl-GPC.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1992

Immunoregulatory functions of paf-acether. VIII. Inhibition of IL-4-induced human IgE synthesis in vitro.

In the present study we showed that paf-acether (paf), a naturally occurring phospholipid cytokine, down-regulated IL-4-induced IgE production by mononuclear cells from healthy nonatopic donors in a dose-dependent fashion from 10 microM to 10 pM. Kinetic studies indicated that addition of paf together with IL-4 strongly decreased IgE synthesis from day 7 up to day 14. By contrast, paf had little or no inhibitory effect on the levels of IgM, total IgG, and IgA production. The inhibition of IgE synthesis by paf occurred independently of known inhibitors of IgE synthesis, IFN-gamma, PGE2, and transforming growth factor-beta because the addition of anti-IFN-gamma (10 micrograms/ml) mAb, indomethacin (0.1 microM), or anti-transforming growth factor-beta (10 micrograms/ml) mAb, together with paf and IL-4, did not overcome the inhibition of IgE synthesis. Finally, paf not only inhibited IL-4-induced IgE production but also reduced both germ-line and productive IgE transcripts levels by 77 and 67%, respectively, suggesting that modulation of IgE production by paf occurred at the transcriptional level. Taken together, these results suggest a novel IgE regulatory mechanism by phospholipid cytokine.

Dinoprostone↗
PubMed1992

Signaling function of reconstituted CD16: zeta: gamma receptor complex isoforms.

Natural killer cells express an Fc receptor for IgG (CD16) in association with disulfide-linked dimers composed of two homologous subunits: the zeta chain of the T cell antigen receptor complex and the gamma chain of the mast cell/basophil Fc receptor for IgE. The ability of zeta and gamma to transduce CD16-mediated activation signals was compared by reconstituting distinct CD16 receptor isoforms composed of various combinations of zeta- and gamma-containing dimers. Stably transformed non-hematopoietic and hematopoietic cell lines were established that expressed chimeric molecules comprising the extracellular domain of CD16 joined to the transmembrane and intracellular domains of zeta or gamma. Reconstituted CD16 receptor complexes triggered Ca2+ influx, tyrosine phosphorylation, and IL-2 production in stable transformants of the Jurkat T cell line. However, cross-linking of the CD16/gamma chimera induced a specific pattern of tyrosine phosphorylation and was more efficient at signal transduction than a CD16, zeta-zeta complex, suggesting that zeta and gamma cytoplasmic domains may be coupled to distinct tyrosine kinase pathways that differentially regulate CD16-mediated activation signals. By contrast, both CD16/zeta and CD16/gamma chimeric molecules were not functional in stable transformants of the fibroblast Chinese Hamster Ovary cell line, indicating a requirement for downstream signaling components present in hematopoietic cells. Finally, the zeta transmembrane domain appears to preferentially associate with CD16 rather than the CD3:TCR complex, suggesting that a hierarchy of molecular interactions governs NK and T cell differentiation.

Animals↗
PubMed1992

Structure and function of the CD16:zeta:gamma complex expressed on human natural-killer cells.

Natural-killer (NK) cells are large granular lymphocytes involved in host defense against tumor cells and virally-infected cells. In addition to natural cytotoxicity, NK cells can effect antibody-dependent cytotoxicity mediated by CD16 (Fc gamma RIIIA alpha). It has recently been shown that CD16 is associated with disulfide-linked dimers composed of 2 homologous sub-units, zeta and gamma. These transducing molecules are also associated with other multimeric cell-surface receptors such as the T-cell antigen receptor (CD3:TCR) complex (zeta and gamma) and the high-affinity Fc receptor for IgE (Fc epsilon RI) expressed on basophils and mast cells (gamma). These results show that distinct cell-surface receptors utilize common transducing sub-units, and emphasize the homology between the CD16, Fc epsilon RI and CD3:TCR complexes. However within the lymphoid cells, the gamma-gamma homodimer is preferentially expressed in NK cells and cytotoxic T cells, suggesting that specific combinations of these transducing dimers might sub-serve distinct signal-transducing functions, and contribute to lymphocyte heterogeneity.

CD3 Complex↗
PubMed1991

Structural similarity between Fc receptors and T cell receptors. Expression of the gamma-subunit of Fc epsilon RI in human T cells, natural killer cells and thymocytes.

The TCR complex is composed of a clonotypic heterodimer (Ti alpha:beta or gamma:delta) noncovalently associated with the CD3 complex (gamma, delta, and epsilon), and with one or more disulfide-linked dimers whose components are designated zeta and eta. zeta and eta are alternative transcripts of a common gene and are structurally related to the gamma-subunit of the FcR for IgE expressed on mast cells and basophils (Fc epsilon RI). Recent evidence suggests that gamma can also be expressed in natural killer cells and in a murine cytotoxic T cell line, CTLL. Because zeta, eta, and gamma have the potential to join together to form disulfide linked homo- and heterodimers, it has been postulated that alternative dimeric forms composed of these zeta-related subunits might subserve unique signal transducing functions in hematopoietic cells. We have used mAb reactive with zeta and gamma to systematically examine the expression of these zeta-related dimers in human T cells, NK cells, and thymocytes. Our results show that each cell type expresses characteristic combinations of zeta-related homo- and hetero-dimers, and are therefore consistent with the possibility that these subunits contribute to the functional heterogeneity of lymphocyte subsets.

Antibodies, Monoclonal↗
PubMed1991

Coassociation of CD26 (dipeptidyl peptidase IV) with CD45 on the surface of human T lymphocytes.

In the present report, we demonstrated that modulation of CD26 from T cell surface induced by antiCD26 (1F7) led to enhanced phosphorylation of CD3 zeta tyrosine residues and increased CD4 associated p56lck tyrosine kinase activity. We further showed that CD26 was comodulated on the T cell surface with CD45, a known membrane-linked protein tyrosine phosphatase and that anti-CD26 was capable of precipitating CD45 from T cell lysates. These findings strongly suggest that CD26 may be closely associated with the CD45 protein tyrosine phosphatase on T cell surface and further support the notion that the interaction of CD26 with CD45 results in enhanced tyrosine kinase activity, zeta chain phosphorylation, and T cell activation.

Antigens, CD↗
PubMed1991

Expression and tyrosine phosphorylation of the T cell receptor zeta-subunit in human thymocytes.

Recent evidence suggests that the zeta-subunit of the TCR complex plays a critical role in transducing signals initiated by the Ag receptor heterodimer. Because thymic maturation involves specific interactions between the TCR complex and thymic stromal cells, the zeta-subunit has been postulated to also play a role in this process. To assess the potential for zeta to contribute to thymocyte maturation, we have used an anti-zeta mAb (TIA-2) to quantitate its expression in mature (CD3bright) and immature (CD3dim and CD3-) populations of human thymocytes. Using both flow cytometric and immunoblotting analysis, we found that the relative expression of TCR-zeta varied directly with the surface expression of CD3. Importantly, TCR-zeta was detected in the majority of CD3- thymocytes, indicating that its expression precedes the surface appearance of CD3:TCR. In thymocytes, TCR-zeta was found to be constitutively phosphorylated on tyrosine residues. The relative expression of phospho-zeta varied directly with the maturational stage of the thymocyte, with the mature (CD3bright), single positive cells accounting for most of the phospho-zeta found in the human thymus. The expression of phospho-zeta could be significantly increased by activating thymocytes with mAb reactive with either CD3 or CD2. These results suggest that TCR-zeta is functionally linked to the major thymocyte activation receptors.

Cell Differentiation↗
PubMed1991

Tyrosine phosphorylation of the Fc gamma RIII(CD16): zeta complex in human natural killer cells. Induction by antibody-dependent cytotoxicity but not by natural killing.

NK cells are large granular lymphocytes capable of killing certain tumor cells and virally infected cells in a non-MHC-restricted manner. NK cells can also effect an antibody dependent cytotoxicity that is triggered by CD16, an FcR for IgG. In NK cells, CD16 is expressed in association with zeta, a signal transducing subunit of the TCR complex. Here we show that, just as T cell activation via the TCR complex results in tyrosine phosphorylation of zeta TCR, NK cell activation via CD16 results in tyrosine phosphorylation of zeta NK. Whereas antibody-dependent cytotoxicity also results in tyrosine phosphorylation of zeta, natural cytotoxicity does not. Our results indicate that zeta functions as a transducing element for antibody dependent, but not antibody independent killing by NK cells. Consequently, NK cells are likely to express at least two distinct receptor complexes capable of triggering cytolytic effector function.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1991

CD2 is functionally linked to the zeta-natural killer receptor complex.

Natural killer (NK) cells express two distinct surface receptors capable of triggering cytolytic effector function. The first is CD16, an immunoglobulin Fc receptor that allows NK cells to mediate antibody-dependent killing (ADCC). NK cells express CD16 in association with zeta, a signal-transducing subunit that is also a component of the T cell receptor complex. Activation of NK cells via CD16 results in tyrosine phosphorylation of zeta. The second NK cell triggering receptor is CD2, a 50-55-kDa cell surface molecule that is also expressed on T cells. Here we show that NK cell activation induced by mAb reactive with CD2 (either anti-T11.1 alone or with anti-T11.2 in combination) also results in the tyrosine phosphorylation of zeta. Our results indicate that CD2 is functionally linked to the CD16-zeta complex and suggest that the zeta subunit plays a central role in the signal transduction pathways utilized by NK cells.

Antibodies, Monoclonal↗
PubMed1991

Immunoregulatory functions of paf-acether. VI. Dual effect on human B cell proliferation.

The role of paf-acether (paf), a phospholipid cytokine, in the modulation of human B cell function was investigated. Paf, from 1 x 10(-5) M to 10(-6) M, decreased B cell proliferation induced by both phorbol myristate acetate (PMA) and anti-IgM antibodies (anti-IgM Ab). By contrast, 1 x 10(-7) M to 1 x 10(-9) M paf enhanced PMA triggered, but not anti-IgM triggered B cell proliferation. B cell proliferation was modulated between 24 and 72 hr of culture indicating that the effect of paf did not merely reflect a shift in proliferation kinetics. Interestingly, paf also enhanced the spontaneous proliferation of a Burkitt lymphoma-derived B cell line, Raji, which suggests that paf can directly act on B cells. The modulatory effect of paf on peripheral blood B cells was independent of PMA concentration, yet the effect on Raji cells was dependent upon cell density. The data suggest that paf is a potent modulator of B cell function, and may be involved in the control of humoral immune response.

B-Lymphocytes↗
PubMed1990

Immunoregulatory functions of paf-acether. IV. Enhancement of IL-1 production by muramyl dipeptide-stimulated monocytes.

paf-Acether (paf) is a phospholipid mediator of inflammation released from monocytes along with IL-1. In this study, we have examined the role of paf on IL-1 production by human monocytes. When paf from 1 nM to 5 microM, but not its precursor lyso paf, was added to monocytes in the presence of muramyl dipeptide (MDP) or LPS, a marked increase in IL-1 activity over the value with MDP alone was observed. In contrast, paf alone had minimal activity over the same dose range. Antibodies against rHu IL-1 alpha and rHu IL-1 beta neutralized the increased IL-1 activity. Interestingly, MDP that prompts monocytes to synthesize IL-1, induced the synthesis of paf, as well. Most of the paf produced remained cell-associated and always preceded IL-1 synthesis. When the paf receptor antagonist, L-652,731 was added to monocytes, it prevented the enhancement of IL-1 activity induced by exogenous paf. In contrast, L-652,731 had little effect on MDP-induced IL-1 synthesis in the absence of exogenous paf. This may indicate that there are alternative mechanisms involved in the sequences of events leading to IL-1 production. It is also conceivable that the paf receptor antagonist is not able to compete or inhibit endogenous paf as well as it does for exogenous paf. Nevertheless, exogenous paf in association with a second signal, modulates IL-1 production from human monocytes in a positive manner. This may constitute another means through which paf can modulate inflammatory and immune reactions.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

Immunoregulatory functions of paf-acether. VI. Inhibition of T cell activation via CD3 and potentiation of T cell activation via CD2.

In the present report we further explored the role of paf-acether (paf), a phospholipid cytokine, in the modulation of T cell activation induced via the CD2 and the CD3 pathways. Evidence was obtained that paf inhibited T cell proliferation induced by immobilized CD3 mAb (OKT3i), but potentiated that induced by a combination with the CD2 mAb, anti-(T11.1 + D66). Both effects were dose-dependent between 2 and 10 microM paf, and specific in that lysoPC, a phospholipid closely related to paf, had no effect. The inhibition became apparent after 48 h and was maintained up to 144 h of culture, whereas the enhancement was observed only by 96 h of culture. Interestingly, paf was able to inhibit OKT3i mAb response when added to cultures as late as 24-48 h after the initiation of a 96 h incubation. By contrast, paf enhanced the proliferative response only when added concomitantly with anti-(T11.1 + D66) mAb, suggesting that it modulates an early event of T cell activation. paf, which enhanced T cell proliferation induced via the CD2 pathway, also led to a substantial up-regulation of IL-2 secretion and CD25 expression. Moreover, paf markedly augmented IL-4 secretion upon CD2 mAb stimulation. Finally, when T cells were triggered via the CD3 molecule, paf inhibited the proliferative response but also down-modulated CD25 expression without impairing IL-2 secretion. When considered together, these data demonstrate that paf, a phospholipid cytokine released during inflammatory reactions, play a differential regulatory role in T cell activation induced via the CD3 and CD2 (T11.1 + D66) pathways.

Antibodies, Monoclonal↗
PubMed1989

Biosynthesis of paf-acether. Paf-acether but not leukotriene C4 production is impaired in cultured macrophages.

After adherence for 24 or 48 h mouse peritoneal macrophages, upon a zymosan challenge, synthesized 114 +/- 55 and 82 +/- 31 pmol of paf-acether (paf)/mg of protein respectively, as compared with 513 +/- 195 pmol of paf/mg of protein in 2 h-adherent macrophages (means +/- S.D., n = 10). By contrast, 24 h- and 48 h-adherent macrophages exposed to zymosan produced more leukotriene C4 (2.7 +/- 1.1 and 1.4 +/- 0.2 nmol/mg of protein respectively, n = 5) than did 2 h-adherent macrophages (0.5 +/- 0.2 nmol/mg of protein, n = 5). Paf production was not altered when 2 h- and 24 h-adherent cells were cultured and/or stimulated in the presence of 5 microM-indomethacin, 10 microM-nordihydroguaiaretic acid or 100 microM-BW755C as compared with untreated cells. These results indirectly exclude the regulation of paf production by arachidonic acid metabolites. We investigated the efficiency of the enzymic steps which govern paf synthesis. We showed that the anabolic process was not impaired since (1) the amounts of alkylacylglycerophosphocholine and lyso-paf were similar in 2 h-, 24 h- and 48 h-adherent macrophages; (2) adding synthetic lyso-paf or acetyl-CoA to intact cells did not increase paf production in zymosan-stimulated 24 h- and 48 h-adherent macrophages; (3) the basal level of acetyltransferase was comparable in 2 h-, 24 h- and 48 h-adherent macrophages and in all cases was increased by 2-3 times upon zymosan challenge. We also showed that impaired paf production in 24 h- and 48 h-cultured macrophages was not due to the nature of the stimulus used to induce its synthesis.

Acetyltransferases↗
PubMed1988

Immunoregulatory functions of paf-acether. I. Effect of paf-acether on CD4+ cell proliferation.

Paf-acether or platelet-activating factor (1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a phospholipid mediator of inflammation initially described as a potent platelet-aggregating compound. It is newly formed by a variety of cells including monocytes and is now recognized as a major mediator of cell-cell interactions. The present studies were undertaken to determine whether paf-acether could modulate T cell function. We found that addition of paf-acether to CD4+ cells cultured with phytohemagglutinin markedly inhibited the proliferative response in a dose-dependent manner. Maximal inhibition occurred when paf-acether was present during the first 24 hr of cell culture and the presence of paf-acether did not alter the kinetics of CD4+ cell proliferation. Importantly, the mechanism by which paf-acether inhibited the proliferative response was not related to inhibition of interleukin 2 (IL-2) secretion since the amount of IL-2 in cultures was not altered and addition of exogenous IL-2 failed to restore the CD4+ cell proliferative response. Further, as judged by indirect immunofluorescence, paf-acether did not inhibit IL-2 receptor expression. Taken together, these data indicate that paf-acether interferes with some processes leading to CD4+ cell proliferation. This new role for the chemically defined monokine paf-acether emphasizes the potential role of inflammatory lipid mediators in the regulation of T cell response.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

Immunoregulatory functions of paf-acether. II. Decrease of CD2 and CD3 antigen expression.

Paf-acether (platelet-activating factor) is a phospholipid initially described as a potent platelet-aggregating compound. It is produced by numerous cell types and is now considered as an important mediator of cell-cell interactions. The effect of paf-acether on the expression of CD2 and CD3, two human T cell surface glycoproteins, was investigated by indirect immunofluorescence and flow cytometry. Paf-acether partially down-regulated, in a time- and dose-dependent manner, CD2 and CD3 but not HLA class I antigen expression on peripheral human T cells and Jurkat cells. Lysophosphatidylcholine, a phospholipid closely related to paf-acether, had no detectable modulatory effect on CD2 and CD3 expression. In addition to CD2/CD3 modulation, paf-acether markedly inhibited T cell proliferative response not only to phytohemagglutinin or concanavalin A but also to anti-CD3 or a stimulatory combination of anti-CD2 monoclonal antibodies. These data demonstrate for the first time that lipid mediators such as paf-acether might be involved in the regulation of the expression of cell surface glycoproteins that are essential in the execution of T cell function.

Antibodies, Monoclonal↗