The Experts below are selected from a list of 42345 Experts worldwide ranked by ideXlab platform
Frederic Triebel - One of the best experts on this subject based on the ideXlab platform.
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Lymphocyte Activation gene 3 lag 3 cd223 in plasmacytoid dendritic cells pdcs a molecular target for the restoration of active antitumor immunity
OncoImmunology, 2014Co-Authors: Chiara Castelli, Frederic Triebel, Licia Rivoltini, Chiara CamisaschiAbstract:We have recently reported that Lymphocyte Activation gene-3 (LAG-3,CD223) mediates the alternative, IFNα-deficient Activation of plasmacytoid dendritic cells (pDCs) at tumor sites. Our findings define a novel tumor-driven strategy that promotes immunosuppression by pDCs, and we have provided more detailed information regarding the immunomodulatory role of of LAG-3. The translational relevance of our results for the treatment of tumors and autoimmune diseases is discussed herein.
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Lymphocyte Activation gene 3 induces tumor regression and antitumor immune responses
European Journal of Immunology, 1999Co-Authors: Philippe Prigent, Michel Dreano, Frederic TriebelAbstract:: The Lymphocyte Activation gene-3 (LAG-3) product is an MHC class II ligand related to CD4. We investigated whether LAG-3 could be used in vivo to stimulate MHC class II(+) antigen-presenting cells (APC), such as resident macrophages or dendritic cells known to play a crucial role in processing and presenting of antigens to the immune system. We first introduced human (h) LAG-3 or mouse LAG-3 into three types of tumor cells (MCA 205, TS / A and RENCA) to evaluate its capacity to stimulate a tumor-specific immune response in vivo. In contrast to the progressive growth of wild-type cells in syngeneic mice, LAG-3-transfected tumors completely regressed or their growth was markedly reduced. Mice were significantly to completely protected against a rechallenge with parental tumor cells. Protection induced by hLAG-3(+) tumor cells involved recruitment of a CD8(+) T cell response since nu / nu mice and CD8-depleted mice did not reject tumors, and a systemic tumor-specific CTL activity was induced. Co-administration of soluble LAG-3 with wild-type tumor cells also markedly reduced primary tumor growth. Interestingly, immunization with LAG-3(+) tumor cells or co-administration of soluble LAG-3 with irradiated wild-type tumor cells reduced the growth of pre-established tumors. We therefore suggest that LAG-3 could be used as a vaccine adjuvant for its ability to trigger APC via MHC class II molecules.
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cd3 tcr complex associated Lymphocyte Activation gene 3 molecules inhibit cd3 tcr signaling
Journal of Immunology, 1998Co-Authors: Sigrid Hannier, Muriel Tournier, Georges Bismuth, Frederic TriebelAbstract:The Lymphocyte Activation gene-3 (LAG-3) molecule is a T cell Activation Ag closely related to CD4 at the gene and protein levels. We investigated whether LAG-3 itself may down-regulate the immune response by interfering with TCR signaling. The binding of Ab to the LAG-3 molecule followed by cross-linking (XL) inhibits cell proliferation and cytokine secretion in response to CD3XL on activated T cells. LAG-3XL-induced down-regulation is associated with functional unresponsiveness, as well as with high CD25 expression levels and reversion by exogenous IL-2. It is also associated with a down-modulation of CD3/TCR complex expression. At the biochemical level, LAG-3XL inhibits calcium response to CD3 stimulation. This inhibition is observed with different LAG-3- and CD3-specific mAbs on condition that the two receptors are cross-linked together. Finally, the capping of CD3 was shown to induce cocapping of LAG-3 molecules. Together, these results show that CD3/TCR complex-associated LAG-3 molecules can play an active role in negatively regulating the CD3/TCR Activation pathway. They ultimately suggest that LAG-3 is an inhibitory receptor in activated T Lymphocytes.
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cd4 major histocompatibility complex class ii interaction analyzed with cd4 and Lymphocyte Activation gene 3 lag 3 ig fusion proteins
European Journal of Immunology, 1995Co-Authors: Bertrand Huard, Philippe Prigent, Muriel Tournier, Denis Bruniquel, Frederic TriebelAbstract:We analyzed CD4 major histocompatibility complex (MHC) class II interactions with CD4 and Lymphocyte Activation gene (LAG)-3 recombinant fusion proteins termed CD4Ig and LAG-3Ig. CD4Ig bound MHC class II molecules expressed on the cell surface only when used in the micromolar range. This weak CD4Ig binding was specific, since it was inhibited by anti-CD4 and anti-MHC class II mAb. LAG-3Ig bound MHC class II molecules with intermediate avidity (Kd = 60 nM at 37 degrees C). Using LAG-3Ig as a competitor in a CD4/MHC class II-dependent cellular adhesion assay, we showed that this recombinant molecule was able to block CD4/MHC class II interaction. In contrast, no inhibition was observed in a CD4/MHC class II-dependent T cell cytotoxicity assay. Together, these results suggest that co-engagement of the TcR with CD4 alters the CD4/MHC class II molecular interaction to become insensitive to LAG-3Ig competition.
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Lymphocyte Activation gene 3 major histocompatibility complex class ii interaction modulates the antigenic response of cd4 t Lymphocytes
European Journal of Immunology, 1994Co-Authors: Bertrand Huard, Frederic Triebel, Muriel Tournier, Thierry Hercend, Florence FaureAbstract:The Activation requirements for antigen-dependent proliferation of CD4+ T cells are well documented, while the events leading to the inActivation phase are poorly understood. Here, we tested the hypothesis that the Lymphocyte-Activation gene 3 (LAG-3), a second major histocompatibility complex (MHC) class II ligand, plays a regulatory role in CD4+ T Lymphocyte Activation. CD4+ class II-restricted T cell clones were stimulated by their relevant antigen (hemagglutinin peptide or diphteria toxoid) and antigen-presenting cells with or without anti-LAG-3 monoclonal antibody (mAb). Kinetic studies were performed to monitor different Activation parameters, including the measurement of thymidine incorporation, expression of Activation antigens and cytokine secretion. Results showed that the time course from the initial time points up to the peak time point was not modified in the presence of anti-LAG-3 mAb. However, addition of these antibodies, either as whole IgG or as Fab fragments, led to increased thymidine incorporation values for late time points and, hence, to a shift in the decreasing proliferation curve. We also showed that expression of Activation antigens, such as CD25, was higher in the presence of anti-LAG-3 mAb, and that cytokine concentrations, i.e. of interferon-γ or interleukin-4, were higher in the corresponding culture supernatants. In addition, we tested whether the effects of anti-LAG-3 mAb were limited to antigen-dependent. MHC class II-restricted responses. The proliferative responses of CD4+ T cell clones following stimulation with either interleukin-2, mitogens, a combination of anti-CD2 mAb, immobilized anti-CD3 or anti-T cell receptor mAb were not altered by anti-LAG-3 mAb. The allogeneic proliferative response of a CD8+ T cell clone was also not affected. Overall, the present analysis reveals a modulating effect of anti-LAG-3 mAb, mediated specifically on antigen-dependent, MHC class II-restricted responses of CD4+ T cell lines. These results support the view that LAG-3/MHC class II interaction down-regulates antigen-dependent stimulation of CD4+ T Lymphocytes.
Charles S. Owen - One of the best experts on this subject based on the ideXlab platform.
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Initiation of antigen receptor endocytosis and B Lymphocyte Activation lie on independent biochemical pathways.
Immunology and Cell Biology, 1993Co-Authors: Randy L. Shuler, Charles S. OwenAbstract:Initiation of antigen receptor endocytosis and B Lymphocyte Activation lie on independent biochemical pathways
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Initiation of antigen receptor endocytosis and B Lymphocyte Activation lie on independent biochemical pathways.
Immunology and cell biology, 1993Co-Authors: Randy L. Shuler, Charles S. OwenAbstract:Peroxidase-conjugated anti-surface immunoglobulin (sIg) was used quantitatively to monitor endocytosis of crosslinked sIg on murine B Lymphocytes. The role of biochemical second messengers in the initiation of endocytosis was assessed by employing several inhibitors. A novel peroxidase detection system was used and temperature-dependent decreases in sIg density on immunoperoxidase-labelled murine Lymphocytes were monitored. Metabolic inhibitors as well as colchicine and cytochalasin D were utilized to confirm that the internalization of sIg could be blocked by classical inhibitors of the endocytosis process. The role of tyrosine kinase activity was established by the fact that endocytosis was significantly reduced with 100 micrograms/mL genistein. Experiments using EGTA or 1,2-bis(beta-aminophenoxy)ethane-N-N,N'-tetraacetic acid (BAPTA) to chelate Ca2+ indicated that Ca2+ plays little role in endocytosis. Likewise, protein kinase C (PKC) was not found to be involved in endocytosis, as Activation of PKC with 50 ng/mL phorbol 12-myristate 13-acetate, or inhibition of the enzyme with 1 nmol/L or 5 nmol/L staurosporin, did not modulate endocytosis. Taken together, results suggested that ligand-induced endocytosis of antigen receptors is mediated primarily through localized membrane events and is not dependent upon the classical B Lymphocyte Activation signals, such as the biochemical events in the inositol phosphate cascade.
Randy L. Shuler - One of the best experts on this subject based on the ideXlab platform.
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Initiation of antigen receptor endocytosis and B Lymphocyte Activation lie on independent biochemical pathways.
Immunology and Cell Biology, 1993Co-Authors: Randy L. Shuler, Charles S. OwenAbstract:Initiation of antigen receptor endocytosis and B Lymphocyte Activation lie on independent biochemical pathways
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Initiation of antigen receptor endocytosis and B Lymphocyte Activation lie on independent biochemical pathways.
Immunology and cell biology, 1993Co-Authors: Randy L. Shuler, Charles S. OwenAbstract:Peroxidase-conjugated anti-surface immunoglobulin (sIg) was used quantitatively to monitor endocytosis of crosslinked sIg on murine B Lymphocytes. The role of biochemical second messengers in the initiation of endocytosis was assessed by employing several inhibitors. A novel peroxidase detection system was used and temperature-dependent decreases in sIg density on immunoperoxidase-labelled murine Lymphocytes were monitored. Metabolic inhibitors as well as colchicine and cytochalasin D were utilized to confirm that the internalization of sIg could be blocked by classical inhibitors of the endocytosis process. The role of tyrosine kinase activity was established by the fact that endocytosis was significantly reduced with 100 micrograms/mL genistein. Experiments using EGTA or 1,2-bis(beta-aminophenoxy)ethane-N-N,N'-tetraacetic acid (BAPTA) to chelate Ca2+ indicated that Ca2+ plays little role in endocytosis. Likewise, protein kinase C (PKC) was not found to be involved in endocytosis, as Activation of PKC with 50 ng/mL phorbol 12-myristate 13-acetate, or inhibition of the enzyme with 1 nmol/L or 5 nmol/L staurosporin, did not modulate endocytosis. Taken together, results suggested that ligand-induced endocytosis of antigen receptors is mediated primarily through localized membrane events and is not dependent upon the classical B Lymphocyte Activation signals, such as the biochemical events in the inositol phosphate cascade.
Dario A A Vignali - One of the best experts on this subject based on the ideXlab platform.
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negative regulation of t cell homeostasis by Lymphocyte Activation gene 3 cd223
Journal of Immunology, 2005Co-Authors: Creg J Workman, Dario A A VignaliAbstract:Lymphocyte homeostasis is a central biological process that is tightly regulated. However, its molecular and cellular control is poorly understood. We show that aged mice deficient in Lymphocyte Activation gene 3 (LAG-3), an MHC class II binding CD4 homologue, have twice as many T cells as wild-type controls. CD4(+) and CD8(+) LAG-3-deficient T cells showed enhanced homeostatic expansion in lymphopenic hosts, which was abrogated by ectopic expression of wild-type LAG-3, but not by a signaling-defective mutant. In addition, in vivo treatment with anti-LAG-3 mAb resulted in enhanced T cell expansion to a level comparable to that in LAG-3-deficient cells. This deregulation of T cell homeostasis also resulted in the expansion of multiple cell types, including B cells, macrophages, granulocytes, and dendritic cells. Lastly, regulatory T cells were dependent on LAG-3 for their optimal control of T cell homeostasis. Our data suggest that LAG-3 negatively regulates T cell homeostasis by regulatory T cell-dependent and independent mechanisms.
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Lymphocyte Activation gene 3 cd223 regulates the size of the expanding t cell population following antigen Activation in vivo
Journal of Immunology, 2004Co-Authors: Creg J Workman, Linda S Cauley, Injeong Kim, Marcia A Blackman, David L Woodland, Dario A A VignaliAbstract:Lymphocyte Activation gene-3 (LAG-3) is a CD4-related, Activation-induced cell surface molecule that binds to MHC class II with high affinity. In this study, we used four experimental systems to reevaluate previous suggestions that LAG-3(-/-) mice had no T cell defect. First, LAG-3(-/-) T cells exhibited a delay in cell cycle arrest following in vivo stimulation with the superantigen staphylococcal enterotoxin B resulting in increased T cell expansion and splenomegaly. Second, increased T cell expansion was also observed in adoptive recipients of LAG-3(-/-) OT-II TCR transgenic T cells following in vivo Ag stimulation. Third, infection of LAG-3(-/-) mice with Sendai virus resulted in increased numbers of memory CD4(+) and CD8(+) T cells. Fourth, CD4(+) T cells exhibited a delayed expansion in LAG-3(-/-) mice infected with murine gammaherpesvirus. In summary, these data suggest that LAG-3 negatively regulates T cell expansion and controls the size of the memory T cell pool.
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cutting edge molecular analysis of the negative regulatory function of Lymphocyte Activation gene 3
Journal of Immunology, 2002Co-Authors: Creg J Workman, Kari Dugger, Dario A A VignaliAbstract:Lymphocyte Activation gene (LAG)-3 (CD223) is a CD4-related Activation-induced cell surface molecule that binds to MHC class II molecules with high affinity and negatively regulates T cell expansion and homeostasis. In this study, we show that LAG-3 inhibits CD4-dependent, but not CD4-independent, T cell function via its cytoplasmic domain. Although high affinity interaction with MHC class II molecules is essential for LAG-3 function, tailless LAG-3 does not compete with CD4 for ligand binding. A single lysine residue (K468) within a conserved "KIEELE" motif is essential for interaction with downstream signaling molecules. These data provide insight into the mechanism of action of this important T cell regulatory molecule.
Aaron J. Marshall - One of the best experts on this subject based on the ideXlab platform.
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Role of the adaptor proteins Bam32, TAPP1 and TAPP2 in Lymphocyte Activation.
Immunology letters, 2005Co-Authors: Atef Allam, Aaron J. MarshallAbstract:Adaptor proteins play critical roles in Lymphocyte Activation by mediating intermolecular interactions and assembling signaling complexes at the activated plasma membrane. Bam32/DAPP1 and the related adaptor proteins TAPP1 and TAPP2 were identified by multiple groups about 5 years ago and considerable progress has been made in elucidating the structure, interaction partners and function of these molecules. These cytoplasmic adaptor proteins are recruited to the plasma membrane through interaction of their PH domains with the lipid products of phosphatidylinositol 3-kinases. They share a unique mode of regulation in that they bind with high affinity to phosphatidylinositol-3,4-bisphosphate and their recruitment is enhanced rather than inhibited by the lipid phosphatase SHIP. Two knockout mouse studies and several gain-and-loss of function studies in cell lines have recently been published, demonstrating multiple functions of Bam32 in B cell Activation. Bam32 is required for biological responses including B cell antigen receptor (BCR)-induced proliferation and antibody responses to type II T-independent antigens. Bam32 regulates multiple BCR signaling events including Activation of the mitogen activated protein kinases ERK and JNK, remodeling of the actin cytoskeleton through the GTPase Rac1 and BCR internalization. Several studies have emerged suggesting that TAPP1 and TAPP2 may play roles in B and T cell Activation; however, the biological functions regulated by these molecules remain to be defined. Here we will comprehensively review the available data on the structure and function of Bam32, TAPP1 and TAPP2 and present an integrated working model for Bam32 function in B cell Activation and a general model for distinct effector pathways of PI 3-kinases.
