3 research outputs found

    Highly Active Microbial Phosphoantigen Induces Rapid yet Sustained MEK/Erk- and PI-3K/Akt-Mediated Signal Transduction in Anti-Tumor Human Ī³Ī“ T-Cells

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    BACKGROUND: The unique responsiveness of Vgamma9Vdelta2 T-cells, the major gammadelta subset of human peripheral blood, to non-peptidic prenyl pyrophosphate antigens constitutes the basis of current gammadelta T-cell-based cancer immunotherapy strategies. However, the molecular mechanisms responsible for phosphoantigen-mediated activation of human gammadelta T-cells remain unclear. In particular, previous reports have described a very slow kinetics of activation of T-cell receptor (TCR)-associated signal transduction pathways by isopentenyl pyrophosphate and bromohydrin pyrophosphate, seemingly incompatible with direct binding of these antigens to the Vgamma9Vdelta2 TCR. Here we have studied the most potent natural phosphoantigen yet identified, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), produced by Eubacteria and Protozoa, and examined its gammadelta T-cell activation and anti-tumor properties. METHODOLOGY/PRINCIPAL FINDINGS: We have performed a comparative study between HMB-PP and the anti-CD3epsilon monoclonal antibody OKT3, used as a reference inducer of bona fide TCR signaling, and followed multiple cellular and molecular gammadelta T-cell activation events. We show that HMB-PP activates MEK/Erk and PI-3K/Akt pathways as rapidly as OKT3, and induces an almost identical transcriptional profile in Vgamma9(+) T-cells. Moreover, MEK/Erk and PI-3K/Akt activities are indispensable for the cellular effects of HMB-PP, including gammadelta T-cell activation, proliferation and anti-tumor cytotoxicity, which are also abolished upon antibody blockade of the Vgamma9(+) TCR Surprisingly, HMB-PP treatment does not induce down-modulation of surface TCR levels, and thereby sustains gammadelta T-cell activation upon re-stimulation. This ultimately translates in potent human gammadelta T-cell anti-tumor function both in vitro and in vivo upon transplantation of human leukemia cells into lymphopenic mice, CONCLUSIONS/SIGNIFICANCE: The development of efficient cancer immunotherapy strategies critically depends on our capacity to maximize anti-tumor effector T-cell responses. By characterizing the intracellular mechanisms of HMB-PP-mediated activation of the highly cytotoxic Vgamma9(+) T-cell subset, our data strongly support the usage of this microbial antigen in novel cancer clinical trials

    Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human VĪ³9VĪ“2 T Cells

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    Abstract VĪ³9VĪ“2 T cells, the main subset of Ī³Ī“ T lymphocytes in human peripheral blood, are endowed with antitumor functions such as cytotoxicity and IFNĪ³ production. These functions are triggered upon T-cell receptorā€“dependent activation by non-peptidic prenyl pyrophosphates (ā€œphosphoantigensā€) that are selective agonists of VĪ³9VĪ“2 T cells, and which have been evaluated in clinical studies. Because phosphoantigens have shown interindividual variation in VĪ³9VĪ“2 T-cell activities, we asked whether metabolic resources, namely lipids such as cholesterol, could affect phosphoantigen-mediated VĪ³9VĪ“2 T-cell activation and function. We show here that VĪ³9VĪ“2 T cells express the LDL receptor upon activation and take up LDL cholesterol. Resulting changes, such as decreased mitochondrial mass and reduced ATP production, correlate with downregulation of VĪ³9VĪ“2 T-cell activation and functionality. In particular, the expression of IFNĪ³, NKG2D, and DNAM-1 were reduced upon LDL cholesterol treatment of phosphoantigen-expanded VĪ³9VĪ“2 T cells. As a result, their capacity to target breast cancer cells was compromised both in vitro and in an in vivo xenograft mouse model. Thus, this study describes the role of LDL cholesterol as an inhibitor of the antitumor functions of phosphoantigen-activated VĪ³9VĪ“2 T cells. Our observations have implications for therapeutic applications dependent on VĪ³9VĪ“2 T cells. Cancer Immunol Res; 6(4); 448ā€“57. Ā©2018 AACR.</jats:p

    CD27 is a thymic determinant of the balance between interferon-gamma-and interleukin 17-producing gamma delta T cell subsets

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    The production of cytokines such as interferon-gamma and interleukin 17 by alphabeta and gammadelta T cells influences the outcome of immune responses. Here we show that most gammadelta T lymphocytes expressed the tumor necrosis factor receptor family member CD27 and secreted interferon-gamma, whereas interleukin 17 production was restricted to CD27(-) gammadelta T cells. In contrast to the apparent plasticity of alphabeta T cells, the cytokine profiles of these distinct gammadelta T cell subsets were essentially stable, even during infection. These phenotypes were established during thymic development, when CD27 functions as a regulator of the differentiation of gammadelta T cells at least in part by inducing expression of the lymphotoxin-beta receptor and genes associated with trans-conditioning and interferon-gamma production. Thus, the cytokine profiles of peripheral gammadelta T cells are predetermined mainly by a mechanism involving CD2
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