title: Notch controls generation and function of human effector CD8+ T cells.
abstract: The generation of effector CD8(+) T cells with lytic capacity is crucial for tumor control. Dendritic cells (DCs) provide important signals to promote naive CD8(+) T cell priming and activation of effector T cells. Here, we report that the Notch pathway has an important role in both these processes in human CD8(+) T cells. Activated monocyte-derived DCs express Notch ligands Jagged1 and Delta-like4, whereas naive CD8(+) T cells express Notch2. The role for Notch signaling in CD8(+) T cell priming was determined using an ex-vivo model system in which tumor antigen-specific primary CD8(+) T cell responses were measured. Inhibition of Notch using γ-secretase inhibitors or soluble Delta-like4-Fc during activation reduced expansion of antigen-specific CD8(+) T cells, which was mirrored by decreased frequencies of interferon (IFN)γ-, tumor necrosis factor-α-, and granzymeB-producing CD8(+) T cells. Moreover, T cells primed when Notch signaling was prevented are functionally low-avidity T cells. In addition, Notch partially regulates established effector T cell function. Activation-induced Notch signaling is needed for IFNγ release but not for cytolytic activity. These data indicate that Notch signaling controls human CD8(+) T cell priming and also influences effector T cell functions. This may provide important information for designing new immunotherapies for treatment of cancer.
authors: Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.
authors: Loes M
authors: LM
authors: Kuijk
authors: Marleen I
authors: MI
authors: Verstege
authors: Niels V
authors: NV
authors: Rekers
authors: Sven C
authors: SC
authors: Bruijns
authors: Erik
authors: E
authors: Hooijberg
authors: Bart O
authors: BO
authors: Roep
authors: Tanja D
authors: TD
authors: de Gruijl
authors: Yvette
authors: Y
authors: van Kooyk
authors: Wendy W J
authors: WW
authors: Unger
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D058965:MART-1 Antigen / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000517:prevention & control; D051881:Receptor, Notch1 / Q000276:immunology* / Q000378:metabolism; D051883:Receptor, Notch2 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D058965:MART-1 Antigen; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D007371:Interferon-gamma