| Autor: |
Kuijk, Loes M., Verstege, Marleen I., Rekers, Niels V., Bruijns, Sven C., Hooijberg, Erik, Roep, Bart O., de Gruijl, Tanja D., van Kooyk, Yvette, Unger, Wendy W.J. |
| Zdroj: |
Blood; April 2013, Vol. 121 Issue: 14 p2638-2646, 9p |
| Abstrakt: |
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. |
| Databáze: |
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