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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 Jaggedi 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 IFN-γ 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. [ABSTRACT FROM AUTHOR]

To increase (tumor) vaccine efficacy, there is an urgent need for phenotypic and functional characterization of human dendritic cell (DC) subsets residing in lymphoid tissues. In this study we identified and functionally tested 4 human conventional DC (cDC) subsets within skin-draining sentinel lymph nodes (SLNs) from early-stage melanoma patients. These SLNs were all tumor negative and were removed on average 44 days after excision of the primary melanoma. As such, they were considered representative of steady-state conditions. On comparison with skin-migrated cDC, 2 CD1a+ subsets were identified as most likely skin-derived CD11cint Langerhans cells (LC) with intracellular langerin and E-cadherin expression or as CD11chi dermal DCs with variable expression of langerin. Two other CD1a- LN-residing cDC subsets were characterized as CD14-BDCA3hiCD103- and CD14+BDCA3loCD103+, respectively. Whereas the CD1a+ skin-derived subsets displayed greater levels of phenotypic maturation, they were associated with lower levels of inflammatory cytokine release and were inferior in terms of allogeneic T-cell priming and IFNγ induction. Thus, despite their higher maturation state, skin-derived cDCs (and LCs in particular) proved inferior T-cell activators compared with the CD1a- cDC subsets residing in melanoma-draining LNs. These observations should be considered in the design of DC-targeting immunotherapies. [ABSTRACT FROM AUTHOR]