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The efficacy of autologous (αβ) T-cell--based treatment strategies in chronic lymphocytic leukemia (CLL) has been modest. The Vγ9Vδ2-T cell subset consists of cytotoxic T lymphocytes with potent antilymphoma activity via a major histocompatibility complex--independent mechanism. We studied whether Vγ9Vδ2 cells can be exploited as autologous effector lymphocytes in CLL. Healthy control Vγ9Vδ2 cells were activated by and had potent cytolytic activity against CLL cells. However, CLL-derived Vγ9Vδ2 cells proved dysfunctional with respect to effector cytokine production and degranulation, despite an increased frequency of the effector-type subset. Consequently, cytotoxicity against malignant B cells was hampered. A comparable dysfunctional phenotype was observed in healthy Vγ9Vδ2 cells after coculture with CLL cells, indicating a leukemia-induced mechanism. Gene-expression profiling implicated alterations in synapse formation as a conceivable contributor to compromised Vγ9Vδ2--cell function in CLL patients. Dysfunction of Vγ9Vδ2 cells was fully reversible upon activation with autologous monocyte-derived dendritic cells (moDCs). moDC activation resulted in efficient expansion and predominantly yielded Vγ9Vδ2 cells with a memory phenotype. Furthermore, ibrutinib treatment promoted an antitumor T helper 1 (TH1) phenotype in Vγ9Vδ2 cells, and we demonstrated binding of ibrutinib to IL-2-inducible kinase (ITK) in Vγ9Vδ2 cells. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2 cells is fully reversible, resulting in potent cytotoxicity toward CLL cells. Our data support the potential use of Vγ9Vδ2 cells as effector T cells in CLL immunotherapy and favor further exploration of combining Vγ9Vδ2-cell--based therapy with ibrutinib. [ABSTRACT FROM AUTHOR]

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]

A response by Mari F.C.M. van den Hout and colleagues to a letter to the editor about their article "Characterization of four conventional dendritic cell subsets in human skin-draining lymph nodes in relation to T-cell activation," in a 2011 issue of the jurnal is presented.