Primarily defined by their antigen presenting function, dendritic cells (DC) are equipped with the unique ability to initiate and regulate immune responses. A less conventional characteristic of DC has been highlighted more recently: their capability to directly kill tumor cells when appropriately activated. The main objectives of the study presented herein were to analyze the molecular regulation of DC cytotoxic activity and to determine how the tumoricidal potential of DC may influence their cardinal antigen presenting function. To address these questions, DC were generated from myeloid precursors with either IL-4 (IL-4 DC) or IL-15 (IL-15 DC). We demonstrate that IL-4 and IL-15 DC exhibit similar iNOS-dependent tumor killing activity when activated with the toll-like receptor (TLR)-4 agonist LPS. However, stimulation with interferon (IFN)-γ selectively induces iNOS-dependent cytotoxic activity of IL-4 but not IL-15 DC. Possible differences in the signaling pathways controlling iNOS expression in these two DC populations were then examined. In both IL-4 and IL-15 DC, LPS initially activates NF-κB, followed by secondary activation of components of the ISGF3 transcription factor. Using inhibitors and knockout mice we established that disruption of the NF-κB or ISGF3 signaling axes impaired LPS-induced iNOS expression in IL-15 DC with little to no effect in IL-4 DC. A distinct and separate JAK-STAT pathway is required for iNOS induction in IL-4 DC activated with IFN-γ. IL-15 DC express high levels of PIAS1 and phosphorylated STAT-3 which act as independent inhibitors of iNOS expression upon stimulation with IFN-γ. Inhibiting PIAS1 with silencing RNA (siRNA) along with STAT-3 inhibition or knockdown restores iNOS expression and the tumor killing activity of IL-15 DC stimulated with IFN-γ. We further established that following culture with cancer cells, DC endowed with cytolytic activity are more efficient at presenting antigens to specific T lymphocytes compared to their counterparts generated from iNOS^(-/-) mice, which are significantly impaired in their tumoricidal function. This indicates that the capability of DC to present tumor-specific antigens may be contingent upon induction of their cytotoxic activity.

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