Trans-presentation of IL-15 dictates IFN-producing killer dendritic cells effector functions

IFN-producing killer dendritic cells (IKDC) were initially described as B220 ⁺CDllc ⁺CD3 ^-NKl.l ⁺ tumor-infiltrating cells that mediated part of the antitumor effects of the combination therapy with imatinib mesylate and IL-2. In this study, we show their functional dependency on IL-15 during homeostasis and inflammatory processes. Trans-presentation of IL-15 by IL-15Rα allows dramatic expansion of IKDC in vitro and in vivo, licenses IKDC for TRAIL-dependent killing and endows IKDC with immunizing potential, all three biological attributes not shared by B220 ^-NK cells. However, IL-15 down-regulates the capacity of IKDC to induce MHC class I-or II-restricted T cell activation in vitro. Trans-presentation of IL-15 by IL-15Rα allows IKDC to respond to TLR3 and TLR4 ligands for the production of CCL2, a chemokine that is critical for IKDC trafficking into tumor beds (as described recently). We conclude that IKDC represent a unique subset of innate effectors functionally distinguishable from conventional NK cells in their ability to promptly respond to IL-15-driven inflammatory processes.