Cutting Edge: Murine Dendritic Cells Require IL-15Rα to Prime NK Cells

Abstract

NK cells protect hosts against viral pathogens and transformed cells, and dendritic cells (DCs) play important roles in activating NK cells. We now find that murine IL-15Rα-deficient DCs fail to support NK cell cytolytic activity and elaboration of IFN-γ, despite the fact that these DCs express normal levels of costimulatory molecules and IL-12. By contrast, IL-15Rα expression on NK cells is entirely dispensable for their activation by DCs. In addition, blockade with anti-IL-15Rα and anti-IL-2Rβ but not anti-IL-2Rα-specific Abs prevents NK cell activation by wild-type DCs. Finally, presentation of IL-15 by purified IL-15Rα/Fc in trans synergizes with IL-12 to support NK cell priming. These findings suggest that murine DCs require IL-15Rα to present IL-15 in trans to NK cells during NK cell priming.

Different NK Cell Developmental Events Require Different Levels of IL-15 Trans-Presentation

“…We first examined the expression of IL-15Ra by Il15ra DIC /TCRa IC KI and Tg BMDCs, as IL-15Ra on BMDCs prime NK cells for IFN-g production and cytotoxicity (26,27). The level of IL-15Ra on KI BMDCs was 3-3.5 times lower compared with WT BMDCs under either resting or poly I:C-stimulated conditions (Fig.…”

“…3A), we examined the NK cell response in total splenocyte culture. As LPS-or CpG-activated murine DCs trans-present IL-15 to prime NK cells (26,27,31,32), we first determined whether IL15Ra on splenocytes affects the NK cell response in the absence of microbial stimulation. WT and KO NK cells expressed a similar level of surface NK1.1 before stimulation (Supplemental Table I).…”

The IL-15/IL-15Rα on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells

“…In contrast, IL-2 remains a soluble factor. Other groups have provided compelling evidence that the transpresentation may be the major style of IL-15 action in vivo (11)(12)(13)(14)(15)(16)(17)(18). IL-15 is produced by activated dendritic cells (DCs), monocytes, and stromal cells (3), whereas IL-2 is produced by antigen (Ag)-stimulated T cells.…”

Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells

“…In particular, DCs secrete soluble IL-12 and IL-18 that elicit IFNγ production and type I IFN that promotes cytotoxicity and proliferation by NK cells (4)(5)(6). Additionally, direct DC-NK contact contributes to NK cell survival, IFNγ production, and cytotoxicity by enabling DCs to present IL-15 in complex with IL-15Rα to NK cells in secondary lymphoid organs (6)(7)(8)(9).…”