Trans-presentation of IL-15 dictates IFN-producing killer dendritic cells effector functions.
IFN-producing killer dendritic cells (IKDC) were initially described as B220(+)CD11c(+)CD3(-)NK1.1(+) 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-15Ralpha 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-15Ralpha 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.
Institut National de la Santé et de la Recherche Médicale U805, Center of Clinical Investigations CBT507, Institut Gustave Roussy, Villejuif, France.
Evelyn
E
Ullrich
Mathieu
M
Bonmort
Gregoire
G
Mignot
Benedikt
B
Jacobs
Daniela
D
Bosisio
Silvano
S
Sozzani
Abdelali
A
Jalil
Fawzia
F
Louache
Elena
E
Bulanova
Frederic
F
Geissman
Bernard
B
Ryffel
Nathalie
N
Chaput
Silvia
S
Bulfone-Paus
Laurence
L
Zitvogel
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D018899:CpG Islands / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000145:classification* / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006706:Homeostasis / Q000276:immunology; D016130:Immunophenotyping; D007372:Interferons / Q000096:biosynthesis*; D019409:Interleukin-15 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D007372:Interferons