1. ¹Gene Therapy Unit, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
2. ²Clínica Universitaria, Universidad de Navarra, Pamplona, Spain
3. ³Immunological Therapy, Istituto Nazionale per la Ricerca sul Cancro (IST-Genova), Genova, Italy

Correspondence: Dr I Melero, Gene Therapy Unit, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Avda Pio XII, 55, Pamplona 31008, Spain. E-mail: imelero@unav.es; Dr S Hervas-Stubbs, mshervas@unav.es

⁴These authors contributed equally to this work.

⁵These authors will equally share credit for senior authorship.

Received 2 August 2007; Revised 26 December 2007; Accepted 29 December 2007; Published online 14 February 2008.

Abstract

The surface phenotype CD3^-NK1.1⁺DX5⁺CD11c^intB220⁺GR1^- has been recently ascribed to a novel subset of mouse leukocytes termed interferon (IFN)-producing killer dendritic cells (IKDCs) that shares functions with natural killer (NK) cells and DCs. Interleukin-15 (IL-15) is critical for NK cells but its relationship with IKDC remained unexplored. An expression cassette encoding human IL-15 (hIL-15) has been transferred by hydrodynamic injection into the liver of mice, resulting in transient expression of the cytokine that is detectable during the first 48 h. hIL-15 hydrodynamic gene transfer resulted in an expansion of NK cells and IKDCs. Relative expansions of IKDCs were more dramatic in the IL-15 gene-transferred hepatic tissue than in the spleen. Adoptively transferred DX5⁺ cells comprising both NK cells and IKDCs proliferated in response to hydrodynamic injection of hIL-15, indicating that quantitative increases are at least in part the result of proliferation from already differentiated cells. Expansion is accompanied by enhanced cytolytic activity and increased expression of TRAIL and CD137 (4-1BB), without augmenting interferon- production. The effects of a single hydrodynamic injection surpassed those of two intraperitoneal doses of the recombinant protein. The novel functional link between circulating IL-15 and IKDCs opens new possibilities to study the biology and applications of this minority cell subset.