Redefining interferon-producing killer dendritic cells as a novel intermediate in NK-cell differentiation

The cell lineage origin of IFN-producing killer dendritic cells (IKDCs), which exhibit prominent antitumoral activity, has been subject to debate. Although IKDCs were first described as a cell type exhibiting both plasmacytoid DC and natural killer (NK) cell properties, the current view reflects that IKDCs merely represent activated NK cells expressing B220, which were thus renamed B220(+) NK cells. Herein, we further investigate the lineage relation of B220(+) NK cells with regard to other NK-cell subsets. We surprisingly find that, after adoptive transfer, B220(+) NK cells did not acquire B220 expression, even in the presence of potent activating stimuli. These findings strongly argue against the concept that B220(+) NK cells are activated NK cells. Moreover, we unequivocally show that B220(+) NK cells are highly proliferative and differentiate into mature NK cells after in vivo adoptive transfer. Additional phenotypic, functional, and transcriptional characterizations further define B220(+) NK cells as immediate precursors to mature NK cells. The characterization of these novel attributes to B220(+) NK cells will guide the identification of their ortholog in humans, contributing to the design of potent cancer immunotherapies. (Blood. 2012; 119(19):4349-4357)