Mir-15/16 antagonizes c-Myb to control natural killer cell maturation (LYM7P.714)

NK cells develop in the bone marrow and complete maturation in peripheral organs, but the factors controlling maturation are incompletely understood. The miR-15/16 family is highly expressed in NK cells, and to study its role in NK cells, we generated a novel mouse model of NK-specific miR-15/16 deficiency (15aKO). 15aKO NK cells have a deficiency of mature (CD11b+CD27-) NK cells, with no alterations in total NK cell numbers or death, consistent with a block in maturation. The transcription factor Myb is expressed highly in immature NK cells, nearly absent in mature NK cells, and has been implicated in NK maturation. We found that miR-15/16 represses Myb, and Myb levels are increased in 15aKO NK cells. To directly investigate the role of Myb in NK cells, we developed a novel NK maturation system in which immature primary NK cells are transduced, adoptively transferred, and matured in vivo. As in the 15aKO mouse, transferred 15aKO NK cells had defective maturation. However, both 1) restoration of miR-15/16, or 2) knockdown of Myb, rescued maturation of the 15aKO NK cells, demonstrating that miR-15/16’s repression of Myb is critical to proper NK cell maturation. Furthermore, WT NK cells overexpressing Myb did not mature as well as control (WT NK+GFP) cells. Thus, the regulation of Myb by miR-15/16 is essential for NK cell maturation, revealing a novel mechanism controlling NK cell development.