Mechanism by Which Exogenous Administration of Flt3 Ligand (FL) Expands Natural Killer Cells In Vivo.

The mechanism underlying the robust expansion of natural killer (NK) cells during exogenous administration of FL is unknown. Endogenous IL-15 had no impact on the in vivo expansion of NK cell precursors during FL administration but was required for the FL-mediated expansion of mature NK cells in the spleen and blood. Studies performed using in vivo BM chimeras showed that cells derived from hematopoietic precursors (HPC), not stromal cells, provided the endogenous IL-15 required for mature NK cell expansion by FL administration. Exogenous administration of FL significantly increased both CD11b(+)CD11c(-) and CD11b(+)CD11c(+) populations but not their relatively abundant expression of IL-15 or IL-15 receptor alpha on a per cell basis. This increase preceded and correlated with NK cell expansion, the latter of which largely resulted from enhanced survival and proliferation of an existing pool of mature NK cells rather than increased de novo production of NK cells from bone marrow precursors. Finally, in vivo elimination of CD11c+ cells during the course of FL treatment significantly decreased NK cell expansion. In summary, FL administration increases NK cells in vivo by expanding antigen presenting cells which in turn provide the requisite IL-15 to enhance survival and proliferation of mature NK cells.