Flt3 ligand treatment modulates parasitemia during infection with rodent malaria parasites via MyD88- and IFN-γ-dependent mechanisms.

We previously showed that treatment of mice with the Flt3 ligand (Flt3L) prevents development of lethal experimental cerebral malaria and inhibits parasitemia during Plasmodium berghei ANKA (PbA) infection. In this study, we investigated the mechanisms underlying the reduction of parasitemia in Flt3L-treated mice. Studies using gene knockout mice and antibody treatment indicated that the anti-parasitemia effect of Flt3L was mediated by innate immune system and was dependent on MyD88, IFN-γ, IL-12 and natural killer (NK) cells. The number of NK cells and their ability to produce IFN-γ was enhanced in Flt3L-treated mice. Phagocytic activity of splenocytes was increased in Flt3L-treated mice after PbA infection when compared with that in untreated mice, and this activity was mainly mediated by the accumulation of F4/80(mid) CD11b(+) cells in the spleen. In both MyD88(-/-) and IFN-γ(-/-) mice, the proportion of F4/80(mid) CD11b(+) cells was not increased in the spleen of Flt3L-treated mice after infection. These correlations suggest that NK cells produce IFN-γ in Flt3L-treated mice, and accumulation of F4/80(mid) CD11b(+) cells in the spleen is promoted by an IFN-γ -dependent manner, culminating in the inhibition of parasitemia. These findings imply that Flt3L promotes effective innate immunity against malaria infection mediated by interplay among varieties of innate immune cells.