Natural killer cells support the induction of protective immunity during dendritic cell-mediated vaccination against Leishmania major.

Dendritic cell (DC)-mediated vaccination against Leishmania major induces a parasite-specific T helper 1 (Th1) response and long-lasting protective immunity in susceptible mice. As the cytokine interleukin-12 required for induction of this Th1 response is not derived from the transferred DC, but has to be produced by the vaccinated host, we examined cross-presentation of transferred DC via resident DC of the host and cross-activation with natural killer (NK) cells as mechanisms supporting the induction of protective immunity after DC-mediated vaccination. Co-culture with DC that had been conditioned ex vivo by loading with L. major lysate and stimulation with CpG-containing oligodeoxynucleotides did not result in the activation of naive DC in vitro. Furthermore, L. major antigen from conditioned DC was not cross-presented to a significant extent in vivo. In contrast, co-culture of DC with NK cells led to cross-activation of both cell populations with induction of interferon-γ, which was dependent on the activation status of the conditioned DC. Transient depletion of NK cells during vaccination of L. major-susceptible mice with conditioned DC resulted in reduced protection. Our findings indicate that cross-presentation of conditioned DC after DC-based vaccination against L. major plays a minor role in the induction of protective immunity. However, we demonstrated for the first time that the capacity of DC to mediate protection against L. major is supported by cross-activation with NK cells of the host and NK-cell-derived interferon-γ.