Batf3 deficiency proves the pivotal role of CD8α+ dendritic cells in protection induced by vaccination with attenuated Plasmodium sporozoites

Increasing evidence indicates that hepatic CD8(+) dendritic cells (DCs) are important antigen cross-presenting cells (APC) involved in the priming of protective CD8(+) T-cell responses induced by live-attenuated Plasmodium sporozoites. Experimental proof for a critical role of CD8(+) DCs in protective pre-erythrocytic malaria immunizations has pivotal implications for vaccine development, including improved vectored subunit vaccines. Employing Batf3(-/-) mice, which lack functional CD8(+) DCs, we demonstrate that deficiency of these particular APCs completely abolishes protection and corresponding signatures of vaccine-induced immunity. We show that in wild-type, but not in Batf3(-/-), mice CD8(+) DCs accumulate in the liver after immunization with live irradiation-attenuated P.berghei sporozoites. IFN- production by Plasmodium antigen-specific CD8(+) T cells is dependent on functional Batf3. In addition, our results demonstrate that the dysfunctional cDC-CD8+ T-cell axis correlates with MHC class II upregulation on splenic CD8(-) DCs. Collectively, these findings underscore the essential role of CD8(+) DCs in robust protection induced by experimental live-attenuated malaria vaccines.