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

Summary Increasing evidence indicates that hepatic CD8α+ 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 CD8α+ DCs in protective pre-erythrocytic malaria immunizations has pivotal implications for vaccine development, including improved vectored subunit vaccines. Employing Batf3−/− mice, which lack functional CD8α+ 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 CD8α+ DCs accumulate in the liver after immunization with live irradiation-attenuated P. berghei sporozoites. IFN-γ 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 CD8α− DCs. Collectively, these findings underscore the essential role of CD8α+ DCs in robust protection induced by experimental live-attenuated malaria vaccines.