AbstractThe poxvirus A39R protein is a member of the semaphorin family that binds to Plexin C1, a molecule expressed on neutrophils and dendritic cells (DC). We previously showed that binding of A39R to Plexin C1 induces local rearrangement of the actin cytoskeleton and inhibits integrin‐mediated adhesion, leading to cell retraction. As phagocytosis is dependent on both cytoskeleton integrity and integrin function, we tested the effect of A39R on DC and neutrophil phagocytosis. We found that A39R treatment strongly inhibits phagocytosis by DC and neutrophils in vitro in a Plexin C1‐dependent fashion. Moreover, A39R treatment inhibited the capacity of CD8α+ DC to take up apoptotic bodies in vivo. As a consequence, A39R impaired the ability of CD8α+ DC to cross‐prime CD8+ T cells ex vivo. In contrast, A39R had no effect on direct priming of CD8+ T cells by peptide‐pulsed CD8α+ DC in vitro. These results suggest that poxviruses may use semaphorin homologs as a means to evade the immune system.