The pore-forming protein APOL7C ruptures Leishmania major-containing parasitophorous vacuoles in dendritic cells to promote IL-12 production and the induction of T helper type 1 immunity

Abstract

Classical dendritic cells (cDCs) are required for the efficient priming of T helper type 1 (Th1) immunity against Leishmania major infections in mice. They do so by producing large quantities of IL-12 in response to L. major infection. IL-12 in turn supports the generation of protective CD4+ Th1 cells. However, the mechanism(s) by which L. major instigates robust IL-12 production by cDCs has not been addressed. Here we show that expression of a pore-forming protein called APOL7C is induced in cDCs by L. major infection. APOL7C is expressed in the cytosol of host cells and, remarkably, upon infection is recruited to L. major parasitophorous vacuoles (PVs) where it induces PV rupture. PV rupture leads to the exposure of L. major-derived pathogen-associated molecular patterns (PAMPs) to cytosolic pattern recognition receptors (PRRs). Cytosolic PRR signaling then drives IL-12 production by cDCs. Consequently, L. major challenge of APOL7C-deficient mice results in reduced numbers of IL-12 producing cDCs as well as a diminished Th1 response. In sum, our data indicate the presence of pore-forming proteins in the cytosol of cDCs that interfere with the intracellular niche of Leishmania to modulate immunity to these parasites.