Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells

During initiation of antiviral and antitumour T cell-mediated immune responses, dendritic cells (DCs) cross-present exogenous antigens on MHC class I. Cross-presentation relies on the unique ‘leakiness’ of endocytic compartments in DCs, whereby internalised proteins escape into the cytosol for proteasome-mediated generation of MHC I-binding peptides. Given that type 1 conventional DCs excel at cross-presentation, we searched for cell-type specific effectors of endocytic escape. We devised an escape assay suitable for genetic screening and identified a pore-forming protein, perforin-2, as a dedicated effector exclusive to cross-presenting cells. Perforin-2 is recruited to antigen-containing compartments, where it undergoes maturation, releasing its pore-forming domain. Mpeg1 -/- mice fail to efficiently prime CD8 + T cells to cell-associated antigens, revealing an important role of perforin-2 in cytosolic entry of antigens during cross-presentation. One-Sentence Summary Pore-forming protein perforin-2 is a dedicated effector of endocytic escape specific to cross-presenting cells