Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells
Pablo Rodríguez-Silvestre, Marco Laub, Patrycja A. Krawczyk, Alexandra K. Davies, Julia P. Schessner, Reejuana Parveen, Benjamin J. Tuck, William A. McEwan, Georg H. H. Borner, Patrycja Kozik
Abstract
During initiation of antiviral and antitumor T cell–mediated immune responses, dendritic cells (DCs) cross-present exogenous antigens on major histocompatibility complex (MHC) class I molecules. Cross-presentation relies on the unusual “leakiness” of endocytic compartments in DCs, whereby internalized 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 assay suitable for genetic screening and identified a pore-forming protein, perforin-2 ( Mpeg1 ), as a dedicated effector exclusive to cross-presenting cells. Perforin-2 was recruited to antigen-containing compartments, where it underwent maturation, releasing its pore-forming domain. Mpeg1 −/− mice failed to efficiently prime CD8 + T cells to cell-associated antigens, revealing an important role for perforin-2 in cytosolic entry of antigens during cross-presentation.