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

T cell receptors; ENDOCYTOSIS; DENDRITIC cells; HISTOCOMPATIBILITY antigens; MAJOR histocompatibility complex; GENETIC testing; T cells

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. [ABSTRACT FROM AUTHOR]

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