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

• 成果类型: Article
• 署名作者: Rodriguez-Silvestre, Pablo; Laub, Marco; Krawczyk, Patrycja A.; Davies, Alexandra K.; Schessner, Julia P.; Parveen, Reejuana; Tuck, Benjamin J.; McEwan, William A.; Borner, Georg H. H.; Kozik, Patrycja
• 署名单位: MRC Laboratory Molecular Biology; Max Planck Society; University of Cambridge; University of Manchester
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12738
• DOI: 10.1126/science.adg8802
• 发表日期: 2023-06-01
• 页码: 1258-1265
• 关键词: controls phagosomal ph; nadph oxidase; expression; cytosol; crosspresentation; maturation; lysosomes; antigens

摘要

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.