Perforin-2 enhances antigen-specific CTL immune response by promoting cross presentation

Abstract Antigen cross-presentation is essential for initiating CD8 + cytotoxic T lymphocyte (CTL) response. Perforin-2 (P2), a pore-forming protein constitutively expressed in dendritic cells (DCs), has been implicated in endocytic cargo escape, but its role in cross-presentation remains poorly defined. Here, we show that loss of P2 markedly impairs DC-mediated cross-presentation of both soluble and particulate antigens, leading to weakened antigen-specific CD8 + T cell responses. Additionally, P2 -/- mice exhibited defective endogenous CTL responses and diminished anti-tumor immunity in melanoma models. Mechanistically, oligomerization of plasma membrane P2 promotes antigen uptake via membrane-repair-mediated macropinocytosis. In parallel, P2 limits excessive endosomal acidification, preserving antigens for efficient loading onto MHC class I molecules. These findings identify P2 as a key regulator that coordinates antigen uptake and processing to support effective cross-presentation and CD8 + T cell immunity.