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<p>Antigen cross-presentation is essential for initiating CD8<sup><b>+</b></sup> 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<sup><b>+</b></sup> T cell responses. Additionally, <i>P2</i><sup><i>-/-</i></sup> 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<sup>+</sup> T cell immunity.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月9日

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  • Zhi-kai Zha,
  • Cheng-jie Deng,
  • Ling-jun Shen,
  • Ling-zhen Liu,
  • Yun-xiao Huang,
  • Yan-hong Li,
  • Li Lv,
  • Ke Zhang,
  • Lin-shuang Chen,
  • Fei-er Chen,
  • Sheng-an Li

摘要

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.