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

  • Cell Death Dis. 2026 Apr 9;17(1):485. doi: 10.1038/s41419-026-08705-1.
Zhi-Kai Zha  #  1 ,  Cheng-Jie Deng  #  2 ,  Ling-Jun Shen  #  3 ,  Ling-Zhen Liu  #  1 ,  Yun-Xiao Huang  1 ,  Yan-Hong Li  1 ,  Li Lv  1 ,  Ke Zhang  1 ,  Lin-Shuang Chen  1 ,  Fei-Er Chen  1 ,  Sheng-An Li  4  5
Affiliations
  • 1. Yunnan Provincial Key Laboratory of Public Health and Bio-safety & Department of Pathogen Biology and Immunology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, China.
  • 2. The Center of Experimental Teaching, Faculty of Basic Medical Science, Kunming Medical University, Kunming, China.
  • 3. Department of Tuberculosis, Yunnan Clinical Medical Center for Infectious Diseases, the Third People's Hospital of Kunming (The Sixth Affiliated Hospital of Dali University), Kunming, China.
  • 4. Yunnan Provincial Key Laboratory of Public Health and Bio-safety & Department of Pathogen Biology and Immunology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, China. [email protected].
  • 5. Key Laboratory of Sepsis and Brain Regulation in Universities of Yunnan Province, Faculty of Basic Medical Science, Kunming Medical University, Kunming, China. [email protected].
  • # Contributed equally.
PMID: 41951589 DOI: 10.1038/s41419-026-08705-1
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.

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