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<p>Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) plays a crucial role in maintaining peripheral immune tolerance, but its mechanisms of action are highly complicated. Here, through the generation of a gene knock-in (KI) mouse carrying a CTLA-4 Y139C human patient-derived pathogenic mutation, we phenocopied the lethal autoimmune diseases in Ctla4 KO mice due to the impairment of Treg functions. Interestingly, although&#xa0;both KO and KI Treg cells lost the ability to endocytose B7 molecules, the KO and KI mice differed in terms of T-cell proliferation since the KI mutation retained its ability to transmit inhibitory signals. Therefore, this study not only dissected the two distinct immunoregulatory mechanisms of CTLA-4 but also provided genetic evidence highlighting the importance of ligand trans-endocytosis in the function of CTLA-4. Our findings enhance our understanding of CTLA-4 function and CTLA-4 insufficiency disease, providing valuable insights for advancing improved immunotherapy strategies targeting CTLA-4.</p>

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Dissection of the trans-endocytosis and signal inhibition functions of CTLA-4 through the study of a disease-associated Y139C mutation

  • 期刊论文

  • 发表日期：

    2025年10月9日

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  • Zhishan Zhao,
  • Peng Wu,
  • Qingman Li,
  • Di Sun,
  • Lize Wu,
  • Yiping Xu,
  • Fan Zhao,
  • Dandan Wu,
  • Ziwei Chen,
  • Pengkun Yuan,
  • Kaixiang Zhu,
  • Xuexiao Jin,
  • Pengfei Wang,
  • Chenyi An,
  • Dante Neculai,
  • Wei Chen,
  • Meiping Lu,
  • Linrong Lu

摘要

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) plays a crucial role in maintaining peripheral immune tolerance, but its mechanisms of action are highly complicated. Here, through the generation of a gene knock-in (KI) mouse carrying a CTLA-4 Y139C human patient-derived pathogenic mutation, we phenocopied the lethal autoimmune diseases in Ctla4 KO mice due to the impairment of Treg functions. Interestingly, although both KO and KI Treg cells lost the ability to endocytose B7 molecules, the KO and KI mice differed in terms of T-cell proliferation since the KI mutation retained its ability to transmit inhibitory signals. Therefore, this study not only dissected the two distinct immunoregulatory mechanisms of CTLA-4 but also provided genetic evidence highlighting the importance of ligand trans-endocytosis in the function of CTLA-4. Our findings enhance our understanding of CTLA-4 function and CTLA-4 insufficiency disease, providing valuable insights for advancing improved immunotherapy strategies targeting CTLA-4.