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一种基于神经节苷脂的免疫检查点使衰老细胞在衰老过程中逃避免疫监视。

A ganglioside-based immune checkpoint enables senescent cells to evade immunosurveillance during aging.

作者信息

Iltis Charlène, Moskalevska Iryna, Debiesse Antoine, Seguin Laetitia, Fissoun Christina, Cervera Ludovic, Moudombi Lyvia, Ardin Maude, Ferrari Anthony, Eliott Coline, Pisani Didier, Ottaviani Alexandre, Bourinet Manon, Luci Carmelo, Gual Philippe, Makulyte Gabriela, Bernard David, Durandy Manon, Duret Lou C, Hamidouche Tynhinane, Kunz Sarah, Croce Olivier, Delannoy Clément, Guérardel Yann, Allain Fabrice, Hofman Paul, Benarroch-Popivker Delphine, Bianchini Laurence, Dadone-Montaudie Berengère, Cosson Estelle, Guglielmi Julien, Pourcher Thierry, Braud Véronique M, Shkreli Marina, Pers Yves-Marie, Jorgensen Christian, Brondello Jean-Marc, Féral Chloé C, Michallet Marie-Cécile, Gilson Eric, Cherfils-Vicini Julien

机构信息

Université Côte d'Azur, Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (INSERM) U1081, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France.

Institut Hospitalo-Universitaire (IHU) RESPIRera and FHU OncoAge, CHU Nice, Nice, France.

出版信息

Nat Aging. 2025 Feb;5(2):219-236. doi: 10.1038/s43587-024-00776-z. Epub 2024 Dec 27.

DOI:10.1038/s43587-024-00776-z
PMID:39730825
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11839482/
Abstract

Although senescent cells can be eliminated by the immune system, they tend to accumulate with age in various tissues. Here we show that senescent cells can evade immune clearance by natural killer (NK) cells by upregulating the expression of the disialylated ganglioside GD3 at their surface. The increased level of GD3 expression on senescent cells that naturally occurs upon aging in liver, lung, kidney or bones leads to a strong suppression of NK-cell-mediated immunosurveillance. In mice, we found that targeting GD3 senescent cells with anti-GD3 immunotherapy attenuated the development of experimentally induced or age-related lung and liver fibrosis and age-related bone remodeling. These results demonstrate that GD3 upregulation confers immune privilege to senescent cells. We propose that GD3 acts as a senescence immune checkpoint (SIC) that allows senescent cells to escape immunosurveillance and to trigger immune anergy during aging.

摘要

尽管衰老细胞可被免疫系统清除，但它们往往会随着年龄增长在各种组织中积累。我们在此表明，衰老细胞可通过上调其表面二唾液酸化神经节苷脂GD3的表达来逃避自然杀伤（NK）细胞的免疫清除。肝脏、肺、肾脏或骨骼中衰老细胞表面自然出现的GD3表达水平升高，会导致NK细胞介导的免疫监视受到强烈抑制。在小鼠中，我们发现用抗GD3免疫疗法靶向GD3衰老细胞可减轻实验性诱导的或与年龄相关的肺和肝纤维化以及与年龄相关的骨重塑的发展。这些结果表明，GD3上调赋予衰老细胞免疫特权。我们提出，GD3作为衰老免疫检查点（SIC），使衰老细胞能够逃避免疫监视并在衰老过程中引发免疫无反应性。

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