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

IF 17 Q1 CELL BIOLOGY
Charlène Iltis, Iryna Moskalevska, Antoine Debiesse, Laetitia Seguin, Christina Fissoun, Ludovic Cervera, Lyvia Moudombi, Maude Ardin, Anthony Ferrari, Coline Eliott, Didier Pisani, Alexandre Ottaviani, Manon Bourinet, Carmelo Luci, Philippe Gual, Gabriela Makulyte, David Bernard, Manon Durandy, Lou C. Duret, Tynhinane Hamidouche, Sarah Kunz, Olivier Croce, Clément Delannoy, Yann Guérardel, Fabrice Allain, Paul Hofman, Delphine Benarroch-Popivker, Laurence Bianchini, Berengère Dadone-Montaudie, Estelle Cosson, Julien Guglielmi, Thierry Pourcher, Véronique M. Braud, Marina Shkreli, Yves-Marie Pers, Christian Jorgensen, Jean-Marc Brondello, Chloé C. Féral, Marie-Cécile Michallet, Eric Gilson, Julien Cherfils-Vicini
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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. This study identifies a novel immune checkpoint in senescent cells that is linked to the ganglioside GD3 and that contributes to the evasion of immune clearance by these cells and to aging and age-related diseases.

Abstract Image

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。
虽然衰老细胞可以被免疫系统清除,但随着年龄的增长,它们往往会在各种组织中积累。在这里,我们发现衰老细胞可以通过上调其表面二散化神经节苷脂GD3的表达来逃避自然杀伤(NK)细胞的免疫清除。随着肝、肺、肾或骨骼老化,衰老细胞中GD3表达水平的增加导致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+衰老细胞可以减轻实验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),允许衰老细胞逃避免疫监视并在衰老过程中触发免疫能量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
14.70
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