德国神经退行性疾病中心Mikael Simons课题组的一项最新研究报道，小胶质细胞激活协调CXCL10介导的CD8⁺ T细胞募集，促进衰老相关的白质变性。2025年5月22日出版的《自然—神经科学》杂志发表了这项成果。

在这里，该研究团队采用药理学和遗传学的方法来研究小鼠髓鞘轴突衰老相关变化的小胶质细胞功能。他们的研究结果表明，适应性不良的小胶质细胞激活促进了有害CD8⁺ T细胞的积累，导致有髓鞘轴突的退化和随后的脑功能和行为损伤。该研究组通过单细胞和空间转录组学表征了白质中胶质异质性和衰老相关的变化，并揭示了复杂的胶质-免疫相互作用。在机制上，该研究组发现CXCL10-CXCR3轴对于CD8⁺ T细胞在老化白质中的募集和保留至关重要，在那里它们发挥致病作用。他们的研究结果表明，髓磷脂相关的小胶质细胞功能障碍促进了衰老过程中的适应性免疫反应，并确定了可能的靶点来减轻其有害影响。

据介绍，衰老是神经退行性变的主要危险因素，与白质的结构和功能改变有关。髓磷脂特别容易受到衰老的影响，导致白质相关的小胶质细胞激活。

附：英文原文

Title: Microglia activation orchestrates CXCL10-mediated CD8+ T cell recruitment to promote aging-related white matter degeneration

Author: Groh, Janos, Feng, Ruoqing, Yuan, Xidi, Liu, Lu, Klein, Dennis, Hutahaean, Gladis, Butz, Elisabeth, Wang, Zhen, Steinbrecher, Lisa, Neher, Jonas, Martini, Rudolf, Simons, Mikael

Issue&Volume: 2025-05-22

Abstract: Aging is the major risk factor for neurodegeneration and is associated with structural and functional alterations in white matter. Myelin is particularly vulnerable to aging, resulting in white matter-associated microglia activation. Here we used pharmacological and genetic approaches to investigate microglial functions related to aging-associated changes in myelinated axons of mice. Our results reveal that maladaptive microglia activation promotes the accumulation of harmful CD8+ T cells, leading to the degeneration of myelinated axons and subsequent impairment of brain function and behavior. We characterize glial heterogeneity and aging-related changes in white matter by single-cell and spatial transcriptomics and reveal elaborate glial–immune interactions. Mechanistically, we show that the CXCL10–CXCR3 axis is crucial for the recruitment and retention of CD8+ T cells in aged white matter, where they exert pathogenic effects. Our results indicate that myelin-related microglia dysfunction promotes adaptive immune reactions in aging and identify putative targets to mitigate their detrimental impact.

DOI: 10.1038/s41593-025-01955-w

Source: https://www.nature.com/articles/s41593-025-01955-w