美国国立卫生研究院Dorian B. McGavern团队取得一项新突破。他们探明了颗粒酶K⁺ CD8 T细胞通过靶向小胶质细胞减缓tau病的进展。2025年6月24日出版的《自然—免疫学》杂志发表了这项成果。

该课题组人员试图确定小鼠和人类在牛头病发展过程中出现的有益免疫压力。研究组使用在神经元中表达突变人类tau的小鼠，观察到小胶质细胞通过控制磷酸化tau （pTau）在中枢神经系统和血液中的扩散来减缓tau病的发展。

然而，随着时间的推移，小胶质细胞转化为受损的抗原呈递细胞，获得神经元转录本，并被驻留的、克隆扩增的CD8⁺ T细胞靶向。这些细胞不表达传统的效应分子，如IFNγ、TNF或颗粒酶a/b/c，而是将颗粒酶K （GZMK）沉积到小胶质细胞上，并受到免疫检查点蛋白（TIGIT、PD-1）的调节，因为TIGIT和PD-1的阻断会促进疾病进展。GZMK⁺CD8⁺ T细胞也可以靶向ptau富集的人类大脑病变中的小胶质细胞，这些病变是由年龄、阿尔茨海默病或慢性创伤性脑病引起的。小鼠中CD8⁺ T细胞的缺失促进了含有神经元转录物的受损小胶质细胞的出现，显著增强了pTau的扩散，加速了神经功能的衰退。这些数据表明，GZMK⁺CD8⁺ T细胞是牛头病发展的标志，可能被用于减缓疾病进展。

据了解，神经退行性疾病激活先天和适应性免疫反应，可以减缓或加速疾病进展。

附：英文原文

Title: Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia

Author: Mason, Hannah D., Latour, Yvonne L., Boughter, Christopher T., Johnson, Kory R., Maric, Dragan, Dorrier, Cayce E., Guedes, Vivian A., Lai, Chen, Duncker, Patrick C., Johnson, Alexis M., Manglani, Monica, Gill, Jessica M., Perl, Daniel P., Meier-Schellersheim, Martin, McGavern, Dorian B.

Issue&Volume: 2025-06-24

Abstract: Neurodegenerative diseases activate innate and adaptive immune responses that can either slow or accelerate disease progression. Here, we sought to define beneficial immune pressures that emerge during tauopathy development in mice and humans. Using mice that express mutant human tau in neurons, we observed that microglia slowed tauopathy development by controlling the spread of phosphorylated tau (pTau) in the central nervous system and blood. However, over time microglia converted into distressed antigen-presenting cells, acquired neuronal transcripts and were targeted by resident, clonally expanded CD8+ T cells. These cells did not express traditional effector molecules, such as IFNγ, TNF or granzymes a/b/c, but instead deposited granzyme K (GZMK) onto microglia and were regulated by immune checkpoint proteins (TIGIT, PD-1), as blockade of TIGIT and PD-1 enhanced disease progression. GZMK+CD8+ T cells also targeted microglia in pTau-rich human brain lesions resulting from age, Alzheimer’s disease or chronic traumatic encephalopathy. Deletion of CD8+ T cells in mice promoted the emergence of distressed microglia containing neuronal transcripts, markedly enhanced pTau spread and accelerated neurological decline. These data demonstrate that GZMK+CD8+ T cells are a signature of tauopathy development and could potentially be harnessed to slow disease progression.

DOI: 10.1038/s41590-025-02198-4

Source: https://www.nature.com/articles/s41590-025-02198-4