Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease

• 成果类型: Article
• 署名作者: Kimura, Kimitoshi; Subramanian, Ayshwarya; Yin, Zhuoran; Khalilnezhad, Ahad; Wu, Yufan; He, Danyang; Dixon, Karen O.; Chitta, Udbhav Kasyap; Ding, Xiaokai; Adhikari, Niraj; Guzchenko, Isabell; Zhang, Xiaoming; Tang, Ruihan; Pertel, Thomas; Myers, Samuel A.; Aastha, Aastha; Nomura, Masashi; Eskandari-Sedighi, Ghazaleh; Singh, Vasundhara; Liu, Lei; Lambden, Conner; Kleemann, Kilian L.; Gupta, Neha; Barry, Jen-Li; Durao, Ana; Cheng, Yiran; Silveira, Sebastian; Zhang, Huiyuan; Suhail, Aamir; Delorey, Toni; Rozenblatt-Rosen, Orit; Freeman, Gordon J.; Selkoe, Dennis J.; Weiner, Howard L.; Blurton-Jones, Mathew; Cruchaga, Carlos; Regev, Aviv; Suva, Mario L.; Butovsky, Oleg; Kuchroo, Vijay K.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Kyoto University; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts Eye & Ear Infirmary; Harvard Medical School; La Jolla Institute for Immunology; University of California System; University of California San Diego; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of California System; University of California Irvine; University of California System; University of California Irvine; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; University of California System; University of California Irvine; Washington University (WUSTL); Washington University (WUSTL); Roche Holding; Roche Holding USA; Genentech
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3209
• DOI: 10.1038/s41586-025-08852-z
• 发表日期: 2025-05-15
• 关键词: single-cell; mouse; macrophage; responses; drives; myelinogenesis; transcriptome; dissection; signatures; mutations

摘要

Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation1,2. This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer's disease3, and it can induce T cell exhaustion4. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGF beta signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGF beta signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-beta pathology in 5xFAD mice (a transgenic model of Alzheimer's disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5xFAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2-deficient 5xFAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGF beta signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer's disease.