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

Kimitoshi Kimura, Ayshwarya Subramanian, Zhuoran Yin, Ahad Khalilnezhad, Yufan Wu, Danyang He, Karen O. Dixon, Udbhav Kasyap Chitta, Xiaokai Ding, Niraj Adhikari, Isabell Guzchenko, Xiaoming Zhang, Ruihan Tang, Thomas Pertel, Samuel A. Myers, Aastha Aastha, Masashi Nomura, Ghazaleh Eskandari-Sedighi, Vasundhara Singh, Lei Liu, Conner Lambden, Kilian L. Kleemann, Neha Gupta, Jen-Li Barry, Ana Durao, Yiran Cheng, Sebastian Silveira, Huiyuan Zhang, Aamir Suhail, Toni Delorey, Orit Rozenblatt-Rosen, Gordon J. Freeman, Dennis J. Selkoe, Howard L. Weiner, Mathew Blurton-Jones, Carlos Cruchaga, Aviv Regev, Mario L. Suvà, Oleg Butovsky () and Vijay K. Kuchroo ()
Additional contact information
Kimitoshi Kimura: Massachusetts General Hospital and Harvard Medical School
Ayshwarya Subramanian: Massachusetts General Hospital and Harvard Medical School
Zhuoran Yin: Massachusetts General Hospital and Harvard Medical School
Ahad Khalilnezhad: Massachusetts General Hospital and Harvard Medical School
Yufan Wu: Massachusetts General Hospital and Harvard Medical School
Danyang He: Massachusetts General Hospital and Harvard Medical School
Karen O. Dixon: Massachusetts General Hospital and Harvard Medical School
Udbhav Kasyap Chitta: Massachusetts General Hospital and Harvard Medical School
Xiaokai Ding: Massachusetts General Hospital and Harvard Medical School
Niraj Adhikari: Massachusetts General Hospital and Harvard Medical School
Isabell Guzchenko: Massachusetts General Hospital and Harvard Medical School
Xiaoming Zhang: Massachusetts General Hospital and Harvard Medical School
Ruihan Tang: Massachusetts General Hospital and Harvard Medical School
Thomas Pertel: Brigham and Women’s Hospital and Harvard Medical School
Samuel A. Myers: Broad Institute of MIT and Harvard
Aastha Aastha: Massachusetts General Hospital and Harvard Medical School
Masashi Nomura: Broad Institute of MIT and Harvard
Ghazaleh Eskandari-Sedighi: University of California, Irvine
Vasundhara Singh: Broad Institute of MIT and Harvard
Lei Liu: Massachusetts General Hospital and Harvard Medical School
Conner Lambden: Massachusetts General Hospital and Harvard Medical School
Kilian L. Kleemann: Massachusetts General Hospital and Harvard Medical School
Neha Gupta: Massachusetts General Hospital and Harvard Medical School
Jen-Li Barry: Massachusetts General Hospital and Harvard Medical School
Ana Durao: Massachusetts General Hospital and Harvard Medical School
Yiran Cheng: Massachusetts General Hospital and Harvard Medical School
Sebastian Silveira: Massachusetts General Hospital and Harvard Medical School
Huiyuan Zhang: Massachusetts General Hospital and Harvard Medical School
Aamir Suhail: Massachusetts General Hospital and Harvard Medical School
Toni Delorey: Broad Institute of MIT and Harvard
Orit Rozenblatt-Rosen: Broad Institute of MIT and Harvard
Gordon J. Freeman: Harvard Medical School
Dennis J. Selkoe: Brigham and Women’s Hospital and Harvard Medical School
Howard L. Weiner: Massachusetts General Hospital and Harvard Medical School
Mathew Blurton-Jones: University of California, Irvine
Carlos Cruchaga: Washington University in St Louis
Aviv Regev: Broad Institute of MIT and Harvard
Mario L. Suvà: Broad Institute of MIT and Harvard
Oleg Butovsky: Massachusetts General Hospital and Harvard Medical School
Vijay K. Kuchroo: Massachusetts General Hospital and Harvard Medical School

Nature, 2025, vol. 641, issue 8063, 718-731

Abstract: Abstract 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 TGFβ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ 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-β pathology in 5×FAD mice (a transgenic model of Alzheimer’s disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5×FAD 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 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFβ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer’s disease.

Date: 2025
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DOI: 10.1038/s41586-025-08852-z

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