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

Author

Listed:
  • Kimitoshi Kimura

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Kyoto University Graduate School of Medicine)

  • Ayshwarya Subramanian

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Zhuoran Yin

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Harvard Medical School)

  • Ahad Khalilnezhad

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Yufan Wu

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Danyang He

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Karen O. Dixon

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Udbhav Kasyap Chitta

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Xiaokai Ding

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Niraj Adhikari

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Isabell Guzchenko

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Xiaoming Zhang

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Ruihan Tang

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s 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
    La Jolla Institute for Immunology
    University of California, San Diego)

  • Aastha Aastha

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Masashi Nomura

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital and Harvard Medical School)

  • Ghazaleh Eskandari-Sedighi

    (University of California, Irvine
    University of California, Irvine)

  • Vasundhara Singh

    (Broad Institute of MIT and Harvard)

  • Lei Liu

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Conner Lambden

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Kilian L. Kleemann

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Neha Gupta

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Jen-Li Barry

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Ana Durao

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Yiran Cheng

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Sebastian Silveira

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Huiyuan Zhang

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Aamir Suhail

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard)

  • 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
    Brigham and Women’s Hospital and Harvard Medical School)

  • Howard L. Weiner

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Mathew Blurton-Jones

    (University of California, Irvine
    University of California, Irvine
    University of California, Irvine)

  • Carlos Cruchaga

    (Washington University in St Louis
    Washington University School of Medicine)

  • Aviv Regev

    (Broad Institute of MIT and Harvard
    Genentech)

  • Mario L. Suvà

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital and Harvard Medical School)

  • Oleg Butovsky

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Vijay K. Kuchroo

    (Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School
    Broad Institute of MIT and Harvard)

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.

Suggested Citation

  • Kimitoshi Kimura & Ayshwarya Subramanian & Zhuoran Yin & Ahad Khalilnezhad & Yufan Wu & Danyang He & Karen O. Dixon & Udbhav Kasyap Chitta & Xiaokai Ding & Niraj Adhikari & Isabell Guzchenko & Xiaomin, 2025. "Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease," Nature, Nature, vol. 641(8063), pages 718-731, May.
    • Handle: RePEc:nat:nature:v:641:y:2025:i:8063:d:10.1038_s41586-025-08852-z
    DOI: 10.1038/s41586-025-08852-z
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