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; Vijay K Kuchroo

doi:10.1038/s41586-025-08852-z

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

Nature. 2025 May;641(8063):718-731. doi: 10.1038/s41586-025-08852-z. Epub 2025 Apr 9.

Authors

Kimitoshi Kimura^#^{1

2

3

4}, Ayshwarya Subramanian^#^{1

2

3

5}, Zhuoran Yin^#^{1

2

3

6}, Ahad Khalilnezhad^#^{1

2

3

5}, Yufan Wu^{1

2

3

5}, Danyang He^{1

2

3}, Karen O Dixon^{1

2

3}, Udbhav Kasyap Chitta^{1

2

3}, Xiaokai Ding^{1

2

3}, Niraj Adhikari^{1

2

3}, Isabell Guzchenko^{1

2

3}, Xiaoming Zhang^{1

2

3}, Ruihan Tang^{1

2

3}, Thomas Pertel³, Samuel A Myers^{5

7

8}, Aastha Aastha^{1

2

3}, Masashi Nomura^{5

9}, Ghazaleh Eskandari-Sedighi^{10

11}, Vasundhara Singh⁵, Lei Liu^{1

2

3}, Conner Lambden^{1

2

3

5}, Kilian L Kleemann^{1

2

3}, Neha Gupta^{1

2

3

5}, Jen-Li Barry^{1

2

3}, Ana Durao^{1

2

3}, Yiran Cheng^{1

2

3}, Sebastian Silveira^{1

2

3}, Huiyuan Zhang^{1

2

3}, Aamir Suhail^{1

2

3

5}, Toni Delorey⁵, Orit Rozenblatt-Rosen⁵, Gordon J Freeman¹², Dennis J Selkoe^{2

3}, Howard L Weiner^{1

2

3}, Mathew Blurton-Jones^{10

11

13}, Carlos Cruchaga^{14

15}, Aviv Regev^{5

16}, Mario L Suvà^{5

9}, Oleg Butovsky^{17

18

19}, Vijay K Kuchroo^{20

21

22

23}

Affiliations

¹ The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³ Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA.
⁷ Laboratory for Immunochemical Circuits, La Jolla Institute for Immunology, La Jolla, CA, USA.
⁸ Department of Pharmacology, University of California, San Diego, San Diego, CA, USA.
⁹ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, USA.
¹¹ Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
¹³ Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
¹⁴ Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
¹⁵ NeuroGenomics and Informatics Center, Washington University School of Medicine, St Louis, MO, USA.
¹⁶ Genentech, South San Francisco, CA, USA.
¹⁷ The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. obutovsky@bwh.harvard.edu.
¹⁸ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. obutovsky@bwh.harvard.edu.
¹⁹ Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. obutovsky@bwh.harvard.edu.
²⁰ The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. vkuchroo@bwh.harvard.edu.
²¹ Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. vkuchroo@bwh.harvard.edu.
²² Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. vkuchroo@bwh.harvard.edu.
²³ Broad Institute of MIT and Harvard, Cambridge, MA, USA. vkuchroo@bwh.harvard.edu.

^# Contributed equally.

Abstract

Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation^1,2. 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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / immunology
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Amyloid beta-Peptides / metabolism
Animals
Cognitive Dysfunction / genetics
Cognitive Dysfunction / pathology
Disease Models, Animal
Female
Hepatitis A Virus Cellular Receptor 2* / chemistry
Hepatitis A Virus Cellular Receptor 2* / deficiency
Hepatitis A Virus Cellular Receptor 2* / genetics
Hepatitis A Virus Cellular Receptor 2* / metabolism
Homeostasis
Humans
Male
Mice
Mice, Transgenic
Microglia* / immunology
Microglia* / metabolism
Microglia* / pathology
Phagocytosis
Phosphorylation
Receptor, Transforming Growth Factor-beta Type II / metabolism
Signal Transduction
Smad2 Protein / metabolism
Transforming Growth Factor beta / metabolism

Substances

Hepatitis A Virus Cellular Receptor 2
Transforming Growth Factor beta
Receptor, Transforming Growth Factor-beta Type II
Havcr2 protein, mouse
Smad2 Protein
Amyloid beta-Peptides

Abstract

Publication types

MeSH terms

Substances

Grants and funding