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

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.

PMID: 40205047
PMCID: PMC12079183 (available on 2025-11-01)
DOI: 10.1038/s41586-025-08852-z

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

Kimitoshi Kimura et al. Nature. 2025 May.

. 2025 May;641(8063):718-731.

doi: 10.1038/s41586-025-08852-z. Epub 2025 Apr 9.

Authors

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.

PMID: 40205047
PMCID: PMC12079183 (available on 2025-11-01)
DOI: 10.1038/s41586-025-08852-z

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.

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Conflict of interest statement

Competing interests: G.J.F. has equity in Nextpoint, iTeos, IgM, Invaria, GV20, Bioentre and Geode. G.J.F. has served on advisory boards for iTeos, NextPoint, IgM, GV20, IOME, Bioentre, Santa Ana Bio, Simcere of America and Geode. G.J.F.’s interests were reviewed and managed by the Dana-Farber Cancer Institute in accordance with their conflict-of-interest policies. D.J.S. is a director of Prothena Biosciences and an ad hoc consultant to Roche and Eisai. M.B.-J. is a co-founder and consultant for Savanna Biotherapeutics (formally NovoGlia). A.R. is a cofounder and equity holder of Celsius Therapeutics, an equity holder in Immunitas and was a scientific advisory board member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov until 31 July 2020. From 1 August 2020, A.R. is an employee of Genentech and has equity in Roche. M.L.S. is an equity holder, scientific cofounder and advisory board member of Immunity Therapeutics. O.B. is a cofounder of and has an ownership interest in Glial Therapeutics and Gliax. O.B. has a financial interest in Glial Therapeutics, a company developing a new therapy to target ITGB8–TGFβ signalling as a treatment for AD. O.B.’s interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies and include collaboration with GSK and Regulus Therapeutics, receiving research funding from Sanofi and GSK, and honoraria for lectures and consultancy from UCB, Camp4 and Ono Pharma USA. V.K.K. has an ownership interest in Tizona Therapeutics, Trishula, Celsius Therapeutics, Bicara Therapeutics, Larkspur Therapeutics and Werewolf Therapeutics. V.K.K. has financial interests in Biocon Biologic, Compass, Elpiscience Biopharmaceutical, Equilium, PerkinElmer and Syngene. V.K.K. is a member of SABs for Cell Signaling Technology, Elpiscience Biopharmaceutical, Larkspur, Tizona Therapeutics, Tr1X and Werewolf. V.K.K.’s interests were reviewed and managed by Mass General Brigham in accordance with their conflict-of-interest policies.

References

1. Colonna M & Butovsky O Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol 35, 441–468 (2017). - PMC - PubMed
1. Butovsky O & Weiner HL Microglial signatures and their role in health and disease. Nat. Rev. Neurosci 19, 622–635 (2018). - PMC - PubMed
1. Wightman DP et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat. Genet 53, 1276–1282 (2021). - PMC - PubMed
1. Wolf Y, Anderson AC & Kuchroo VK TIM3 comes of age as an inhibitory receptor. Nat. Rev. Immunol 20, 173–185 (2020). - PMC - PubMed
1. Jansen IE et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat. Genet 51, 404–413 (2019). - PMC - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials