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Cited by 85Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsPhagocytosis and Immune Regulation

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

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Kimura, Kimitoshi, Subramanian, Ayshwarya, Yin, Zhuoran, Khalilnezhad, Ahad, Wu, Yufan, He, Danyang, Dixon, Karen O., Chitta, Udbhav Kasyap +32 more·2025·Nature
DOI 10.1038/s41586-025-08852-zPMC PMC12079183
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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 disease 3, and it can induce T cell exhaustion 4. 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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  • TIM3 deficiency promotes a protective microglia state in 5xFAD mice, characterized by increased phagocytic and reduced pro-inflammatory activity.

    “TIM3 deficiency promotes a protective microglia state in 5xFAD mice, characterized by increased phagocytic and reduced pro-inflammatory activity.”

    From Lymphoid gene expression supports neuroprotective microglia function (2025) · cites this paper as [49]

  • The T cell immunoglobulin and mucin domain 3 (TIM-3) receptor is a novel regulator of microglial activity in Alzheimer's disease.

    “The importance of CD28 (refs. 3,4) and probably other functionally related immunoregulatory receptors in governing microglial responses is underscored by recent findings identifying the T cell immunoglobulin and mucin domain 3 (TIM-3) receptor as a novel regulator of microglial activity in AD49.”

    From Lymphoid gene expression supports neuroprotective microglia function (2025) · cites this paper as [49]

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Authors
Kimura, K., Subramanian, A., Yin, Z., Khalilnezhad, A., Wu, Y., He, D., Dixon, K. O., Chitta, U. K., Ding, X., Adhikari, N., Guzchenko, I., Zhang, X., Tang, R., Pertel, T., Myers, S. A., Aastha, A., Nomura, M., Eskandari-Sedighi, G., Singh, V., Liu, L., Lambden, C., Kleemann, K. L., Gupta, N., Barry, J.-L., Durao, A., Cheng, Y., Silveira, S., Zhang, H., Suhail, A., Delorey, T., Rozenblatt-Rosen, O., Freeman, G. J., Selkoe, D. J., Weiner, H. L., Blurton-Jones, M., Cruchaga, C., Regev, A., Suvà, M. L., Butovsky, O., & Kuchroo, V. K.
Affiliations
  • Brigham and Women's Hospital (US)
  • Broad Institute (US)
  • Harvard University (US)
  • University of California, Irvine (US)
  • Washington University in St. Louis (US)
Corresponding author
  • Butovsky, Oleg
  • Kuchroo, Vijay K.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2025-04-09
Volume
641
Issue
8063
Pages
718-731
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-025-08852-z
PMC
PMC12079183
OpenAlex
W4409283791
Cited by
85
References
39
Citations by year
2026: 62 · 2025: 23
FWCI
30.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institute on Aging (R21AG076982, R01AG051812, RF1AG082704, R01AG054672, R01AG075509, R01AG080992, U19AG069701, P30AG066519)
  • National Eye Institute (R01EY027921)
  • National Institute of Allergy and Infectious Diseases (P01AI073748, P01AI056299, R01AI144166)
  • National Institute of Neurological Disorders and Stroke (R01NS088137)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
TIM-3, microglia, Alzheimer's disease, TGF-beta signaling, Smad2, TGFBR2, disease-associated microglia, microglial homeostasis, phagocytosis, amyloid-beta pathology, cognitive impairment, 5xFAD mice, neuroinflammation, immune checkpoint
MeSH terms
Hepatitis A Virus Cellular Receptor 2, Receptor, Transforming Growth Factor-beta Type II, Alzheimer Disease, Animals, Disease Models, Animal, Female, Homeostasis, Humans, Male, Mice, Transgenic, Phagocytosis, Phosphorylation, Signal Transduction, Transforming Growth Factor beta, Amyloid beta-Peptides, Microglia, Mice, Smad2 Protein, Cognitive Dysfunction

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