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Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease
Kimura K, Subramanian A, Yin Z, Khalilnezhad A, Wu Y, He D, Dixon KO, Chitta UK, Ding X, Adhikari N, Guzchenko I, Zhang X, et al.. Nature, 2025-04-09
Topic: Brain proteins, microglia and lab models
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.
Key findings
- 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.
- 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.
Why it matters
In mouse models, deleting Havcr2 in microglia increased phagocytic activity and ameliorated cognitive impairment and reduced amyloid-beta pathology in 5xFAD mice. These findings in a transgenic animal model highlight the therapeutic potential of targeting microglial TIM-3, but no human treatment or prevention is demonstrated.
Study details
- Evidence strengthEarly
How this study scored 59/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 58 of the 98 points we could judge it on, which is 59 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| Journal's citation record | 4 / 4 | Nature: journal h-index 1,841 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 2 / 5 | Rated “early” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 81 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 27.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 5 / 6 | Cited 24.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 3 / 4 | Cited 81 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Vijay Kumar Kuchroo: h-index 161 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 12 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40205047) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 58 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 58 of the 98 points we could judge it on is 59 out of 100. |
| Total | 59 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Kimura, K., Subramanian, A., Yin, Z., Khalilnezhad, A., Wu, Y., He, D., et al. (2025). Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease. Nature. https://doi.org/10.1038/s41586-025-08852-z
Vancouver
Kimura K, Subramanian A, Yin Z, Khalilnezhad A, Wu Y, He D, et al. Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease. Nature. 2025. doi:10.1038/s41586-025-08852-z. PMID: 40205047.
BibTeX
@article{kimura2025-40205047,
author = {Kimura, K. and Subramanian, A. and Yin, Z. and Khalilnezhad, A. and Wu, Y. and He, D. and Dixon, K. O. and Chitta, U. K. and Ding, X. and Adhikari, N. and Guzchenko, I. and Zhang, X. and others},
title = {{Immune checkpoint TIM-3 regulates microglia and Alzheimer's disease}},
journal = {Nature},
year = {2025},
doi = {10.1038/s41586-025-08852-z},
pmid = {40205047},
url = {https://doi.org/10.1038/s41586-025-08852-z}
}
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