biostudies-literatureKimura KNEI NIH HHSNIA NIH HHSNIAID NIH HHSNINDS NIH HHS718-731https://www.ebi.ac.uk/biostudies/studies/S-EPMC12079183biostudies-literatureUnknown641(8063)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 mNatureImmune checkpoint TIM-3 regulates microglia and Alzheimer's disease.PMC12079183R01 AG054672U19 AG069701R21 AG076982R01 EY027921R01 NS088137P30 AG066519RF1 AG082704R01 AG051812R01 AG075509P01 AI056299P01 AI073748R01 AG080992R01 AI144166Aastha ALiu LSuhail ASuva MLZhang HKimura KKleemann KLKuchroo VKSubramanian ACheng YDing XAdhikari NLambden CSilveira SGuzchenko ITang RWeiner HLGupta NWu YKhalilnezhad ASingh VDixon KORozenblatt-Rosen OHe DBlurton-Jones MChitta UKYin ZNomura MCruchaga CFreeman GJDurao AEskandari-Sedighi GDelorey TMyers SARegev AZhang XSelkoe DJBarry JLPertel TButovsky OfalseImmune checkpoint TIM-3 regulates microglia and Alzheimer's disease.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 m2025-01-01T00:00:00Z2025 May2026-06-05T09:28:28.148Z2026-05-15T03:12:44.822ZS-EPMC120791834020504710.1038/s41586-025-08852-z