Gamma-Delta T cell—microglia crosstalk drives CD8+ T cell infiltration and promotes Alzheimer’s-like pathology in APP/PS1 mice 2257327

Introduction Neuroinflammation is a central feature of Alzheimer’s disease (AD), driving neuronal injury, synaptic dysfunction, and the accumulation of amyloid plaques and neurofibrillary tangles. In AD, microglia transition from a homeostatic (M0) to a neurodegenerative (MGnD) phenotype that promotes recruitment of peripheral immune cells to the brain. We identified γδ T cells as key modulators of this process. Methods We used flow cytometry, IF, and behavioral testing in APP/PS1Jucker and APP/PS1:γδ⁻/⁻ mice to assess immune infiltration, cytokine production, microglial phenotypes, and cognition; photoconversion and cell tracking in APP/PS1:Kaede mice to trace gut- and lymphoid-derived γδ T cells; and single-cell RNA sequencing of PBMCs and brain tissues from AD patients to profile γδ T cell transcriptional programs. Results In the APP/PS1Jucker model, γδ T cells infiltrated the brain by 3 months of age - preceding CD8+ T cell recruitment - and correlated with the emergence of an MGnD microglial signature. Infiltrating Vγ1 cells predominantly produced IFN-γ, while Vγ4 cells secreted IL-17. γδ T cell deficiency improved cognition, reduced amyloid deposition, shifted microglia toward a homeostatic phenotype, and diminished CD8+ T cell infiltration. Using photoconvertible APP/PS1:Kaede mice, we demonstrated that gut-derived Vγ4 γδ T cells preferentially migrate to the brain, supporting a microbiota-dependent gut—brain axis, whereas Vγ1 cells originate from lymphoid organs. Single-cell RNA sequencing of PBMCs and brains from AD patients revealed γδ T cell enrichment for IFN-γ and IL-17 transcriptional programs, mirroring mouse data. Conclusion Together, these findings uncover a pathogenic γδ T cell—microglia—CD8+ T cell axis linking gut immunity to neuroinflammation, identifying γδ T cells and their cytokines as promising therapeutic targets for AD.