Gamma-delta T cell-microglia crosstalk promotes CD8 T cells infiltration into the brain and contributes to AD pathogenesis in APP/PS1 model 3382

Abstract Description Neuroinflammation is a key driver of Alzheimer’s disease (AD), contributing to neuronal damage, synaptic dysfunction, amyloid plaque accumulation, and neurofibrillary tangle formation. In AD, microglia transition from a homeostatic (M0) to a neurodegenerative (MGnD) phenotype, recruiting peripheral immune cells to the brain. Gamma-delta (γδ) T cells are pivotal in sustaining neuroinflammation. We found that in a traumatic brain injury model, which exhibits amyloid plaque accumulation associated with neuroinflammation, γδ T cell-deficient mice exhibited fewer plaques and improved cognitive and motor functions. Notably, Vγ1 and Vγ4 γδ T cell subsets play opposing roles, with Vγ1 producing TGF-β and Vγ4 secreting IFN-γ and IL-17. Using scRNA-seq data from PBMCs and hippocampus of AD patients, we identified enriched IFN-γ and IL-17 signatures in γδ T cells. In the APP/PS1Jucker mouse model of AD, γδ and CD8 T cells infiltrated the brain, correlating with a MGnD microglial phenotype. Importantly, γδ T cell deficiency in APP/PS1 mice resulted in improved cognition, reduced amyloid plaques, a shift from MGnD to M0 microglia, and diminished CD8 T cell infiltration. Both Vγ1 and Vγ4 subsets were present in the brains of APP/PS1 mice. These findings suggest γδ T cells play a detrimental role in AD by mediating pathological crosstalk with microglia and CD8 T cells. Funding Sources AARGD-NTF-23-1144264 Topic Categories Neuroimmunology (NEUR)