Tu197 - Gamma-delta T Cells Exacerbate Neuroinflammation in a Mouse Model of Alzheimer's Disease by Modulating Microglial Cells

Abstract Text: Neuroinflammation is a central driver of Alzheimer’s disease (AD), with microglia transitioning from a homeostatic (M0) to a neurodegenerative (MGnD) phenotype, further amplifying inflammation. MGnD microglia recruit and activate peripheral immune cells, including CD8 T cells, contributing to neuroinflammation and neuronal death. Gamma-delta (γδ) T cells, a unique subset of T lymphocytes, sustain neuroinflammation by secreting pro-inflammatory cytokines such as IFN-γ and IL-17. In a traumatic brain injury (TBI) model, we found that γδ T cell-deficient (γδ-/-) mice exhibited fewer amyloid plaques and improved cognitive functions. Vγ4 γδ T cells, producing IFN-γ and IL-17, exacerbated inflammation, while Vγ1 γδ T cells, producing TGF-β, mitigated it. These findings led to the hypothesis that γδ T cells drive microglial activation toward the MGnD phenotype, recruiting and activating peripheral immune cells, thereby perpetuating neuroinflammation and neurodegeneration. Accordingly, scRNA-seq analysis of public datasets showed enriched IFN-γ and IL-17 signatures in γδ T cells from PBMCs and brains of AD patients. In the APP/PS1jucker AD model, both Vγ1 and Vγ4 γδ T cells infiltrated the brain, coinciding with an MGnD microglial phenotype and increased CD8 T cells. APP/PS1:γδ-/- mice exhibited improved cognition, reduced amyloid plaques, a shift in microglial phenotypes from MGnD to M0, and fewer CD8 T cells. These findings suggest that γδ T cells, particularly Vγ1 and Vγ4, play a detrimental role in AD by driving neuroinflammation through interactions with microglia and CD8 T cells. This study may build on the growing number of clinical studies exploring γδ T cells as therapeutical tools.