Fig. 1

Two distinct Alzheimer’s disease mouse models for studying T cells in AD pathogenesis. (A) In aged 5xFAD mice with amyloid beta (Aβ) plaque deposition and cognitive impairment, an aberrantly higher presence of brain CD8⁺ T cells, but not CD4⁺ T cells or γδT cells, is linked to these AD pathologies. Among brain cells, microglia produce the highest levels of CXCL16. The communication between microglia and CXCR6-expressing CD8⁺ T cells, facilitated by CXCL16-CXCR6 interaction, allows CXCR6⁺ CD8⁺ T cells from peripheral blood to enter the brain and migrate towards Aβ plaques, where microglia are also concentrated (left panel). In the 5xFAD mice, depleting brain CD8⁺ T cells or disrupting CD8⁺ T function by creating CXCR6, B2m, or T-cell receptor alpha chain (TCRα)-deficient mice results in an increased Aβ plaque deposition and worsened cognitive impairment (right panel). These findings suggest that brain CD8⁺ T cells serve a protective role during AD development. (B) In aged human ApoE4-expressing P301S Tau transgenic (TE4) mice with tauopathy and brain atrophy, an aberrantly higher presence of brain T cells is found to be colocalized with microglia (left panel). In the TE4 mice, depleting brain T cells by injecting anti-CD4 (αCD4) and anti-CD8 (αCD8) antibodies results in reduced tauopathy, brain atrophy, cognitive impairment, and inflammation (panel right). These findings suggest that brain T cells, including CD8⁺ T cells, exhibit a detrimental role during AD development. Interestingly, in both mouse models, PD-1 immune checkpoint blockade in TE4 mice mitigates AD pathologies (A & B). Created with BioRender (Biorender.com)