The involvement of microglia and the CXCL16-CXCR6 axis in the recruitment of CD8+ T cells to an amyloidogenic mouse brain

Alzheimer's disease (AD) progression has been associated with the presence of brain-resident CD8⁺ T cells, and recent studies suggest a potential role of the CXCL16-CXCR6 axis in their recruitment to the brain. Here, we examined publicly available single-cell RNA sequencing datasets revealing that in the mouse brain, the receptor Cxcr6 is mainly expressed by CD8⁺ T cells, while the expression of its ligand Cxcl16 is predominantly observed in microglial cells. We found higher levels of Cxcl16 and Cxcr6 expression in APP/PS1 compared to wild-type mice. Furthermore, in vitro experiments using immortalized and primary murine cells suggested that Cxcl16 expression is driven by Aβ pathology. In contrast to our expectations, no changes in the number of Cxcr6⁺CD8⁺ cells was evident in the brains of microglia-depleted APP/PS1 mice, treated with the CSF1R antagonist PLX5622. This was related to an increased compensatory Cxcl16 expression by depletion-resistant microglia or by other brain-resident myeloid cells. Although we demonstrated a strong association between microglial Cxcl16 and AD pathology, PLX5622-sensitive microglia are dispensable in the recruitment of Cxcr6⁺CD8⁺ T cells to the brain of APP/PS1 mice. Future in vivo analysis will help to dissect the mechanism of CD8⁺ T cell recruitment to the brain.