ABSTRACT Resident memory T cells (T RM ) have been described in barrier tissues as having a ‘sensing and alarm’ function where, upon sensing cognate antigen, they alarm the surrounding tissue and orchestrate local recruitment and activation of immune cells. In the immunologically unique and tightly restricted CNS, it remains unclear if and how brain T RM , which express the inhibitory receptor PD-1, alarm the surrounding tissue during antigen re-encounter. Here, we reveal that T RM are sufficient to drive the rapid remodeling of the brain immune landscape through activation of microglia, DCs, NK cells, and B cells, expansion of Tregs, and recruitment of macrophages and monocytic dendritic cells. Moreover, we report that while PD-1 restrains granzyme B expression by reactivated brain T RM , it has no effect on cytotoxicity or downstream alarm responses. We conclude that T RM are sufficient to trigger rapid immune activation and recruitment in the CNS and may have an unappreciated role in driving neuroinflammation.

Alarm functions of PD-1+ brain resident memory T cells