Alarm Functions of PD-1+ Brain-Resident Memory T Cells

Resident memory T cells (TRM cells) have been described in barrier tissues as having a "sensing and alarm" function where, upon sensing cognate Ag, 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 whether and how brain TRM cells, which express the inhibitory receptor programmed cell death protein 1 (PD-1), alarm the surrounding tissue during Ag re-encounter. Using mouse models, we reveal that TRM cells are sufficient to drive the rapid remodeling of the brain immune landscape through activation of microglia, dendritic cells, NK cells, and B cells, expansion of regulatory T cells, and recruitment of macrophages and monocytic dendritic cells. Moreover, we report that although PD-1 restrained granzyme B upregulation in brain TRM cells reactivated via viral peptide, we observed no apparent effect on cytotoxicity in vivo, or downstream alarm responses within 48 h of TRM reactivation. We conclude that TRM cells are sufficient to trigger rapid immune activation and recruitment in the CNS and may have an unappreciated role in driving neuroinflammation.