Reactive glia promote development of CD103(+)CD69(+) CD8(+) T‐cells through programmed cell death‐ligand 1 (PD‐L1)

INTRODUCTION: Previous work from our laboratory has demonstrated in vivo persistence of CD103(+)CD69(+) brain resident memory CD8(+) T‐cells (bT(RM)) following viral infection, and that the PD‐1: PD‐L1 pathway promotes development of these T(RM) cells within the brain. Although glial cells express low basal levels of PD‐L1, its expression is upregulated upon IFN‐γ‐treatment, and they have been shown to modulate antiviral T‐cell effector responses through the PD‐1: PD‐L1 pathway. METHODS: We performed flow cytometric analysis of cells from co‐cultures of mixed glia and CD8(+) T‐cells obtained from wild type mice to investigate the role of glial cells in the development of bT(RM). RESULTS: In this study, we show that interactions between reactive glia and anti‐CD3 Ab‐stimulated CD8(+) T‐cells promote development of CD103(+)CD69(+) CD8(+) T‐cells through engagement of the PD‐1: PD‐L1 pathway. These studies used co‐cultures of primary murine glial cells obtained from WT animals along with CD8(+) T‐cells obtained from either WT or PD‐1 KO mice. We found that αCD3 Ab‐stimulated CD8(+) T‐cells from WT animals increased expression of CD103 and CD69 when co‐cultured with primary murine glial cells. In contrast, significantly reduced expression of CD103 and CD69 was observed using CD8(+) T‐cells from PD‐1 KO mice. We also observed that reactive glia promoted high levels of CD127, a marker of memory precursor effector cells (MPEC), on CD69(+) CD8(+) T‐cells, which promotes development of T(RM) cells. Interestingly, results obtained using T‐cells from PD‐1 KO animals showed significantly reduced expression of CD127 on CD69(+) CD8(+) cells. Additionally, blocking of glial PD‐L1 resulted in decreased expression of CD103, along with reduced CD127 on CD69(+) CD8(+) T‐cells. CONCLUSIONS: Taken together, these results demonstrate a role for activated glia in promoting development of bT(RM) through the PD‐1: PD‐L1 pathway.