Maintenance of PD‐1 on brain‐resident memory CD8 T cells is antigen independent

Abstract

Infection of the central nervous system (CNS) by murine polyomavirus (MuPyV), a persistent natural mouse pathogen, establishes brain-resident memory CD8 T cells (bT_RM) that uniformly and chronically express programmed cell death protein 1 (PD-1) irrespective of the expression of α_E integrin CD103, a T_RM cell marker. In contrast, memory antiviral CD8 T cells in the spleen are PD-1^-, despite viral loads being similar in both the brain and spleen during persistent infection. Repetitive antigen engagement is central to sustained PD-1 expression by T cells in chronic viral infections; however, recent evidence indicates that expression of inhibitory receptors, including PD-1, is part of the T_RM differentiation program. Here we asked whether PD-1 expression by CD8 bT_RM cells during persistent MuPyV encephalitis is antigen dependent. By transferring MuPyV-specific CD8 bT_RM cells into the brains of naive mice and mice infected with cognate epitope-sufficient and -deficient MuPyVs, we demonstrate that antigen and inflammation are dispensable for PD-1 maintenance. In vitro and direct ex vivo analyses indicate that CD103^- MuPyV-specific CD8 bT_RM retain functional competence. We further show that the Pdcd-1 promoter of anti-MuPyV bT_RM cells is epigenetically fixed in a demethylated state in the brain. In contrast, the PD-1 promoter of splenic antiviral memory CD8 T cells undergoes remethylation after being demethylated during acute infection. These data show that PD-1 expression is an intrinsic property of brain T_RM cells in a persistent CNS viral infection.