Infection of the central nervous system by murine polyomavirus (MuPyV), a persistent natural mouse pathogen, establishes brain-resident memory CD8 T cells (bT(RM)) that uniformly and chronically express PD-1 irrespective of expression of the 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 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.
Maintenance of PD-1 on brain-resident memory CD8 T cells is antigen-independent