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

Abstract

Infection of the central nervous system by murine polyomavirus (MuPyV), a persistent natural mouse pathogen, establishes brain-resident memory CD8 T cells (bTRM) that uniformly and chronically express PD-1 irrespective of expression of the αE integrin CD103, a TRM 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 TRM differentiation program. Here, we asked whether PD-1 expression by CD8 bTRM cells during persistent MuPyV encephalitis is antigen-dependent. By transferring MuPyV-specific CD8 bTRM 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 bTRM retain functional competence. We further show that the Pdcd-1 promoter of anti-MuPyV bTRM 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 TRM cells in a persistent CNS viral infection.

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

“…We know that PD‐1 expression in CD8 + T cells results from chronic antigenic exposure in the tumour tissue [37]. However, recent evidence describes that in the case of chronic infection, permanent PD‐1 expression in T RM cells is imprinted epigenetically and is antigen‐independent [38, 39]. Additionally, PD‐1 signalling has been demonstrated to be important for antigen‐independent maintenance of memory CD8 + T cells [40].…”

PD‐1: always on my mind

“…Factors regulating T RM cell inhibitory checkpoint molecule expression in both the steady‐state and during chronic disease are not well understood. In this issue, Shwetank et al 7 show that high‐PD‐1 expression is an inherent property of brain T RM cells, ingrained independently of both antigen and inflammation.…”

Immunology & Cell Biology's top 10 original research articles 2017–2018

“…ICB 's top 10 from July 1, 2017 to June 30, 2018 (in chronological order of publication): Shwetank et al . Maintenance of PD‐1 on brain‐resident memory CD8 T cells is antigen independent Wirasinha et al .…”

“…Two of the ten articles (Shwetank et al 1 and Desai et al 3 ) focus on the maintenance of memory. Shwetank et al investigate the brain-resident memory CD8 T cells (bT RM ) induced by murine polyomavirus and discover that, in contrast to peripheral CD8 T RM cells, bT RM retain high PD-1 expression independent of inflammation or antigen.…”

“…1 Importantly, the authors delved more deeply into the mechanism, by which PD-1 expression was maintained in the brain-resident but not peripheral CD8 T RM cells, and found sustained PD-1 correlated with more extensive demethylation in the Pdcd1 promoter region. 1 This article highlights how different microenvironments can regulate immune memory and effector functions during persistent infections to minimize the potential for immunopathology. The second article, by Desai et al, identifies the role of inflammatory monocytes in CXCR3 hi CX3CR1 lo CD8 memory T-cell persistence in the lung.…”