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Maintenance of PD-1 on brain-resident memory CD8 T cells is antigen independent
Shwetank1, Hossam A Abdelsamed2, Elizabeth L Frost1
1Department of Microbiology and Immunology, Penn State College of Medicine, Hershey, PA, USA.
Abstract:
Infection of the central nervous system (CNS) by murine polyomavirus (MuPyV), a persistent natural mouse pathogen, establishes brain-resident memory CD8 T cells (bTRM) that uniformly and chronically express programmed cell death protein 1 (PD-1) irrespective of the expression of 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 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 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.
Insights
Brain CD8 T cells (bTRM) in persistent infections express PD-1 intrinsically, independent of antigen. This PD-1 expression is epigenetically fixed in the brain, unlike splenic T cells.
Area of Science:
- Immunology
- Neurovirology
- Cellular Immunology
Background:
- Murine polyomavirus (MuPyV) establishes persistent central nervous system (CNS) infections, generating brain-resident memory CD8 T cells (bTRM).
- These bTRM cells uniformly express programmed cell death protein 1 (PD-1), a marker typically associated with T cell exhaustion, even without CD103 expression.
- Splenic memory CD8 T cells from MuPyV-infected mice are PD-1 negative, despite similar viral loads, suggesting a unique brain environment influence.
Purpose of the Study:
- To investigate whether PD-1 expression on CD8 bTRM cells during persistent MuPyV encephalitis is dependent on continued antigen exposure.
- To determine the epigenetic mechanisms underlying PD-1 expression in brain-resident versus splenic memory CD8 T cells.
Main Methods:
- Transfer of MuPyV-specific CD8 bTRM cells into naive mice and mice infected with MuPyV strains expressing or lacking cognate epitopes.
- In vitro and ex vivo analyses of CD103- bTRM cell function.
- Epigenetic analysis of the Pdcd-1 (PD-1) promoter in brain and splenic CD8 T cells using methylation assays.
Main Results:
- Antigen and inflammation are dispensable for maintaining PD-1 expression on CD8 bTRM cells in the CNS.
- CD103- MuPyV-specific CD8 bTRM cells remain functionally competent despite PD-1 expression.
- The Pdcd-1 promoter in anti-MuPyV bTRM cells is epigenetically demethylated and fixed in the brain.
- In contrast, the PD-1 promoter in splenic memory CD8 T cells undergoes remethylation after acute infection.
Conclusions:
- PD-1 expression is an intrinsic property of CD8 bTRM cells during persistent CNS viral infections, not solely driven by antigen.
- Epigenetic modifications, specifically promoter demethylation, establish and maintain PD-1 expression in brain-resident T cells.
- This epigenetic regulation differentiates brain TRM cells from their splenic counterparts, highlighting unique CNS immune cell programming.
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