PD-1 regulates CD4+ T cell-mediated CD8+ T cell responses in the brain to balance viral control and neuroinflammation

Sep 30, 2026

Programmed cell death protein 1 (PD-1) is expressed by T cells during progressive multifocal leukoencephalopathy (PML), a fatal brain disease caused by the human-only JC polyomavirus. Variable patient responses to PD-1 blockade remain unclear. Brain CD4+ and CD8+ T cells show high PD-1 levels during mouse polyomavirus encephalitis. PD-1 loss during infection increases brain-infiltrating T-cell magnitude and boosts virus-specific CD8+ T-cell function, lowering viral burden while increasing neuroinflammation.

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CategoryResearch & Report

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Pages52

Reading Time2 h 11 min

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Abstract

Introduction

Penn State College of Medicine [https://orcid.org/0000-0002-7969-2841](https://orcid.org/0000-0002-7969-2841) Penn State College of Medicine McGill University Penn State College of Medicine Penn State College of Medicine Penn State College of Medicine The Pennsylvania State University [https://orcid.org/0000-0001-8749-5744](https://orcid.org/0000-0001-8749-5744) Penn State College of Medicine Penn State Cancer Institute [https://orcid.org/0000-0002-7001-9730](https://orcid.org/0000-0002-7001-9730) Penn State College of Medicine [https://orcid.org/0000-0003-4960-131X](https://orcid.org/0000-0003-4960-131X) [https://orcid.org/0000-0002-7497-8488](https://orcid.org/0000-0002-7497-8488) [https://orcid.org/0000-0002-1205-1353](https://orcid.org/0000-0002-1205-1353) December 12th, 2025 [https://doi.org/10.21203/rs.3.rs-8215051/v1](https://doi.org/10.21203/rs.3.rs-8215051/v1) 􀁱 􀅏 This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License There is Competing Interest. 1 PD-1 regulates CD4+ T cell-mediated CD8+ T cell responses in the brain to balance viral 2 control and neuroinflammation 3 4 Arrienne B. Butic 1, Elia Afanasiev2, Samantha A. Spencer 1, Mofida Abdelmageed3, Anirban 5 Paul3, Kalynn M. Alexander 1, Katelyn N. Ayers 1, Todd D. Schell 1, Matthew D. Lauver 1, Ge Jin 1, 6 Samantha M. Borys4, Laurent Brossay4, Jo Anne A. Stratton2, Vonn Walter5, and Aron E. 7 Lukacher 1* 8 1Department ofCell and Biological Systems, Pennsylvania State University College of 9 Medicine, Hershey, PA, 17033, USA 10 2Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill 11 University, Montreal, QC, Canada 12 3Department of Neuroscience and Experimental Therapeutics, Pennsylvania State University 13 College of Medicine, Hershey, PA, 17033, USA 14 4Division of Biology and Medicine, Department of Molecular Microbiology & Immunology, 15 Brown University, Providence, RI, 02906, USA 16 5Department of Public Health Sciences, Pennsylvania State University College of Medicine, 17 Hershey, PA, 17033, USA 18 19 *Corresponding author: [ael17@psu.edu](ael17@psu.edu) 20 Short title: PD-1+ brain CD4+ T cells balance infection versus inflammation 21 Abstract 22 Programmed cell death protein 1 (PD-1) is expressed by T cells during progressive multifocal 23 leukoencephalopathy (PML), a life-threatening brain disease caused by the human-only JC 24 polyomavirus. Why PD-1 blockade finds variable success in PML patients is unclear. Brain 25 CD4+ and CD8+ T cells are PD-1high during mouse polyomavirus (MuPyV) encephalitis. Here, 26 we show that PD-1 loss during MuPyV infection acts in a brain-autonomous manner to increase 27 the magnitude of brain-infiltrating CD4+ and CD8+ T cells and the function of virus-specific 28 CD8+ T cells; in concert, brain virus levels decline and neuroinflammation increases. Deletion of 29 PD-1 in CD4+ T cells, but not CD8+ T cells, recapitulates effects of global PD-1 loss. Single-cell 30 RNA sequencing shows that PD-1-deficient CD8+ T cells cluster as effectors while transcripts 31 associated with proliferation and function are upregulated with loss of PD-1 . Thus, CD4+ T cell- 32 intrinsic PD-1 signaling balances antiviral defense against neural injury during polyomavirus 33 CNS infection. 34 35 36 Introduction 37 Programmed cell death protein (PD-1) is an immune inhibitory receptor expressed on activated T 38 cells and maintained on precursor exhausted T cells 1. Binding of PD-1 to either of its two 39 ligands, programmed death-ligand 1 (PD-L1 or CD274) and programmed death-ligand 2 (PD-L2 40 or CD273), triggers a series of dephosphorylation events that counter costimulatory signals 41 required for T cell activation 1. With repetitive TCR stimulation, PD-1 signaling directs epigenetic 42 changes that divert T cells toward an exhaustion differentiation state

FAQs

Why are PD-1 blockade outcomes variable in PML patients?

The document states that why PD-1 blockade finds variable success in PML patients is unclear.

What happens to brain-infiltrating CD4+ and CD8+ T cells when PD-1 is lost during MuPyV infection?

PD-1 loss increases the magnitude of brain-infiltrating CD4+ and CD8+ T cells and the function of virus-specific CD8+ T cells.

How do PD-1-deficient CD4+ versus CD8+ T cells affect infection and neuroinflammation?

Deletion of PD-1 in CD4+ T cells, but not CD8+ T cells, recapitulates effects of global PD-1 loss, with brain virus levels declining while neuroinflammation increases.

Sep 30, 2026

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