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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.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/pd-1-regulates-cd4-t-cell-mediated-cd8-t-cell-responses-in-the-brain-to-balance-viral-control-and-neuroinflammation/455731/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/pd-1-regulates-cd4-t-cell-mediated-cd8-t-cell-responses-in-the-brain-to-balance-viral-control-and-neuroinflammation/455731.png","ImageObject",300,407,{"name":92,"@type":93},"Valentina","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-06","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why are PD-1 blockade outcomes variable in PML patients?","Question",{"text":112,"@type":113},"The document states that why PD-1 blockade finds variable success in PML patients is unclear.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What happens to brain-infiltrating CD4+ and CD8+ T cells when PD-1 is lost during MuPyV infection?",{"text":117,"@type":113},"PD-1 loss increases the magnitude of brain-infiltrating CD4+ and CD8+ T cells and the function of virus-specific CD8+ T cells.",{"name":119,"@type":110,"acceptedAnswer":120},"How do PD-1-deficient CD4+ versus CD8+ T cells affect infection and neuroinflammation?",{"text":121,"@type":113},"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.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},455731,1790851229,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},13056703020460,"https://ap-avatar.wpscdn.com/avatar/be000253dac470eee5d?_k=1778207105932848923","Penn State College of Medicine [https://orcid.org/0000-0002-7969-2841](https://orcid.org/0000-0002-7969-2841)  \nPenn State College of Medicine  \nMcGill University  \nPenn State College of Medicine  \nPenn State College of Medicine  \nPenn State College of Medicine  \nThe Pennsylvania State University [https://orcid.org/0000-0001-8749-5744](https://orcid.org/0000-0001-8749-5744)  \nPenn State College of Medicine  \nPenn State Cancer Institute  \n[https://orcid.org/0000-0002-7001-9730](https://orcid.org/0000-0002-7001-9730)  \nPenn State College of Medicine  \n[https://orcid.org/0000-0003-4960-131X](https://orcid.org/0000-0003-4960-131X)  \n[https://orcid.org/0000-0002-7497-8488](https://orcid.org/0000-0002-7497-8488)  \n[https://orcid.org/0000-0002-1205-1353](https://orcid.org/0000-0002-1205-1353)  \nDecember 12th, 2025  \n [https://doi.org/10.21203/rs.3.rs-8215051/v1](https://doi.org/10.21203/rs.3.rs-8215051/v1)  \n 􀁱 􀅏 This work is licensed under a Creative Commons Attribution 4.0 International License.  \nRead Full License  \n There is  Competing Interest.  \n1 PD-1 regulates CD4+ T cell-mediated CD8+ T cell responses in the brain to balance viral  \n2 control and neuroinflammation  \n3  \n4 Arrienne B. Butic 1, Elia Afanasiev2, Samantha A. Spencer 1, Mofida Abdelmageed3, Anirban  \n5 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.  \n7 Lukacher 1*  \n8 1Department ofCell and Biological Systems, Pennsylvania State University College of  \n9 Medicine, Hershey, PA, 17033, USA  \n10 2Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill  \n11 University, Montreal, QC, Canada  \n12 3Department of Neuroscience and Experimental Therapeutics, Pennsylvania State University  \n13 College of Medicine, Hershey, PA, 17033, USA  \n14 4Division of Biology and Medicine, Department of Molecular Microbiology & Immunology, 15 Brown University, Providence, RI, 02906, USA  \n16 5Department of Public Health Sciences, Pennsylvania State University College of Medicine, 17 Hershey, PA, 17033, USA  \n18  \n19 *Corresponding author: [ael17@psu.edu](ael17@psu.edu)  \n20 Short title: PD-1+ brain CD4+ T cells balance infection versus inflammation  \n21 Abstract  \n22 Programmed cell death protein 1 (PD-1) is expressed by T cells during progressive multifocal  \n23 leukoencephalopathy (PML), a life-threatening brain disease caused by the human-only JC  \n24 polyomavirus. Why PD-1 blockade finds variable success in PML patients is unclear. Brain  \n25 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  \n27 the magnitude of brain-infiltrating CD4+ and CD8+ T cells and the function of virus-specific  \n28 CD8+ T cells; in concert, brain virus levels decline and neuroinflammation increases. Deletion of  \n29 PD-1 in CD4+ T cells, but not CD8+ T cells, recapitulates effects of global PD-1 loss. Single-cell  \n30 RNA sequencing shows that PD-1-deficient CD8+ T cells cluster as effectors while transcripts  \n31 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  \n33 CNS infection.  \n34  \n35  \n36 Introduction  \n37 Programmed cell death protein (PD-1) is an immune inhibitory receptor expressed on activated T  \n38 cells and maintained on precursor exhausted T cells 1. Binding of PD-1 to either of its two  \n39 ligands, programmed death-ligand 1 (PD-L1 or CD274) and programmed death-ligand 2 (PD-L2  \n40 or CD273), triggers a series of dephosphorylation events that counter costimulatory signals  \n41 required for T cell activation 1. With repetitive TCR stimulation, PD-1 signaling directs epigenetic  \n42 changes that divert T cells toward an exhaustion differentiation state","cbCaib5LuC6HkEj1","https://ap.wps.com/l/cbCaib5LuC6HkEj1","pdf",7316852,52,"English","# Abstract\n# Introduction","[{\"question\":\"Why are PD-1 blockade outcomes variable in PML patients?\",\"answer\":\"The document states that why PD-1 blockade finds variable success in PML patients is unclear.\"},{\"question\":\"What happens to brain-infiltrating CD4+ and CD8+ T cells when PD-1 is lost during MuPyV infection?\",\"answer\":\"PD-1 loss increases the magnitude of brain-infiltrating CD4+ and CD8+ T cells and the function of virus-specific CD8+ T cells.\"},{\"question\":\"How do PD-1-deficient CD4+ versus CD8+ T cells affect infection and neuroinflammation?\",\"answer\":\"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.\"}]","PD-1 regulates CD4+ T cell-mediated CD8+ T cell responses in the brain to balance viral control and neuroinflammation | PDF",1790744045,131]