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Why PD-1 blockade finds variable success in PML patients is unclear. Brain CD4\n                  <jats:sup>+<\/jats:sup>\n                  and CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells are PD-1\n                  <jats:sup>high<\/jats:sup>\n                  during mouse polyomavirus (MuPyV) encephalitis. Here, we show that PD-1 loss during MuPyV infection acts in a brain-autonomous manner to increase the magnitude of brain-infiltrating CD4\n                  <jats:sup>+<\/jats:sup>\n                  and CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells and the function of virus-specific CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells; in concert, brain virus levels decline and neuroinflammation increases. Deletion of PD-1 in CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells, but not CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells, recapitulates effects of global PD-1 loss. Single-cell RNA sequencing shows that PD-1-deficient CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells cluster as effectors while transcripts associated with proliferation and function are upregulated with loss of PD-1. Thus, CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cell-intrinsic PD-1 signaling balances antiviral defense against neural injury during polyomavirus CNS infection.\n                <\/jats:p>","DOI":"10.1101\/2025.11.26.690770","type":"posted-content","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T16:40:28Z","timestamp":1764607228000},"source":"Crossref","is-referenced-by-count":0,"title":["PD-1 regulates CD4\n                  <sup>+<\/sup>\n                  T cell-mediated CD8\n                  <sup>+<\/sup>\n                  T cell responses in the brain to balance viral control and neuroinflammation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5991-7305","authenticated-orcid":false,"given":"Arrienne B.","family":"Butic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6527-4550","authenticated-orcid":false,"given":"Elia","family":"Afanasiev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5048-1736","authenticated-orcid":false,"given":"Samantha A.","family":"Spencer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9507-4296","authenticated-orcid":false,"given":"Mofida","family":"Abdelmageed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3559-9335","authenticated-orcid":false,"given":"Anirban","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8749-5744","authenticated-orcid":false,"given":"Kalynn M.","family":"Alexander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6156-8685","authenticated-orcid":false,"given":"Katelyn N.","family":"Ayers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6788-6518","authenticated-orcid":false,"given":"Todd D.","family":"Schell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7001-9730","authenticated-orcid":false,"given":"Matthew D.","family":"Lauver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4960-131X","authenticated-orcid":false,"given":"Samantha M.","family":"Borys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7497-8488","authenticated-orcid":false,"given":"Laurent","family":"Brossay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo Anne A.","family":"Stratton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6114-6714","authenticated-orcid":false,"given":"Vonn","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7969-2841","authenticated-orcid":false,"given":"Aron E.","family":"Lukacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025120216201542000_2025.11.26.690770v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.108"},{"key":"2025120216201542000_2025.11.26.690770v1.2","doi-asserted-by":"crossref","unstructured":"Sacrist\u00e1n, C. et al. 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