{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:41:33Z","timestamp":1788932493700,"version":"build-2803163510"},"posted":{"date-parts":[[2025,2,15]]},"group-title":"Immunology","reference-count":65,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,15]],"date-time":"2025-02-15T00:00:00Z","timestamp":1739577600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,15]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Immune checkpoint blockade can facilitate tumor clearance by T cells, resulting in long term patient survival. However, the capacity of exhausted CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells (Tex), present during chronic antigen exposure, to form memory after antigen clearance remains unclear. Here, we performed longitudinal single cell RNA\/T cell receptor sequencing and ATAC-sequencing on antigen-specific T cells after the clearance of chronic lymphocytic choriomeningitis virus (LCMV) infection. These data revealed the formation of a robust population of memory CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells that transcriptionally, epigenetically, and functionally resemble central memory T cells (Tcm) that form after clearance of acute infection. To lineage trace the origin and memory recall response of Tex-derived memory clones, we utilized T cell receptor sequencing over the course of primary infection and rechallenge. We show that chronic Tcm are a clonally distinct lineage of Tex derived from progenitor exhausted cells, persist long-term in the absence of antigen, and undergo rapid clonal expansion during rechallenge. Finally, we demonstrate that \u03b1PD-L1 immune checkpoint blockade after chronic LCMV infection preferentially expands clones which form Tcm after clearance. Together, these data support the concept that chronically stimulated T cells form\n                  <jats:italic>bona fide<\/jats:italic>\n                  functional memory T cells through an analogous differentiation pathway to acutely stimulated T cells, which may have significant implications for enhancing immune memory to cancer through checkpoint blockade and vaccination.\n                <\/jats:p>","DOI":"10.1101\/2025.02.10.637523","type":"posted-content","created":{"date-parts":[[2025,2,15]],"date-time":"2025-02-15T22:05:14Z","timestamp":1739657114000},"source":"Crossref","is-referenced-by-count":3,"title":["Functional memory T cells are derived from exhausted clones and expanded by checkpoint blockade"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5230-7931","authenticated-orcid":false,"given":"Colin J.","family":"Raposo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6124-1615","authenticated-orcid":false,"given":"Patrick K.","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5018-355X","authenticated-orcid":false,"given":"Andy Y.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saba","family":"Majidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1956-0257","authenticated-orcid":false,"given":"Kamir J.","family":"Hiam-Galvez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5167-537X","authenticated-orcid":false,"given":"Ansuman T.","family":"Satpathy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025021714350463000_2025.02.10.637523v1.1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.8.4911-4927.2003"},{"key":"2025021714350463000_2025.02.10.637523v1.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-012017-043208"},{"key":"2025021714350463000_2025.02.10.637523v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055318"},{"key":"2025021714350463000_2025.02.10.637523v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407192101"},{"key":"2025021714350463000_2025.02.10.637523v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.09.006"},{"key":"2025021714350463000_2025.02.10.637523v1.6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.9.1383"},{"key":"2025021714350463000_2025.02.10.637523v1.7","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.12.2205"},{"key":"2025021714350463000_2025.02.10.637523v1.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009731107"},{"key":"2025021714350463000_2025.02.10.637523v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.04.014"},{"key":"2025021714350463000_2025.02.10.637523v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.11.002"},{"key":"2025021714350463000_2025.02.10.637523v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01337-5"},{"key":"2025021714350463000_2025.02.10.637523v1.12","first-page":"e20220679","article-title":"Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection","volume":"220","year":"2022","journal-title":"J. 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