{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T05:43:14Z","timestamp":1775886194187,"version":"3.50.1"},"posted":{"date-parts":[[2025,1,18]]},"group-title":"Immunology","reference-count":23,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T00:00:00Z","timestamp":1737158400000},"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":[[2025,1,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Durable T cell immunity against cancer depends on the continual replenishment of effector CD8+ T cells. Thymic output has been correlated with favorable prognosis in cancer patients across a range of ages, suggesting that the thymus is an important source for replenishing T cells capable of controlling cancer progression. However, the effector potential of thymic mature CD8+ T cells and their regulation have not been clearly defined. In this study, we identified the ability of thymic single positive CD8+ T cells to gain effector potential after thymic selection, but they are subject to the regulation of PD-1. We found a previously undisclosed role of PD-1 in limiting both the cytotoxic and exhaustion potential of thymic and peripheral CD8+ T cells. Our results show that although PD-1 inhibition facilitates the expansion of effector CD8+ T cells, effector CD8+ cells gradually lose their antitumor activity within tumor tissues due to advanced exhaustion in the absence of PD-1. Thus, although the preset effector potential in thymic mature CD8+ T cells allows them to rapidly respond to malignant cells in the periphery, PD-1, as a checkpoint, is embedded in the thymic mature CD8+ T cells after positive selection to balance their effector function from exaggeration and exhaustion. Therefore, we propose that a strategy capable of upholding the cytotoxic capacity and avoiding exhaustion of CD8+ T cells during the early stages of PD-1 inhibition therapy is needed to achieve durable antitumor immunity.<\/jats:p>","DOI":"10.1101\/2025.01.18.631253","type":"posted-content","created":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T20:40:15Z","timestamp":1737232815000},"source":"Crossref","is-referenced-by-count":1,"title":["PD-1 prelimits both the cytotoxic and exhaustion potential in thymic CD8+ T cells and impacts the maintenance of peripheral tumor immunity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7705-9575","authenticated-orcid":false,"given":"Zhiming","family":"Mao","sequence":"first","affiliation":[{"name":"Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob B.","family":"Hirdler","sequence":"additional","affiliation":[{"name":"Department of Urology, Mayo Clinic, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanina K.","family":"Gicobi","sequence":"additional","affiliation":[{"name":"Department of Urology, Mayo Clinic, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Maynes","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle A.","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilia R.","family":"Dellacecca","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob J.","family":"Teske","sequence":"additional","affiliation":[{"name":"Department of Urology, Mayo Clinic, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geoffrey","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabrice","family":"Lucien-Matteoni","sequence":"additional","affiliation":[{"name":"Department of Urology, Mayo Clinic, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrique","family":"Borges da Silva","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic College of Medicine and Science, Phoenix, AZ"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel D.","family":"Billadeau","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN"},{"name":"Division of Oncology Research, Mayo Clinic, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haidong","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN"},{"name":"Department of Urology, Mayo Clinic, Rochester, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041021472776000_2025.01.18.631253v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0522-3"},{"key":"2026041021472776000_2025.01.18.631253v1.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2302892"},{"key":"2026041021472776000_2025.01.18.631253v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/J.IMMUNI.2024.08.019"},{"key":"2026041021472776000_2025.01.18.631253v1.4","doi-asserted-by":"crossref","unstructured":"Steier, Z. et al. 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