Abstract
Durable T cell immunity against cancer depends on the continual replenishment of effector CD8⁺ T cells. Thymic output has been associated 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, whether CD8⁺ T cells acquire effector potential within the thymus, and how thymic output of effector CD8⁺ T cells contribute to peripheral tumor immunity, remain unclear. In this study, we discover that thymic single-positive (SP) CD8⁺ T cells undergo latent effector differentiation following thymic selection, but this process is subject to PD-1 regulation. We further demonstrate that PD-1 limits the contribution of thymic output of CD8⁺ T cells in shaping the TCR repertoire within the tumor tissues for tumor immunosurveillance. Although PD-1 inhibition facilitates the expansion of effector CD8⁺ T cells in the periphery, these cells gradually lose antitumor activity within tumors due to accelerated exhaustion in the absence of PD-1. Thus, while latent effector differentiation of thymic CD8⁺ T cells enables a rapid response to malignant cells in the periphery, PD-1 restrains this process to prevent overt or terminal effector differentiation, which may compromise balanced and durable peripheral immunity.
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Acknowledgements
We thank all members of the Dong laboratory for helpful discussions and critical analysis of the manuscript. We acknowledge that part of the research reported here was presented at the annual meeting of the American Association of Immunologists: IMMUNOLOGY 2025 conference in Honolulu, Hawaii, USA42. We appreciate Fotini Gounari, Hu Zeng, and Svetomir Markovic at Mayo Clinic for insightful discussion. We appreciate Cindy Liu and Susan Harrington for animal breeding and care. We appreciate Roxane Lavoie for assisting in immunofluorescent staining and Yohan Kim for assisting labeling the NKG7 antibody. We acknowledge the Genome Analysis Core at Mayo Clinic, including technologists Vernadette A. Simon and Fariborz Rakhshan-Rohakhtar, as well as supervisors Julie S. Lau, Samantha J. McDonough, and Mark Mutawe. We are grateful for the spatial transcriptome service provided by Zhenglong Liu, Will Sherman, Christy Trussoni, as well as the center director Dr. Tamas Ordog. BioRender was used to create the graphics throughout the manuscript.
Funding
This study was supported by NIH grant R01 CA256927 (H.D.), the Eric & Wendy Schmidt Fund (H.D.) and Scholarship of Mayo Clinic Graduate School of Biomedical Sciences (Z.M.).
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H.B.d.S. is an advisor for the International Genomics Consortium. The remaining authors declare no competing interests.
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Mao, Z., Hirdler, J.B., Gicobi, J.K. et al. PD-1 regulates latent effector differentiation of thymic cytotoxic CD8+ T cells. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73392-7
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Received23 May 2025
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Accepted12 May 2026
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Published23 May 2026
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DOIhttps://doi.org/10.1038/s41467-026-73392-7
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