CD25 expressed on keratinocytes sustains CD8+ T cell homeostasis and promotes anti-tumor responses 2258211

Abstract

Abstract Introduction CD8+ T cells are crucial for anti-tumor immunity, with IL-2 signaling essential for maintaining their homeostasis. While IL-2 typically signals through cis-presentation via the IL-2R alpha, beta, and gamma subunits, trans-presentation by IL-2R alpha (CD25)-expressing antigen-presenting cells is also important. Notably, we observed CD25 expression on keratinocytes and investigated its role in maintaining CD8+ T cell homeostasis and enhancing anti-tumor responses. Methods Keratinocyte-specific CD25-deficient (K14creCD25fl/fl) mice were generated using the LoxP-Cre system. Under steady-state conditions, CD8+ T cell homeostasis was assessed in skin and secondary lymphoid organs between wild-type (WT) and K14creCD25fl/fl mice. Anti-tumor responses were assessed in a B16 melanoma model, evaluating tumor progression, CD8+ T cell infiltration, effector function. Co-culture experiments examined the direct effects of keratinocyte-derived CD25 on CD8+ T cell. Results Compared to WT mice, K14creCD25fl/fl mice exhibited significantly reduced resident memory CD8+ T cells in dorsal skin and decreased CD8+ T cell homeostasis in secondary lymphoid organs, especially peripheral lymph nodes under steady-state conditions. Co-culture experiments confirmed that CD8+ T cells showed impaired homeostasis when cultured with CD25-deficient keratinocytes. In the B16 melanoma model, K14creCD25fl/fl mice exhibited accelerated tumor progression with reduced CD8+ T cell infiltration into the tumor microenvironment, decreased production of cytotoxic molecules, and suppressed proliferation. Conclusion Keratinocyte-expressed CD25 plays a critical role in maintaining CD8+ T cell homeostasis under steady-state conditions and significantly enhances anti-tumor immunity. These findings reveal a novel mechanism by which skin keratinocytes contribute to systemic immune surveillance through IL-2 trans-presentation, providing new insight into the skin immune system and potential therapeutic targets for enhancing anti-tumor responses. Funding Source This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : RS-2024-00440637). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)