Regulatory T cells restrain IL-15-mediated cytotoxic and bystander T cell activity in mucosal tissue without compromising antigen-driven memory

Cruz Talavera, I.; Graham, J. B.; Swarts, J. L.; Traxinger, B. R.; Peters, M. Q.; Warrier, L.; Koehne, A. L.; Arkatkar, T.; Jerome, K. R.; Prlic, M.; Lund, J. M.

doi:10.64898/2026.02.25.708034

bioRxiv · 10.64898/2026.02.25.708034

Regulatory T cells restrain IL-15-mediated cytotoxic and bystander T cell activity in mucosal tissue without compromising antigen-driven memory

Cruz Talavera, I.·Graham, J. B.·Swarts, J. L.·Traxinger, B. R.·Peters, M. Q.·Warrier, L.·Koehne, A. L.·Arkatkar, T.·Jerome, K. R.·Prlic, M.·Lund, J. M.

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Abstract

ABSTRACT/SUMMARYMany pathogenic human infections enter the host via a mucosal surface. These nonlymphoid tissues are abundantly populated by polyclonal memory CD8 T cells that persist following infections for protection upon repeat exposure. Memory T cells can be triggered via T cell receptor recognition of their cognate antigen upon re-infection to exert effector functions, including cytotoxicity and cytokine production, and assist in pathogen elimination. Alternatively, some T cells are bystander activated by cytokines without an antigenic signal. This layered approach boosts efacient pathogen clearance but also poses a threat to host tissues if this response is not properly controlled. Here, we investigate the regulatory mechanisms modulating the tissue memory CD8 T cell response upon recall, leveraging viral rechallenge mouse models to distinguish antigen-driven versus cytokine-activated memory tissue CD8 T cell immunity. We and that regulatory T cells (Treg) participate in restricting cytotoxic and bystander activity without compromising the antigen-driven protective memory CD8 T cell response in mucosal T cells. Critically, Treg provide extrinsic regulation of tissue CD8 T cell cytotoxicity in part through restriction of available IL-2 and IL-15 trans-presentation. Our andings help deane the extrinsic environmental and cellular cues in mucosal tissues that direct tissue-memory CD8 T cells.

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Cruz Talavera, I., Graham, J. B., Swarts, J. L., Traxinger, B. R., Peters, M. Q., Warrier, L., Koehne, A. L., Arkatkar, T., Jerome, K. R., Prlic, M., Lund, J. M.. 2026-02-27. Regulatory T cells restrain IL-15-mediated cytotoxic and bystander T cell activity in mucosal tissue without compromising antigen-driven memory. https://doi.org/10.64898/2026.02.25.708034

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