Hernández-García, ElenaGalán, MiguelKhouili, Sofía CMoya-Ruiz, ElenaRedondo-Urzainqui, AnaCueto, Francisco JMartínez-Cano, SaraíRodrigo-Tapias, ManuelTomasello, ElenaMañes, SantosDalod, MarcSancho, DavidIborra, Salvador2025-12-102025-12-102026-02-02J Exp Med. 2026 Feb 2;223(2):e20250099.https://hdl.handle.net/20.500.12105/27003Resident memory CD8+ T cells (Trms) are essential for protecting barrier nonlymphoid tissues (NLTs) against reinfection, yet the involvement of dendritic cells (DCs) in this process and the nature of Trm-DC interactions within these tissues remain poorly understood. Our study demonstrates that upon reactivation, memory CD8+ T cells located in the skin-independently of circulating memory counterparts-initiate the infiltration and maturation of plasmacytoid DCs (pDCs) in the tissue. This, in turn, promotes the maturation of conventional type 1 DCs (cDC1s) through type I IFN (IFN-I) signaling in a pDC-dependent manner. Depletion of pDCs or blocking IFN-I signaling disrupts this axis, severely impairing Trm-driven protection against secondary infections with vaccinia virus (VACV) in the skin. Notably, this pDC-dependent, IFN-I-mediated pathway is also essential for Trm-mediated protection against secondary respiratory infections with influenza A virus (IAV). Our findings uncover a crucial collaboration between Trm, pDCs, and cDC1s, offering new insights for enhancing vaccines.Funding for Salvador Iborra: PID2021-125415OB-I00 grant from the Agencia Estatal de Investigación (AEI), co-funded by European Regional Development Fund (FEDER), European Union (EU). Funding for the David Sancho lab: CNIC core funding. Grants PID2022-137712OB-I00, CPP2021-008310, and CPP2022-009762 from AEI/Ministerio de Ciencia e Innovación (MICINN), co-funded by FEDER, EU. Comunidad de Madrid (P2022/BMD-7333 INMUNOVAR-CM). Scientific Foundation of the Spanish Association Against Cancer (AECC-PRYGN246642SANC). Worldwide Cancer Research (WWCR-25-0080). European Union ERC-2023-PoC. Research agreement with Inmunotek Ltd., “la Caixa” Foundation (LCF/PR/HR23/52430012 and LCF/ PR/HR22/52420019). Fellowships: Elena Hernandez-Garc ´ ´ıa: Formación de Personal Investigador (FPI) fellowship (PRE2019- 087509) from the Spanish Ministry of Science, Innovation, and Universities. Miguel Gala´n: Formación de Personal Universitario (FPU) fellowship (FPU20/01418) from the Spanish Ministry of Science, Innovation, and Universities. Sof´ıa C. Khouili: FPU fellowship (FPU16/03142) from the Spanish Ministry of Science, Innovation, and Universities. Elena Moya-Ruiz: Ayuda para la contratación de personal investigador predoctoral en formación 2023 (PIPF-2023/SAL-GL-29932) from the Community of Madrid. Ana Redondo-Urzainqui: Ayuda para la contratación de personal investigador predoctoral en formación 2022 (PIPF-2022/SAL-GL-24581) from the Community of Madrid. Francisco J. Cueto: Sara Borrell grant (CD21/00185) from the Spanish Ministry of Science, Innovation, and Universities. Funding for the Santos Mañes lab: PID2023-147125OB-I00 from AEI/MICINN, co-funded by FEDER, UE. The CNIC is supported by the Instituto de Salud Carlos III, the MICINN, and the Pro CNIC Foundation. We acknowledge the National Institutes of Health Tetramer Core Facility (contract HHSN272201300006C) for providing tetramers.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 International41288524223(2)e20250099JOURNAL OF EXPERIMENTAL MEDICINEopen access