Prior Plasmodium infection establishes a monocyte-CD8+ T cell circuit for targeted, broad-spectrum respiratory antiviral immunity

The principles governing how the immune system integrates distal infectious histories to orchestrate long-term, heterologous defense at remote mucosal barriers remain poorly defined. While trained immunity is well-characterized as a myeloid-mediated mechanism for antibacterial protection, the determinants of multi-lineage antiviral resistance are not established. Here, we show that recovery from systemic Plasmodium yoelii infection induces an integrated circuit between the respiratory epithelium, inflammatory monocytes, and CD8+ effector memory T cells (Tem) to provide broad protection against influenza A and respiratory syncytial viruses. In contrast to myeloid-dependent models, this resistance is strictly dependent on the synergy between both compartments; genetic or cellular ablation of either inflammatory monocytes or CD8+ T cells completely abolishes protection. Spatial and single-cell transcriptomics reveal that infected epithelial niches selectively recruit imprinted monocytes, which subsequently direct the site-specific accumulation and acute expansion of CD8+ Tem a Ccl4/Ccl5–Ccr5 axis. Within these localized foci, activated Tem executed rapid viral clearance through a T cell-intrinsic, INF- dependent manner. These findings define a multi-lineage "triad" synergy as an alternative arm of trained immunity, shifting the paradigm from cell-autonomous myeloid reprogramming toward an integrated innate–adaptive circuit for niche-restricted mucosal defense.