Innate Imprinting of Transcriptional Trajectories Governs Respiratory TRM Fate and Persistence

Respiratory T cell immunity wanes rapidly, and inducing durable mucosal memory remains a major challenge. We demonstrate that precision adjuvancy, using distinct PRR agonists to shape innate inflammation, imprints transcriptional trajectories that govern CD8 T cell fate. Using a nano-emulsion platform, TLR4 signaling induces neutrophilic inflammation and a C/EBP–NF-κB–HIF program that promotes durable, stem-like Type 3 CD127⁺ TRMs. Conversely, STING drives DC–monocytic inflammation and activates an IRF–STAT–T-bet axis that programs attrition-prone Type 1 TRMs. We reconcile systemic and tissue divergence models by identifying distinct TRM precursors. During influenza, Ly6CloPD-1hiLAG-3hiCD69hi precursors differentiate via local reprogramming (tissue divergence). In contrast, vaccination generates Ly6CloLAG-3loCD103hi precursors in lymph nodes and lungs that bypass inhibitory stages (systemic divergence). Mechanistically, T-bet limits TRM precursor formation and differentiation into long-lived Type 3 TRMs. Thus, selecting precision adjuvants that limit T-bet activity is critical for durable mucosal T cell immunity.