Innate imprinting of transcriptional trajectories governs respiratory T_RM fate and persistence

Respiratory T cell immunity wanes rapidly, and inducing durable mucosal memory remains a major challenge. We demonstrate that precision adjuvant activity, using distinct pattern recognition receptor (PRR) agonists to shape innate inflammation, imprints transcriptional trajectories that govern CD8 T cell fate. Using a nano-emulsion platform, Toll-like receptor (TLR)4 signaling induces neutrophilic inflammation and a C/EBP-NF-κB-HIF program that promotes durable, stem-like type 3 CD127⁺ tissue-resident memory T cells (T_RMs). Conversely, stimulator of interferon genes (STING) drives dendritic cell (DC)-monocytic inflammation and activates an IRF-STAT-T-bet axis that programs attrition-prone type 1 T_RMs. We reconcile systemic and tissue divergence models by identifying distinct T_RM precursors. During influenza, Ly6C^loPD-1^hiLAG-3^hiCD69^hi precursors differentiate via local reprogramming (tissue divergence). In contrast, vaccination generates Ly6C^loLAG-3^loCD103^hi precursors in lymph nodes and lungs that bypass inhibitory stages (systemic divergence). Mechanistically, T-bet limits T_RM precursor formation and differentiation into long-lived type 3 T_RMs. Thus, selecting precision adjuvants that limit T-bet activity is critical for durable mucosal T cell immunity.