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 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 (TRMs). 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 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.