Innate Imprinting of Transcriptional Trajectories Governs Respiratory TRM Fate and Persistence

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).