Retinoic acid and TGF-β orchestrate organ-specific programs of tissue-residency [dnRARa]

Tissue-resident memory T (TRM) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common TRM cell fate remains poorly understood. Here, we show that while skin TRM cells strictly require TGF-β for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive the TRM cells in the small intestine. Effector P14 T cells were transduced with either empty (Ctrl-RV) or dnRARα (dnRARα-RV) retroviruses. Transduced cells were co-transferred into LCMV infected recipient mice and isolated from the SI and liver for RNA sequencing 14 days post LCMV infection.