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

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. Congenically marked naïve P14 T cells were transferred into LCMV-infected mice. At >30 d p.i., mice were treated with DMSO or AGN194310 (RA antag.) every other day for 6 d and CD69+ P14 TRM cells were sorted from the liver and SI the following day