GPR183 targets lung-resident CD301b+ conventional dendritic cells type 2 to a subtissular TSLP – TSLP receptor mediated survival niche within the adventital cuff

Summary Conventional dendritic cells (cDCs) are strategically localized throughout non-lymphoid tissues. How such spatially regulated subtissular placement is achieved remains largely elusive. Here, we reveal that GPR183 targets CD301b + cDC2 to a TSLP-dependent survival niche within the adventital cuff. We identified a close association of CD301b + cDC2 with PDGFRα + fibroblasts within the adventitial region of the lung. Genetic ablation of GPR183 within the cDC lineage leads to a selective loss of CD301b + cDC2 in conjunction with the loss of CD301b + cDC2 : fibroblast colocalization. Next bone marrow chimeric experiments and expression studies suggested adventitial fibroblasts as the main source of 7α,25 hydroxycholesterol, the natural ligand of GPR183. Single cell transcriptomic receptor ligand inference and subsequent genetic validation revealed TSLP receptor signalling as a crucial fibroblast derived CD301b + cDC2 survival factor. These data expose a subtissular localization mechanism for tissue-specific functionalization of CD301b + cDC2.