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

Abstract

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 adventitial 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 hydroxycholesterols, the natural ligand of GPR183. Single-cell transcriptomic receptor ligand inference and subsequent genetic validation revealed TSLP receptor signaling as a crucial fibroblast-derived CD301b+ cDC2 survival factor. These data expose a subtissular localization mechanism for tissue-specific functionalization of CD301b+ cDC2.