Skin-resident immune cells actively coordinate their distribution with epidermal cells during homeostasis
Our organs consist of multiple cell types that ensure proper architecture and function. How different cell types coexist and interact to maintain their homeostasis in vivo remain elusive. The skin epidermis comprises mostly epithelial cells, but also harbors Langerhans cells (LCs) and Dendritic Epidermal T cells (DETCs). In response to injury or infection, LCs and DETCs become activated and play critical immunological roles. During homeostasis, they coexist with epithelial cells in the basal layer of the epidermis. Whether, and how, distributions of LCs and DETCs are regulated during homeostasis is unclear. Here, we addressed this question by tracking LCs, DETCs and epithelial basal cells over time within the skin of live adult mice. We show that LCs and DETCs maintain their overall position despite continuous turnover of neighboring basal epithelial stem cells. Moreover, LCs and DETCs rapidly and maximally explore basal epithelial cell junctions through their dendritic extensions. Altering the epithelial cell density triggers corresponding changes in the immune cell density, but not vice versa, suggesting that epithelial cells determine immune tissue composition in the epidermis. Moreover, LCs and DETCs are organized in a tiling pattern that is actively maintained. When LCs or DETCs are ectopically removed, neighboring epidermal LCs or DETCs, respectively, move into the emptied spaces and re-establish the tiling pattern. Finally, LCs require the GTPase Rac1 to maintain their positional stability, density and tiling pattern. Overall, we discovered that epidermal cells regulate the density of immune cells during homeostasis, and that immune cells actively maintain a non-random spatial distribution, reminiscent of neuronal self-avoidance. We propose that these cellular mechanisms provide the epidermis with an optimal response to environmental insults.