The skin has to effectively combat external attacks, while maintaining skin immune homeostasis under steady state conditions. To fulfill these challenging tasks, the dermis harbors a variety of heterogeneous cell types which are able to suppress T cell proliferation similar to bone marrow mesenchymal stromal cells. Here we show that plastic-adherent, human dermal cells induce FoxP3 expression in TCR-complex-stimulated CD25(-)CD4(+)CD45RA(+) T cells in the absence of CD28 co-ligation in a cell-contact dependent manner. These FoxP3(+) T cells reveal an effective suppressive capacity in vitro. Moreover, we found that the vast majority of CD90(+) dermal cells are perivascular located and generate a significantly higher percentage of regulatory T cells than cells expressing markers such as CD271 in vitro. Importantly, we further demonstrate that plastic-adherent dermal cells are also able to differentiate towards the endothelial lineage. Our data show that human skin harbors specific cell types with immunosuppressive potential, which are located in close vicinity to their likely operational area and provide evidence for a CD28-independent regulatory mechanism. Further, the differentiation potential into endothelial cells suggests the existence of a tissue-resident cell pool for vessel regeneration. These findings might have important implications for the clinical use of allogeneic dermal cells to rebuild an imbalanced human skin immune homeostasis.Journal of Investigative Dermatology accepted article preview online, 22 July 2014; doi:10.1038/jid.2014.309.