Steady state migratory RelB+ langerin+ dermal dendritic cells mediate peripheral induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells

Tolerance to self-antigens expressed in peripheral organs is maintained by CD4+ CD25+ Foxp3+ Treg cells, which are generated as a result of thymic selection or peripheral induction. Here, we demonstrate that steady-state migratory DCs from the skin mediated Treg conversion in draining lymph nodes of mice. These DCs displayed a partially mature MHC IIint CD86int CD40hi CCR7+ phenotype, used endogenous TGF-β for conversion and showed nuclear RelB translocation. Deficiency of the alternative NF-κB signaling pathway (RelB/p52) reduced steady-state migration of DCs. These DCs transported and directly presented soluble OVA provided by s.c. implanted osmotic minipumps, as well as cell-associated epidermal OVA in transgenic K5-mOVA mice to CD4+ OVA-specific TCR-transgenic OT-II T cells. The langerin+ dermal DC subset, but not epidermal Langerhans cells, mediated conversion of naive OT-II×RAG-1−/− T cells into proliferating CD4+ CD25+ Foxp3+ Tregs. Thus, our data suggest that steady-state migratory RelB+ TGF-β+ langerin+ dermal DCs mediate peripheral Treg conversion in response to epidermal antigen in skin-draining lymph nodes.