Long-term tolerance to skin commensals is established neonatally through a specialized dendritic cell subgroup

Early-life establishment of tolerance to commensal bacteria at barrier surfaces carries enduring implications for immune health but remains poorly understood. Here, we showed that tolerance in skin was controlled by microbial interaction with a specialized subset of antigen-presenting cells. More particularly, CD301b+ type 2 conventional dendritic cells (DCs) in neonatal skin were specifically capable of uptake and presentation of commensal antigens for the generation of regulatory T (Treg) cells. CD301b+ DC2 were enriched for phagocytosis and maturation programs, while also expressing tolerogenic markers. In both human and murine skin, these signatures were reinforced by microbial uptake. In contrast to their adult counterparts or other early-life DC subsets, neonatal CD301b+ DC2 highly expressed the retinoic-acid-producing enzyme, RALDH2, the deletion of which limited commensal-specific Treg cell generation. Thus, synergistic interactions between bacteria and a specialized DC subset critically support early-life tolerance at the cutaneous interface. [Display omitted] •Neonatal skin CD301b+ DC2 efficiently capture, traffic, and present commensal antigens•CD301b+ DC2 have a mature tolerogenic phenotype, accentuated by commensal uptake•Neonatal Treg generation by CD301b+ DC2 supports commensal-specific tolerance•CD301b+ DC2 RALDH expression is higher neonatally, promoting their Treg generation Maintenance of cutaneous immune homeostasis, and by extension skin health, requires early-life establishment of antigen-specific tolerance to commensal bacteria. Here, Weckel et al. identify that CD301b+ type 2 dendritic cells in neonatal skin critically support this tolerance via retinoic-acid-medicated generation of commensal-specific regulatory T cells.