Oral CD103CD11b classical dendritic cells present sublingual antigen and induce Foxp3 regulatory T cells in draining lymph nodes.

Sublingual immunotherapy (SLIT) is a safe and efficient treatment for type 1 allergies; however, the underlying immunological mechanisms, particularly the phenotype of oral antigen-presenting cells (APCs) responsible for the induction of regulatory T (Treg) cells, remain unclear. We show here that the sublingual application of ovalbumin (OVA) induced antigen-specific Foxp3 Treg cells in draining submandibular lymph nodes (ManLNs). Oral APCs were classified into macrophages, classical dendritic cells (cDCs), and Langerhans cells by flow cytometry. A major subset of oral cDCs with the CD103CD11b phenotype showed retinoic acid (RA)-producing activity and converted naive CD4 T cells to Foxp3 Treg cells in a transforming growth factor-β- and RA-dependent manner in vitro. In the ManLNs, migratory CD103CD11b cDCs also showed RA-producing activity. After the sublingual application of fluorescent OVA, fluorescence was detected in oral macrophages in tissues, followed by migratory CD103CD11b cDCs in ManLNs and migratory CD103CD11b cDCs were the main APCs responsible for the induction of sublingual antigen-specific Treg cells. The transfer of OVA-SLIT-induced Treg cells suppressed the OVA-induced hypersensitivity response. These results suggest that oral CD103CD11b cDCs transport sublingual antigens to draining ManLNs and induce antigen-specific Foxp3 Treg cells, and, thus, provide a rationale for developing cDC-based therapeutic approaches in SLIT.