Classical dendritic cells are required for dietary antigen-mediated peripheral regulatory T cell and tolerance induction

Oral tolerance prevents pathological inflammatory responses towards innocuous foreign antigens via peripheral regulatory T cells (pT(reg) cells). However, whether a particular subset of antigen-presenting cells (APCs) is required during dietary antigen exposure to instruct naïve CD4(+) T cells to differentiate into pT(reg) cells has not been defined. Using myeloid lineage-specific APC depletion in mice, we found that monocyte-derived APCs are dispensable, while classical dendritic cells (cDCs) are critical for pT(reg) cell induction and oral tolerance. CD11b(−) cDCs from the gut-draining lymph nodes efficiently induced pT(reg) cells, and conversely, loss of IRF8-dependent CD11b(−) cDCs impaired their polarization, although oral tolerance remained intact. These data reveal the hierarchy of cDC subsets in pT(reg) cell induction and their redundancy during oral tolerance development.