Colonic Tolerance Develops in the Iliac Lymph Nodes Independent of CD103+CD11b+ Dendritic Cells

Mucosal tolerance to protein antigen relies on the local microenvironment and antigen-carriage by dendritic cells (DCs) to the draining lymph nodes. Previously, we demonstrated that colonically applied OVA leads to antigen-specific T cell proliferation in the iliac lymph nodes (ILN) while oral antigen elicited proliferation in the mesenteric lymph nodes (MLN). Despite the difference in draining site, both small intestinal and colonic antigen administration induced tolerance. Here, we investigated whether distinct locally adapted regulatory mechanisms maintain tolerance in the small and large intestine. Colonic antigen administration increased the number of CD11c⁺MHCII^hi migratory CD103^-CD11b⁺ and CD103⁺CD11b^- DCs in the ILN. These ILN-derived DCs were nearly devoid of RALDH2 expression and the CD103⁺CD11b⁺ DCs representing the major migratory DC population in the MLN were virtually absent in the ILN. Colonic tolerance was intact in Batf3-deficient mice specifically lacking CD103⁺CD11b^- DCs, demonstrating that CD103^-CD11b⁺ DCs in the ILN are sufficient to drive mucosal tolerance induction after protein antigen encounter in the colon. In agreement, ILN-derived CD11c⁺ DCs from Batf3-deficient mice were effective in driving TGFβ-mediated Foxp3⁺ Treg differentiation. Altogether, we identify different inductive sites for small intestinal and colonic T cell responses and reveal that distinct mechanisms are operative to maintain tolerance.