TRAF6 expression in dendritic cells is essential for tolerance to dietary antigens (MUC8P.723)

Abstract TRAF6 is critical for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). Recently, by studying mice DC-specific deletion of TRAF6 (TRAF6ΔDC) we have reported that TRAF6 expression in DCs is important to prevent a spontaneous Th2-associated gut inflammatory disease. We also found amelioration of TRAF6ΔDC disease by treatment with broad-spectrum antibiotics, suggesting a role for commensal microbiota. To formally demonstrate an involvement of commensal microbiota, we have now generated TRAF6ΔDC bone marrow chimeras under germ-free (GF) conditions. Unexpectedly, the Th2-associated disease in GF TRAF6ΔDC chimeras was exacerbated compared with TRAF6ΔDC chimeras generated under conventional conditions, indicating a beneficial role of commensal microbiota. Moreover, treatment of GF TRAF6ΔDC chimeras with broad-spectrum antibiotics also ameliorated the Th2-associated disease, suggesting a previously unrealized direct immunomodulating effect of antibiotics. Finally, to test whether the Th2-associate disease is driven by dietary antigens (Ags), we established TRAF6ΔDC bone marrow chimeras in “Ag-free” mice, in which GF mice are raised with a chemically-defined elemental diet devoid of macromolecules. Strikingly, the induction of a spontaneous intestinal Th2-associated inflammatory disease was dramatically averted in “Ag-free” TRAF6ΔDC chimeras, indicating that TRAF6 expression in DCs is essential to establish and/or maintain oral tolerance to dietary Ags.