The intracellular signaling mediator TRAF6 is critical for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). We now report that DC-specific deletion of TRAF6 (TRAF6ΔDC) results, quite unexpectedly, in loss of mucosal tolerance, characterized by spontaneous rise in lamina propria Th2 cells, and development of eosinophilic enteritis and fibrosis of the small intestine. Loss of TRAF6ΔDC mucosal tolerance requires the presence of commensal microbiota in a manner that appears independent of the MyD88 pathway. Further, TRAF6ΔDC mice exhibit decreased regulatory T cell (Treg) numbers in the small intestine, and diminished induction of iTregs in response to model antigen. Evidence suggests this defect may be associated with diminished DC-expressed IL-2. Finally, we demonstrate that aberrant Th2-associated responses in TRAF6ΔDC mice can be mitigated via restoration of Treg activity. Collectively, our findings reveal a novel role for TRAF6 in directing DC maintenance of intestinal immune tolerance through balanced induction of Tregs versus Th2 immunity.
- Copyright © 2013 by The American Association of Immunologists, Inc.