1. Dendritic Cell Expression of the Signaling Molecule TRAF6 Is Critical for Gut Microbiota-Dependent Immune Tolerance
- Author
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Han, Daehee, Walsh, Matthew C, Cejas, Pedro J, Dang, Nicholas N, Kim, Youngmi F, Kim, Jihyun, Charrier-Hisamuddin, Laetitia, Chau, Lillian, Zhang, Qin, Bittinger, Kyle, Bushman, Frederic D, Turka, Laurence A, Shen, Hao, Reizis, Boris, DeFranco, Anthony L, Wu, Gary D, and Choi, Yongwon
- Subjects
Biomedical and Clinical Sciences ,Immunology ,HIV/AIDS ,Digestive Diseases ,Underpinning research ,1.1 Normal biological development and functioning ,Oral and gastrointestinal ,Inflammatory and immune system ,Animals ,Cells ,Cultured ,Dendritic Cells ,Enteritis ,Eosinophilia ,Eosinophils ,Gastritis ,Gene Expression Regulation ,Immune Tolerance ,Interleukin-2 ,Intestines ,Lymphocyte Activation ,Metagenome ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Myeloid Differentiation Factor 88 ,Signal Transduction ,T-Lymphocytes ,Regulatory ,TNF Receptor-Associated Factor 6 ,Th2 Cells - Abstract
The intracellular signaling molecule TRAF6 is critical for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). We now report that DC-specific deletion of TRAF6 (TRAF6ΔDC) resulted, unexpectedly, in loss of mucosal tolerance, characterized by spontaneous development of T helper 2 (Th2) cells in the lamina propria and eosinophilic enteritis and fibrosis in the small intestine. Loss of tolerance required the presence of gut commensal microbiota but was independent of DC-expressed MyD88. Further, TRAF6ΔDC mice exhibited decreased regulatory T (Treg) cell numbers in the small intestine and diminished induction of iTreg cells in response to model antigen. Evidence suggested that this defect was associated with diminished DC expression of interleukin-2 (IL-2). Finally, we demonstrate that aberrant Th2 cell-associated responses in TRAF6ΔDC mice could be mitigated via restoration of Treg cell activity. Collectively, our findings reveal a role for TRAF6 in directing DC maintenance of intestinal immune tolerance through balanced induction of Treg versus Th2 cell immunity.
- Published
- 2013