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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cells, Cultured
-
Dendritic Cells / immunology*
-
Dendritic Cells / microbiology
-
Enteritis / genetics
-
Enteritis / immunology*
-
Eosinophilia / genetics
-
Eosinophilia / immunology*
-
Eosinophils / immunology*
-
Gastritis / genetics
-
Gastritis / immunology*
-
Gene Expression Regulation / genetics
-
Gene Expression Regulation / immunology
-
Immune Tolerance / genetics
-
Interleukin-2 / genetics
-
Interleukin-2 / metabolism
-
Intestines / immunology*
-
Intestines / microbiology
-
Intestines / pathology
-
Lymphocyte Activation / genetics
-
Metagenome / immunology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Myeloid Differentiation Factor 88 / genetics
-
Myeloid Differentiation Factor 88 / metabolism
-
Signal Transduction / genetics
-
T-Lymphocytes, Regulatory / immunology*
-
T-Lymphocytes, Regulatory / microbiology
-
TNF Receptor-Associated Factor 6 / genetics
-
TNF Receptor-Associated Factor 6 / immunology
-
TNF Receptor-Associated Factor 6 / metabolism*
-
Th2 Cells / immunology*
-
Th2 Cells / microbiology
Substances
-
Interleukin-2
-
Myeloid Differentiation Factor 88
-
TNF Receptor-Associated Factor 6