title: Dendritic cell expression of the signaling molecule TRAF6 is critical for gut microbiota-dependent immune tolerance.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Daehee
authors.initials: D
authors.lastname: Han
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walsh
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Cejas
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Dang
authors.forename: Youngmi F
authors.initials: YF
authors.lastname: Kim
authors.forename: Jihyun
authors.initials: J
authors.lastname: Kim
authors.forename: Laetitia
authors.initials: L
authors.lastname: Charrier-Hisamuddin
authors.forename: Lillian
authors.initials: L
authors.lastname: Chau
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Kyle
authors.initials: K
authors.lastname: Bittinger
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.forename: Hao
authors.initials: H
authors.lastname: Shen
authors.forename: Boris
authors.initials: B
authors.lastname: Reizis
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Defranco
authors.forename: Gary D
authors.initials: GD
authors.lastname: Wu
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D004751:Enteritis / Q000235:genetics / Q000276:immunology*; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology*; D004804:Eosinophils / Q000276:immunology*; D005756:Gastritis / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D007422:Intestines / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D054892:Metagenome / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000382:microbiology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology* / Q000382:microbiology
chemical_list: D007376:Interleukin-2; D053594:Myeloid Differentiation Factor 88; D048029:TNF Receptor-Associated Factor 6