title: TNF receptor-associated factor 6 deficiency during hemopoiesis induces Th2-polarized inflammatory disease.
abstract: Toll-like receptors (TLR) initiate rapid innate immune responses by recognizing microbial products. These events in turn lead to the development of an efficient adaptive immune response through the up-regulation of a number of costimulatory molecules, including members of the TNF/TNFR superfamily, on the surface of an APC. TNFR-associated factor 6 (TRAF6) is a common signaling adapter used by members of both the TNFR and the TLR/IL-1R superfamilies, and as such plays a critical role in the development of immune responses. As TRAF6-deficient mice die prematurely, we generated chimeras reconstituted with TRAF6-deficient fetal liver cells to analyze functions of TRAF6 in vivo in the hemopoietic compartment. We found that TRAF6-deficient chimeras develop a progressive lethal inflammatory disease associated with massive organ infiltration and activation of CD4(+) T cells in a Th2-polarized phenotype, and a defect in IL-18 responsiveness. When recombination-activating gene 2(-/-) blastocysts were complemented with TRAF6-deficient embryonic stem cells, a marked elevation of activated CD4(+) T cells and progressive inflammatory disease were also observed. Moreover, T cell activation and lethal inflammation were not reversed in mixed chimeric mice generated from normal and TRAF6-deficient fetal liver cells. These results suggest that deletion of TRAF6 induces a dominant Th2-type polarized autoimmune response. Therefore, in addition to playing a critical role in innate and adaptive immunity, TRAF6 is likely to play a previously unrecognized role in the maintenance of self-tolerance.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Elise
authors.initials: E
authors.lastname: Chiffoleau
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walsh
authors.forename: Carolyn G
authors.initials: CG
authors.lastname: King
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Walsh
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006410:Hematopoiesis / Q000235:genetics* / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000503:physiopathology; D007371:Interferon-gamma / Q000378:metabolism; D020382:Interleukin-18 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000235:genetics*; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6; D018417:Th1 Cells / Q000166:cytology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D015431:Weight Loss / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D020382:Interleukin-18; D011506:Proteins; C499308:Rag2 protein, mouse; D048029:TNF Receptor-Associated Factor 6; C064655:V(D)J recombination activating protein 2; D007371:Interferon-gamma