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TNF Receptor-Associated Factor 6 Deficiency during Hemopoiesis Induces Th2-Polarized Inflammatory Disease ¹

Elise Chiffoleau^*, Takashi Kobayashi^,, Matthew C. Walsh^,, Carolyn G. King^,, Patrick T. Walsh^*, Wayne W. Hancock^,, Yongwon Choi^, and Laurence A. Turka^2,*

Departments of ^* Medicine and Pathology and Laboratory Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania, and Biesecker Pediatric Liver Center, Children’s Hospital of Philadelphia, Philadelphia, PA 19104

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.

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