Chiffoleau Elise, Kobayashi Takashi, Walsh Matthew C, King Carolyn G, Walsh Patrick T, Hancock Wayne W, Choi Yongwon, Turka Laurence A
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Immunol. 2003 Dec 1;171(11):5751-9. doi: 10.4049/jimmunol.171.11.5751.
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.
Toll样受体（TLR）通过识别微生物产物引发快速的固有免疫反应。这些事件进而通过上调抗原呈递细胞（APC）表面的多种共刺激分子，包括TNF/TNFR超家族的成员，导致有效的适应性免疫反应的发展。TNF受体相关因子6（TRAF6）是TNFR超家族和TLR/IL-1R超家族成员共同使用的信号转导衔接蛋白，因此在免疫反应的发展中起关键作用。由于TRAF6缺陷小鼠过早死亡，我们构建了用TRAF6缺陷型胎儿肝细胞重建的嵌合体，以分析TRAF6在造血系统中的体内功能。我们发现，TRAF6缺陷型嵌合体发生进行性致命性炎症性疾病，伴有大量器官浸润和Th2极化表型的CD4(+) T细胞活化，以及IL-18反应性缺陷。当重组激活基因2（-/-）囊胚用TRAF6缺陷型胚胎干细胞进行互补时，也观察到活化的CD4(+) T细胞显著升高和进行性炎症性疾病。此外，由正常和TRAF6缺陷型胎儿肝细胞产生的混合嵌合小鼠中，T细胞活化和致命性炎症并未逆转。这些结果表明，TRAF6的缺失诱导了显性的Th2型极化自身免疫反应。因此，除了在固有免疫和适应性免疫中起关键作用外，TRAF6可能在维持自身耐受性方面发挥了以前未被认识到的作用。
