期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 51, 页码 13051-13056出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1807499115
关键词
neuroinflammation; EAE; TNF/TNFR2; T regulatory cells; humanized mice
资金
- Russian Science Foundation [14-50-00060]
- Deutsche Forschungsgemeinschaft (DFG) [NE 1466/2]
- DFG [CRC/TR 128]
- independent European Federation of Immunological Societies-Immunology Letters (EFIS-IL) fellowships
TNF is a multifunctional cytokine involved in autoimmune disease pathogenesis that exerts its effects through two distinct TNF receptors, TNFR1 and TNFR2. While TNF- and TNFR1-deficient (but not TNFR2-deficient) mice show very similar phenotypes, the significance of TNFR2 signaling in health and disease remains incompletely understood. Recent studies implicated the importance of the TNF/TNFR2 axis in T regulatory (T-reg) cell functions. To definitively ascertain the significance of TNFR2 signaling, we generated and validated doubly humanized TNF/TNFR2 mice, with the option of conditional inactivation of TNFR2. These mice carry a functional human TNF-TNFR2 (hTNF-hTNFR2) signaling module and provide a useful tool for comparative evaluation of TNF-directed biologics. Conditional inactivation of TNFR2 in FoxP3(+) cells in doubly humanized TNF/TNFR2 mice down-regulated the expression of T-reg signature molecules (such as FoxP3, CD25, CTLA-4, and GITR) and diminished T-reg suppressive function in vitro. Consequently, T-reg-restricted TNFR2 deficiency led to significant exacerbation of experimental autoimmune encephalomyelitis (EAE), accompanied by reduced capacity to control Th17mediated immune responses. Our findings expose the intrinsic and beneficial effects of TNFR2 signaling in T-reg cells that could translate into protective functions in vivo, including treatment of autoimmunity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据