Reissig Sonja, Hövelmeyer Nadine, Tang Yilang, Weih Debra, Nikolaev Alexey, Riemann Marc, Weih Falk, Waisman Ari
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
Immunology Group, Leibniz-Institute for Age Research-Fritz-Lipmann-Institute (FLI), Jena, Germany.
Immunol Cell Biol. 2015 Jul;93(6):558-66. doi: 10.1038/icb.2014.122. Epub 2015 Jan 20.
The cross talk between thymocytes and the thymic epithelium is critical for T-cell development and the establishment of central tolerance. Medullary thymic epithelial cells (mTECs) are located in the thymic medulla and mediate the elimination of self-reactive thymocytes, thereby preventing the onset of autoimmunity. Previous studies identified the deubiquitinating enzyme CYLD as a critical regulator of T-cell development by activating proximal T-cell receptor signaling during the transition of double-positive to single-positive thymocytes. Here we evaluated the impact of the naturally occurring short-splice variant of the cyld gene (sCYLD) on the development and maturation of mTECs. We found that thymi of CYLD(ex7/8) mice, solely expressing sCYLD, displayed a reduced number of mature mTECs caused by a developmental block during the transition of immature to mature mTECs. Further, we could demonstrate an impaired negative selection of thymocytes in these mice. Our data demonstrate that inefficient negative selection in the thymus of CYLD(ex7/8) mice result from a defect in mTEC maturation.
胸腺细胞与胸腺上皮之间的相互作用对于T细胞发育和中枢耐受的建立至关重要。髓质胸腺上皮细胞（mTECs）位于胸腺髓质，介导自身反应性胸腺细胞的清除，从而预防自身免疫的发生。先前的研究确定去泛素化酶CYLD是T细胞发育的关键调节因子，它在双阳性胸腺细胞向单阳性胸腺细胞转变过程中激活近端T细胞受体信号。在此，我们评估了cyld基因天然存在的短剪接变体（sCYLD）对mTECs发育和成熟的影响。我们发现，仅表达sCYLD的CYLD(ex7/8)小鼠的胸腺，由于未成熟mTECs向成熟mTECs转变过程中的发育阻滞，成熟mTECs数量减少。此外，我们能够证明这些小鼠中胸腺细胞的阴性选择受损。我们的数据表明，CYLD(ex /8)小鼠胸腺中阴性选择效率低下是由mTEC成熟缺陷导致的。
