Liepinsh Dmitry J, Kruglov Andrei A, Galimov Arthur R, Shakhov Alexander N, Shebzukhov Yuriy V, Kuchmiy Anna A, Grivennikov Sergei I, Tumanov Alexei V, Drutskaya Marina S, Feigenbaum Lionel, Kuprash Dmitry V, Nedospasov Sergei A
Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia.
Eur J Immunol. 2009 Oct;39(10):2906-15. doi: 10.1002/eji.200839191.
TNF, lymphotoxin (LT)-alpha, LT-beta and LIGHT are members of a larger superfamily of TNF-related cytokines that can cross-utilize several receptors. Although LIGHT has been implicated in thymic development and function, the role of TNF and LT remains incompletely defined. To address this, we created a model of modest homeostatic overexpression of TNF/LT cytokines using the genomic human TNF/LT locus as a low copy number Tg. Strikingly, expression of Tg TNF/LT gene products led to profound early thymic atrophy characterized by decreased numbers of thymocytes and cortical thymic epithelial cells, partial block of thymocyte proliferation at double negative (DN) 1 stage, increased apoptosis of DN2 thymocytes and severe decline of T-cell numbers in the periphery. Results of backcrossing to TNFR1-, LTbetaR- or TNF/LT-deficient backgrounds and of reciprocal bone marrow transfers implicated both LT-alpha/LT-beta to LTbetaR and TNF/LT-alpha to TNFR1 signaling in accelerated thymus degeneration. We hypothesize that chronic infections can promote thymic atrophy by upregulating LT and TNF production.
肿瘤坏死因子（TNF）、淋巴毒素（LT）-α、LT-β和LIGHT是一个更大的TNF相关细胞因子超家族的成员，它们可以交叉利用多种受体。尽管LIGHT与胸腺发育和功能有关，但TNF和LT的作用仍未完全明确。为了解决这个问题，我们利用基因组人类TNF/LT基因座作为低拷贝数转基因，创建了一个适度稳态过表达TNF/LT细胞因子的模型。令人惊讶的是，转基因TNF/LT基因产物的表达导致了严重的早期胸腺萎缩，其特征是胸腺细胞和皮质胸腺上皮细胞数量减少，双阴性（DN）1期胸腺细胞增殖部分受阻，DN2胸腺细胞凋亡增加，以及外周T细胞数量严重下降。与TNFR1-、LTβR-或TNF/LT缺陷背景回交的结果以及相互骨髓移植的结果表明，LT-α/LT-β至LTβR和TNF/LT-α至TNFR1的信号传导均参与了加速的胸腺退化。我们假设慢性感染可通过上调LT和TNF的产生促进胸腺萎缩。
