Role of endogenous annexin-A1 in the regulation of thymocyte positive and negative selection
Role of endogenous annexin-A1 in the regulation of thymocyte positive and negative selection
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DOI：
10.4161/cc.9.4.10673
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发表时间：
2010-02-15
期刊：
影响因子：
4.3
通讯作者：
D'Acquisto, Fulvio
中科院分区：
文献类型：
--
作者：
Paschalidis, Nikolaos;Huggins, Anthony;D'Acquisto, Fulvio
我们最近发现内源性膜联蛋白a1 （AnxA1）通过调节TCR信号的强度在成熟T细胞中发挥稳态调节作用。本研究探讨了内源性AnxA1在胸腺细胞成熟中的作用。对未成熟CD4(-)CD8（-）双阴性（DN）阶段的AnxA1（-/-）胸腺细胞群的分析显示，与对照组相比，DN1亚群比例减少，DN3亚群比例增加。Anx1（-/-）和AnxA1（+/+）小鼠胸腺细胞数量及CD4（+）和CD8（+）单阳性（SP）群体比例无显著差异。然而，当我们将AnxA1（-/-）小鼠与HY-TCR转基因小鼠杂交时，我们观察到雄性AnxA1(-/-)/HY-TCR中CD4(+)CD8（+）双阳性（DP）和CD4 SP细胞比AnxA1(+/+)/HY-TCR增加。相反，雌性AnxA1(-/-)/HY-TCR小鼠与雌性AnxA1(+/+)/HY-TCR相比，DP增加，CD8 （SP）细胞减少。对这些作用的信号通路的生化分析显示，与对照组相比，抗cd3诱导的Erk磷酸化和NF κ B激活在AnxA1（-/-）胸腺细胞中减少。总之，这些发现证明了内源性AnxA1在调节TCR库的阳性和阴性选择中的作用。这些结果表明，靶向T细胞中的AnxA1表达或功能可能为开发治疗自身免疫性疾病的新疗法提供了一条有用的途径。
We have recently shown that endogenous Annexin-A1 (AnxA1) plays a homeostatic regulatory role in mature T cells by modulating the strength of TCR signaling. In this study we investigated the role of endogenous AnxA1 in thymocyte maturation. Analysis of AnxA1(-/-) thymocyte populations at the immature CD4(-)CD8(-) double negative (DN) stage showed a proportional decrease in the DN1 and an increase in the DN3 subsets compared to control littermates. There were no significant differences in thymocyte numbers or proportions of CD4(+) and CD8(+) single positive (SP) populations between Anx1(-/-) and AnxA1(+/+) mice. However, when we crossed AnxA1(-/-) mice onto HY-TCR transgenic mice, we observed an increase in CD4(+)CD8(+) double positive (DP) and CD4 SP cells in male AnxA1(-/-)/HY-TCR compared to AnxA1(+/+)/HY-TCR. Conversely, female AnxA1(-/-)/HY-TCR mice showed an increase in DP and a decrease in CD8 (SP) cells compared to female AnxA1(+/+)/HY-TCR. Biochemical analysis of the signaling pathways responsible for these effects showed a decrease in anti-CD3-induced Erk phosphorylation and NF kappa B activation in AnxA1(-/-) thymocytes compared to control littermates. Together these findings demonstrate a role for endogenous AnxA1 in regulating both positive and negative selection of the TCR repertoire. These results suggest that targeting AnxA1 expression or function in T cells could represent a useful approach for the development of novel therapies for the treatment of autoimmune diseases.