Plasma membrane sphingomyelin modulates thymocyte development by inhibiting TCR-induced apoptosis
Plasma membrane sphingomyelin modulates thymocyte development by inhibiting TCR-induced apoptosis
复制标题
DOI：
10.1093/intimm/dxy082
复制
发表时间：
2019-04-01
影响因子：
4.4
通讯作者：
Inokuchi, Jin-ichi
中科院分区：
文献类型：
--
作者：
Toshima, Kaoru;Nagafuku, Masakazu;Inokuchi, Jin-ichi
鞘磷脂（SM）与胆固醇结合形成专门的膜脂质微区，其中特定的受体和信号分子被定位或募集以介导细胞内信号传导。在胸腺选择之前的早期CD 4（+）CD 8（+）双阳性（DP）阶段，小鼠胸腺中的SM-微结构域水平较低，并且在晚期选择期间增加>10倍。T细胞受体（TCR）信号强度是决定DP胸腺细胞是否经历阳性或阴性选择的关键因素。我们研究了SM-微结构域在胸腺细胞发育和相关TCR信号传导中的作用，使用SM合酶1（SMS 1）缺陷（SMS 1（-/-））小鼠，其在所有胸腺细胞群体中显示低SM表达。在TCR转基因模型中，SMS 1缺陷导致DP晚期后细胞数量减少。在体内和体外，抗CD 3处理诱导的TCR依赖性凋亡在SMS 1（-/-）DP胸腺细胞中均增强。与对照组相比，SMS 1（-/-）DP胸腺细胞显示TCR近端激酶ZAP-70的磷酸化增加，以及TCR刺激后参与阴性选择的Bim和Nur 77蛋白表达增加。此外，SM培养的正常DP胸腺细胞的SM-微结构域的表面表达大大增加，与相关的减少TCR信号和TCR诱导的细胞凋亡。我们的研究结果表明，SM-微结构域在DP晚期增加，作为TCR信号传导的负调节剂，调节TCR近端信号传导的效率，促进胸腺选择事件，导致随后的发育阶段。
Sphingomyelin (SM) in combination with cholesterol forms specialized membrane lipid microdomains in which specific receptors and signaling molecules are localized or recruited to mediate intracellular signaling. SM-microdomain levels in mouse thymus were low in the early CD4(+)CD8(+) double-positive (DP) stage prior to thymic selection and increased >10-fold during late selection. T-cell receptor (TCR) signal strength is a key factor determining whether DP thymocytes undergo positive or negative selection. We examined the role of SM-microdomains in thymocyte development and related TCR signaling, using SM synthase 1 (SMS1)-deficient (SMS1(-/-)) mice which display low SM expression in all thymocyte populations. SMS1 deficiency caused reduced cell numbers after late DP stages in TCR transgenic models. TCR-dependent apoptosis induced by anti-CD3 treatment was enhanced in SMS1(-/-) DP thymocytes both in vivo and in vitro. SMS1(-/-) DP thymocytes, relative to controls, showed increased phosphorylation of TCR-proximal kinase ZAP-70 and increased expression of Bim and Nur77 proteins involved in negative selection following TCR stimulation. Addition of SM to cultured normal DP thymocytes led to greatly increased surface expression of SM-microdomains, with associated reduction of TCR signaling and TCR-induced apoptosis. Our findings indicate that SM-microdomains are increased in late DP stages, function as negative regulators of TCR signaling and modulate the efficiency of TCR-proximal signaling to promote thymic selection events leading to subsequent developmental stages.Sphingomyelin-microdomains fine-tune TCR signalling in thymocytes