Premature TCRαβ expression and signaling in early thymocytes impair thymocyte expansion and partially block their development
Premature TCRαβ expression and signaling in early thymocytes impair thymocyte expansion and partially block their development
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DOI：
10.4049/jimmunol.166.5.3184
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发表时间：
2001-03-01
影响因子：
4.4
通讯作者：
Nikolich-Zugich, J
中科院分区：
文献类型：
--
作者：
Lacorazza, HD;Tucek-Szabo, C;Nikolich-Zugich, J
在胸腺细胞个体发育中。TCR-a基因在TCR-b基因之后重排。TCRαβ转基因(TG)小鼠没有这种延迟，因此在个体发育早期表达重排的TCRαβ蛋白。这些小鼠表现出胸腺细胞密度降低，并积累成熟的非前体TCR(+)CD8(-)4(-)胸腺细胞，据信是由TGTCRαβ过早表达引起的，机制不明(S)。在这里，我们发现在早期胸腺细胞上过早表达TCRαβ会抑制胸腺细胞的扩张，并损害CD8(-)4(-)->；CD8(+)4(+)的转变。这一效果是通过两种不同的机制实现的。首先，TCRαβ的早期形成似乎损害了前TCR的形成和功能，这与最近发表的结果一致，其次，TCRαβ过早与胸腺内MHC分子接触进一步表明了增殖和分化的障碍。这些结果表明，非同步TCR-a和TCR-b重排的好处不仅是减少胸腺生成过程中的浪费，而且还可以同时允许TCR前的正确表达/功能，并保护CD8(-)4(-)胸腺细胞免受TCRα信号的影响，TCRα信号会损害胸腺细胞的增殖和CD8(-)4(-)-GT；CD8(+)4(+)转换。
In thymocyte ontogeny. Tcr-a genes rearrange after Tcr-b genes. TCR alpha beta transgenic (Tg) mice have no such delay, consequently expressing rearranged TCR alpha beta proteins early in the ontogeny. Such mice exhibit reduced thymic cellularity and accumulate mature, nonprecursor TCR(+)CD8(-)4(-) thymocytes, believed to be caused by premature Tg TCR alpha beta expression via unknown mechanism(s). Here, we show that premature expression of TCR alpha beta on early thymocytes curtails thymocyte expansion and impairs the CD8(-)4(-) --> CD8(+)4(+) transition. This effect is accomplished by two distinct mechanisms. First, the early formation of TCR alpha beta appears to impair the formation and function of pre-TCR, consistent with recently published results, Second, the premature TCR alpha beta contact with intrathymic MHC molecules further pronounces the block in proliferation and differentiation. These results suggest that the benefit of asynchronous Tcr-a and Tcr-b rearrangement is not only to minimize waste during thymopoiesis, hut also to simultaneously allow proper expression/function of the pre-TCR and to shield CD8(-)4(-) thymocytes from TCR alpha beta signals that impair thymocyte proliferation and CD8(-)4(-) --> CD8(+)4(+) transition.