Lacorazza H D, Tucek-Szabo C, Vasović L V, Remus K, Nikolich-Zugich J
Laboratory of T Cell Development, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J Immunol. 2001 Mar 1;166(5):3184-93. doi: 10.4049/jimmunol.166.5.3184.
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, but 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.
在胸腺细胞个体发育过程中，Tcr-a基因在Tcr-b基因之后发生重排。TCRαβ转基因（Tg）小鼠不存在这种延迟，因此在个体发育早期就表达重排的TCRαβ蛋白。这类小鼠胸腺细胞数量减少，并积累成熟的、非前体TCR(+)CD8(-)4(-)胸腺细胞，据信这是由Tg TCRαβ通过未知机制过早表达所致。在此，我们表明早期胸腺细胞上TCRαβ的过早表达会抑制胸腺细胞扩增，并损害CD8(-)4(-)向CD8(+)4(+)的转变。这种效应通过两种不同机制实现。首先，TCRαβ的早期形成似乎会损害前TCR的形成和功能，这与最近发表的结果一致。其次，TCRαβ与胸腺内MHC分子的过早接触进一步加剧了增殖和分化的阻滞。这些结果表明，Tcr-a和Tcr-b重排不同步的好处不仅在于使胸腺生成过程中的浪费最小化，还在于同时允许前TCR的正常表达/功能，并使CD8(-)4(-)胸腺细胞免受损害胸腺细胞增殖和CD8(-)4(-)向CD8(+)4(+)转变的TCRαβ信号的影响。
