Dudley E C, Girardi M, Owen M J, Hayday A C
Department of Biology, Yale University, New Haven, Connecticut 06510, USA.
Curr Biol. 1995 Jun 1;5(6):659-69. doi: 10.1016/s0960-9822(95)00131-x.
The subdivision of T cells into alpha beta and gamma delta subtypes is conserved throughout vertebrate development. The respective alpha beta and gamma delta T-cell receptors (TCRs) are encoded by somatically rearranged genes. There has been broad speculation as to whether an individual thymocyte can become either a gamma delta T cell or an alpha beta T cell as a result of stochastic gene rearrangement processes, or whether the two types of T cell are derived from separate lineages. Many of the experimental findings are apparently conflicting, however, and the issue--a basic one in immunology and development--remains unresolved.
To address this issue, we have used the recently developed polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, which allows us to examine quantitatively the status of TCR gamma and delta genes in postnatal alpha beta T cells and their progenitors. Interestingly, such cells are depleted of productively rearranged delta and gamma genes, which can encode delta and gamma TCR polypeptide chains. However, in mice that can rearrange TCR delta gene segments, but in which the TCR delta gene is non-functional in other respects, no such depletion of productive rearrangements is seen.
The quantitative data that we have obtained fulfill the predictions of the stochastic hypothesis: that is, a progenitor T cell first attempts to become a gamma delta T cell and, if unsuccessful, then attempts to become an alpha beta T cell. Thus, alpha beta and gamma delta T cells can derive from a common precursor thymocyte. In the simplest case, therefore, lineage-determining factors are the successful rearrangement of both gamma and delta genes before TCR alpha gene rearrangements occur, which lead to deletion of the TCR delta locus and thereby preclude further gamma delta T-cell differentiation. In contrast, successful rearrangement of the TCR beta locus remains compatible with cells becoming either gamma delta or alpha beta T cells.
T细胞分为αβ和γδ亚型这一现象在整个脊椎动物发育过程中是保守的。各自的αβ和γδT细胞受体（TCR）由体细胞重排基因编码。关于单个胸腺细胞是否会由于随机基因重排过程而成为γδT细胞或αβT细胞，或者这两种类型的T细胞是否源自不同谱系，一直存在广泛的猜测。然而，许多实验结果显然相互矛盾，这个免疫学和发育学中的基本问题仍未解决。
为了解决这个问题，我们使用了最近开发的聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术，该技术使我们能够定量检测出生后αβT细胞及其祖细胞中TCRγ和δ基因的状态。有趣的是，这些细胞中可编码δ和γTCR多肽链的有效重排的δ和γ基因缺失。然而，在能够重排TCRδ基因片段但TCRδ基因在其他方面无功能的小鼠中，未观察到这种有效重排的缺失。
我们获得的定量数据符合随机假说的预测：即祖细胞T细胞首先尝试成为γδT细胞，如果不成功，然后尝试成为αβT细胞。因此，αβ和γδT细胞可源自共同的前体胸腺细胞。因此，在最简单的情况下，谱系决定因素是在TCRα基因重排发生之前γ和δ基因的成功重排，这会导致TCRδ基因座的缺失，从而排除进一步的γδT细胞分化。相比之下，TCRβ基因座的成功重排仍与细胞成为γδ或αβT细胞兼容。
