Multiple rearrangements in T cell receptor alpha chain genes maximize the production of useful thymocytes.
Multiple rearrangements in T cell receptor alpha chain genes maximize the production of useful thymocytes.
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DOI：
10.1084/jem.178.2.615
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发表时间：
1993-08-01
期刊：
影响因子：
--
通讯作者：
Shortman K
中科院分区：
文献类型：
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作者：
Petrie HT;Livak F;Schatz DG;Strasser A;Crispe IN;Shortman K
每个外周T淋巴细胞都表达单一特异性的表面T细胞受体(TCR)α链和β链。这些基因是在TCRα和β生殖系基因随机体细胞重排后产生的。已发表的使用表达TCRα和/或β链转基因小鼠的模型系统表明，TCR-β基因通常发生等位基因排斥。然而，TCRα链的表达似乎不那么严格，因为在TCRα/β转基因小鼠中，经常发现内源性TCRα链与转基因TCRβ链相关。这一发现，再加上TCRα基因座的独特结构，导致了TCRα基因与TCRβ基因和免疫球蛋白重链基因不同，TCRα基因可能在每条染色体上进行多次重排。在目前的研究中，我们证明了大多数TCR-，非周期胸腺细胞自发地获得CD3/TCR的表面表达。此外，我们发现，培养的未成熟胸腺细胞最初表达特定的TCRα和β链可能会失去原始TCRα链的表面表达，但不会失去β链的表达。这些数据提供的证据表明，不仅必须发生多次重排，而且TCRα基因重排甚至在TCRα/β异源二聚体表面表达后仍在继续，显然直到正选择停止重组过程，否则细胞死亡。TCRα链基因的顺序重排通过增加框内重排和可正向选择的TCRα/β异源二聚体的产生频率，促进有用胸腺细胞的产生。
Peripheral T lymphocytes each express surface T cell receptor (TCR) alpha and beta chains of a single specificity. These are produced after random somatic rearrangements in TCR alpha and beta germline genes. Published model systems using mice expressing TCR alpha and/or beta chain transgenes have shown that allelic exclusion occurs conventionally for TCR-beta. TCR alpha chain expression, however, appears to be less strictly regulated, as endogenous TCR alpha chains are often found in association with transgenic TCR beta chains in TCR alpha/beta transgenic mice. This finding, coupled with the unique structure of the TCR alpha locus, has led to the suggestion that unlike TCR beta and immunoglobulin heavy chain genes, TCR alpha genes may make multiple rearrangements on each chromosome. In the current study, we demonstrate that the majority of TCR-, noncycling thymocytes spontaneously acquire surface expression of CD3/TCR. Further, we show that cultured immature thymocytes originally expressing specific TCR alpha and beta chains may lose surface expression of the original TCR alpha, but not beta chains. These data provide evidence that not only must multiple rearrangements occur, but that TCR alpha gene rearrangement continues even after surface expression of a TCR alpha/beta heterodimer, apparently until the recombination process is halted by positive selection, or the cell dies. Sequential rearrangement of TCR alpha chain genes facilitates enhanced production of useful thymocytes, by increasing the frequency of production of both in-frame rearrangements and positively selectable TCR alpha/beta heterodimers.