αβ versus γδ fate choice: counting the T-cell lineages at the branch point.
αβ versus γδ fate choice: counting the T-cell lineages at the branch point.
复制标题
DOI：
10.1111/j.1600-065x.2010.00947.x
复制
发表时间：
2010-11
影响因子：
8.7
通讯作者：
von Boehmer H
中科院分区：
文献类型：
--
作者：
Kreslavsky T;Gleimer M;Garbe AI;von Boehmer H
αβ和γδ T细胞在胸腺中由一个共同的祖细胞发育而来。历史上以它们的t细胞受体（TCR）来区分，这些谱系现在是根据不同的分子程序来定义的。有趣的是，在许多转基因和敲除系统中，这些程序与TCR类型不匹配，导致αβTCR驱动γδ谱系细胞的发育，反之亦然。这些令人困惑的观察结果最近得到了解释：TCR信号强度，而不是TCR类型本身，指示了谱系命运，较强的TCR信号有利于γδ，较弱的TCR信号有利于αβ谱系命运。这些研究还强调了ERK（细胞外信号调节激酶）-Egr（早期生长反应）-Id3（分化抑制剂3）轴作为TCR下游决定谱系选择的潜在分子开关。事实上，即使存在强烈的TCR信号，去除Id3也足以使TCRγδ转基因细胞重定向到αβ谱系。然而，在TCR非转基因Id3敲除小鼠中，由于v - γ 1v δ6.3亚群的生长，γδ谱系细胞的总数增加，这表明并非所有γδ T细胞都依赖于这种分子开关来进行谱系承诺。因此，γδ谱系实际上可能是两个或多个不共享共同分子程序的谱系的集合，因此等同于αβ谱系。TCR信号不是αβ和γδ系细胞发育所需的唯一因素；其他通路，如来自Notch和CXCR4受体的信号，在这一过程中与TCR合作。
Both αβ and γδ T cells develop in the thymus from a common progenitor. Historically distinguished by their T-cell receptor (TCR), these lineages are now defined on the basis of distinct molecular programs. Intriguingly, in many transgenic and knockout systems these programs are mismatched with the TCR type, leading to the development of γδ lineage cells driven by αβTCR and vice versa. These puzzling observations were recently explained by the demonstration that TCR signal strength, rather than TCR type per se, instructs lineage fate, with stronger TCR signal favoring γδ and weaker signal favoring αβ lineage fates. These studies also highlighted the ERK (extracellular signal regulated kinase)-Egr (early growth response)-Id3 (inhibitor of differentiation 3) axis as a potential molecular switch downstream of TCR that determines lineage choice. Indeed, removal of Id3 was sufficient to redirect TCRγδ transgenic cells to the αβ lineage, even in the presence of strong TCR signal. However, in TCR non-transgenic Id3 knockout mice the overall number of γδ lineage cells was increased due to an outgrowth of a Vγ1Vδ6.3 subset, suggesting that not all γδ T cells depend on this molecular switch for lineage commitment. Thus, the γδ lineage may in fact be a collection of two or more lineages not sharing a common molecular program and thus equipollent to the αβ lineage. TCR signaling is not the only factor that is required for development of αβ and γδ lineage cells; other pathways, such as signaling from Notch and CXCR4 receptors, cooperate with the TCR in this process.