Role of the pre-T cell receptor in lineage commitment

描述(由申请人提供)：依赖T细胞抗原受体(TCR)的谱系承诺是免疫系统T细胞臂的一个关键特征，这是使TCR特异性和T淋巴细胞的功能潜力相匹配所必需的。CD4辅助细胞和CD8杀伤细胞与II类和I类MHC特异性受体的T谱系承诺机制已被广泛研究，最近的研究被压倒性地解释为由不同的TCR配体启动的不同的TCR信号指示发育中的T细胞发育成不同的谱系。TCR的作用？？以及Y5发展中的前TCR与？？T细胞发育的早期检查点的谱系细胞目前尚不清楚。虽然很明显，TCR发出的特定信号？？和前TCR不同，并有助于谱系承诺，一些实验被解释为表明TCR的教育作用，而另一些实验表明，谱系承诺是预先确定的，并仅通过特定TCR的表达来证实。一些已报道的实验的另一个复杂性是，当实验不是在竞争条件下进行时，即具有不同TCR的前体竞争胸腺中的利基(空间)和资源(TCR以外的受体的配体)时，特定TCR对谱系承诺的贡献可能被误判。在这里，我们建议区分TCR？？、TCR？？的启发性和确认性作用。血统承诺中的TCR前增加了1。)T细胞发育的分析。在体内和体外竞争性和非竞争性条件下，前体表达TCR？？、TCR？还是TCR？转基因。将特别强调Notch信号在这一过程中的作用，2.)诱导后基因表达随时间变化的分析？？和前TCR的表达和3)。用RNAi技术分析谱系特异性基因表达下调后的发育。

DESCRIPTION (provided by applicant): T cell antigen receptor (TCR) dependent lineage commitment is a key feature of the T cell arm of the immune system that is required to align TCR specificity and functional potential of T lymphocytes. Mechanisms of T lineage commitment of CD4 helper and CD8 killer cells with class II and class I MHC- specific receptors have been studied extensively and recent studies were overwhelmingly interpreted to indicate that distinct TCR signaling that is initiated by different TCR ligands instructs developing T cells to develop into the different lineages. The role of TCR?? and the pre-TCR in development of y5 versus ?? lineage cells at an earlier checkpoint in T cell development is at present not clear. While it is clear that specific signaling by the TCR?? and pre-TCR differs and contributes to lineage commitment, some experiments have been interpreted to be indicative of an instructive role of the TCR while others suggest that lineage commitment is predetermined and only confirmed by expression of a particular TCR. An additional complication in some of the reported experiments is the fact that the contribution of a particular TCR to lineage commitment can be misjudged when experiments are not conducted under competitive conditions i.e. where precursors with different TCRs compete for niches (space) and resources (ligands for receptors other than TCR) in the thymus. Here we propose to discriminate between an instructive and confirmatory role of the TCR??, TCR?? and the pre-TCR in lineage commitment by 1.) The analysis of T cell development in. vivo and in vitro under competitive and non-competitive conditions with precursors expressing TCR??, TCR? or TCR? transgenes. Special emphasis will be given to the role of Notch-signaling in this process, 2.) Gene expression analysis as a function of time after inducible ?? and pre-TCR expression and 3.) Analysis of development after knockdown of lineage-specific gene expression by RNAi.