Role of the pre-T cell receptor in lineage commitment

描述（由申请人提供）：T细胞抗原受体（TCR）依赖谱系承诺是免疫系统T细胞臂的一个关键特征，需要将TCR特异性和T淋巴细胞的功能潜力结合起来。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谱系承诺机制已经被广泛研究，最近的研究绝大多数解释表明，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？和y5发育中的前tcr相比？？谱系细胞在T细胞发育早期检查点的作用目前尚不清楚。虽然很明显，TCR的特定信号？和pre-TCR不同并有助于谱系承诺，一些实验被解释为表明TCR具有指导作用，而另一些实验则表明谱系承诺是预先确定的，仅由特定TCR的表达来确认。在一些报道的实验中，一个额外的复杂性是，当实验不是在竞争条件下进行时，即具有不同TCR的前体在胸腺中竞争生态位（空间）和资源（非TCR受体的配体），特定TCR对谱系承诺的贡献可能会被误判。在这里，我们建议区分TCR的指导性和确证性作用。, TCR ? ?谱系承诺的前tcr为1。)T细胞发育的分析。在体内和体外，在竞争和非竞争条件下，用表达TCR的前体,识别?或细胞?转基因产品。我们将特别强调notch信号在这一过程中的作用。诱导后基因表达随时间的变化分析？和tcr前表达；用RNAi敲低谱系特异性基因表达后的发育分析。

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.