Role of the pre-T cell receptor in lineage commitment

描述（由申请方提供）：T细胞抗原受体（TCR）依赖性谱系定型是免疫系统T细胞臂的一个关键特征，其是T淋巴细胞TCR特异性和功能潜力对齐所必需的。已经广泛研究了具有II类和I类MHC特异性受体的CD 4辅助细胞和CD 8杀伤细胞的T谱系定型机制，并且最近的研究被压倒性地解释为表明由不同TCR配体引发的不同TCR信号传导指导发育中的T细胞发育成不同的谱系。TCR的作用？？和前TCR在发展中的y 5与？谱系细胞在T细胞发育的早期检查点目前尚不清楚。虽然很明显，TCR的特异性信号传导？？和pre-TCR不同并有助于谱系定型，一些实验被解释为指示TCR的指导作用，而其他实验表明谱系定型是预先确定的，并且仅通过特定TCR的表达来确认。在一些报道的实验中的另一个复杂性是，当实验不是在竞争性条件下进行时，即具有不同TCR的前体竞争胸腺中的小生境（空间）和资源（TCR以外的受体的配体）时，特定TCR对谱系定型的贡献可能被误判。在这里，我们建议区分TCR的指导性和证实性作用，TCR？？和谱系定型中的前TCR。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与表达TCR？？的前体，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。基因表达分析作为诱导后时间的函数？和前TCR表达和3.）通过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.