Role of the pre-T cell receptor in lineage commitment

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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.