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 CDSkiller 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 TCRyS and the pre-TCR in development of y5 versus ap lineage cells at an earlier checkpoint in T cell development is at present not clear. While it is clear that specific signaling by the TCRyS 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 TCRyS, TCRa0 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 TCRyS, TCRa or TCRp 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 ySand pre-TCR expression and 3.) Analysis of development after knockdown of lineage-specific gene expression by RNAi.
| Kreslavsky, Taras; Gleimer, Michael; Miyazaki, Masaki et al. (2012) ýý-Selection-induced proliferation is required for ýýýý T cell differentiation. Immunity 37:840-53 |
| von Boehmer, Harald; Melchers, Fritz (2010) Checkpoints in lymphocyte development and autoimmune disease. Nat Immunol 11:14-20 |
| Kreslavsky, Taras; Gleimer, Michael; von Boehmer, Harald (2010) Alphabeta versus gammadelta lineage choice at the first TCR-controlled checkpoint. Curr Opin Immunol 22:185-92 |
| Kreslavsky, Taras; Gleimer, Michael; Garbe, Annette I et al. (2010) ?? versus ?? fate choice: counting the T-cell lineages at the branch point. Immunol Rev 238:169-81 |
| Kreslavsky, Taras; von Boehmer, Harald (2010) gammadeltaTCR ligands and lineage commitment. Semin Immunol 22:214-21 |
| Kreslavsky, Taras; Garbe, Annette I; Krueger, Andreas et al. (2008) T cell receptor-instructed alphabeta versus gammadelta lineage commitment revealed by single-cell analysis. J Exp Med 205:1173-86 |
| Egawa, Takeshi; Kreslavsky, Taras; Littman, Dan R et al. (2008) Lineage diversion of T cell receptor transgenic thymocytes revealed by lineage fate mapping. PLoS One 3:e1512 |
| Li, Xiaoyu; Gounari, Fotini; Protopopov, Alexei et al. (2008) Oncogenesis of T-ALL and nonmalignant consequences of overexpressing intracellular NOTCH1. J Exp Med 205:2851-61 |
| Garbe, Annette I; von Boehmer, Harald (2007) TCR and Notch synergize in alphabeta versus gammadelta lineage choice. Trends Immunol 28:124-31 |
| Krueger, Andreas; von Boehmer, Harald (2007) Identification of a T lineage-committed progenitor in adult blood. Immunity 26:105-16 |
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