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Opposite Ability of Pre-TCR and TCR to Induce Apoptosis

Ann-Muriel Steff^*, Sébastien Trop^1,, Mario Maira, Jacques Drouin and Patrice Hugo^2,*,

^* Division of Research and Development, PROCREA BioSciences, Montreal, Quebec, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada; and Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada

In early CD4^-CD8^- pro-thymocytes, signaling through the pre-TCR is crucial for survival and differentiation into CD4⁺CD8⁺ cells. At this more mature stage, interactions between TCR and self-Ag/MHC complexes in turn lead either to cell survival and differentiation (positive selection) or to cell death (negative selection). Intrinsic differences must therefore exist between pre-TCR signals in CD4^-CD8^- thymocytes and TCR signals in CD4⁺CD8⁺ cells, since only the latter can mediate a death signal. In this work, we directly compared the capability of pre-TCR and TCR to induce apoptosis in a CD4^-CD8^- thymoma cell line following receptor cross-linking with mAbs. Cross-linking of TCR triggered high levels of programmed cell death, mimicking the negative selection signal usually induced in CD4⁺CD8⁺ thymocytes. In contrast, pre-TCR was very inefficient at inducing apoptosis upon cross-linking, despite similar levels of surface receptor expression. Importantly, inefficient apoptosis induction by the pre-TCR did not result from its weak association with TCR chain, since TCRs containing -pT chimeric chains, binding weakly to TCR, were still able to induce apoptosis. Although similar tyrosine phosphorylation and calcium influx were induced after either pre-TCR or TCR cross-linking, the two pathways diverged at the level of Fas ligand induction. Among putative transcription factors involved in Fas ligand mRNA induction, Nur77 and NFAT transcriptional activities were readily induced after TCR, but not pre-TCR, stimulation. Together, these results support the view that the structure of the pre-TCR and TCR directly influences their apoptosis-inducing capabilities by activating distinct signaling pathways.

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