Opposite Ability of Pre-TCR and abTCR to Induce Apoptosis

Abstract 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 αβTCR 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 αβTCR 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 αβTCR to induce apoptosis in a CD4−CD8− thymoma cell line following receptor cross-linking with mAbs. Cross-linking of αβTCR 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 TCRζ chain, since TCRs containing α-pTα chimeric chains, binding weakly to TCRζ, were still able to induce apoptosis. Although similar tyrosine phosphorylation and calcium influx were induced after either pre-TCR or αβTCR 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 αβTCR, but not pre-TCR, stimulation. Together, these results support the view that the structure of the pre-TCR and αβTCR directly influences their apoptosis-inducing capabilities by activating distinct signaling pathways.