Opposite ability of pre-TCR and alpha beta TCR to induce apoptosis

In early CD4(-)CD8(-) pro-thymocytes, signaling through the pre-TCR is cruc ial for survival and differentiation into CD4(+)CD8(+) cells. At this more mature stage, interactions between alpha beta TCR and self-Ag/MHC complexes In turn lead either to cell survival and differentiation (positive selecti on) or to cell death (negative selection). Intrinsic differences must there fore exist between pre-TCR signals in CD4(-)CD8(-) thymocytes and alpha bet a TCR signals in CD4(+)CD8(+) cells, since only the latter can mediate a de ath signal. In this work, we directly compared the capability of pre-TCR an d alpha beta TCR to induce apoptosis in a CD4(-)CD8(-) thymoma cell line fo llowing receptor cross-linking with mAbs. Cross-linking of alpha beta TCR t riggered high levels of programmed cell death, mimicking the negative selec tion signal usually induced in CD4(+)CD8(+) thymocytes. In contrast, pre-TC R was very inefficient at inducing apoptosis upon cross-linking, despite si milar levels of surface receptor expression. Importantly, inefficient apopt osis induction by the pre-TCR did not result from its weak association with TCR chain, since TCRs containing alpha -pT alpha chimeric chains, binding weakly to TCR, were still able to induce apoptosis. Although similar tyrosi ne phosphorylation and calcium influx were induced after either pre-TCR or alpha beta TCR cross-linking, the two pathways diverged at the level of Fas ligand induction. Among putative transcription factors involved in Fas lig and mRNA induction, Nur77 and NFAT transcriptional activities were readily induced after alpha beta TCR, but not pre-TCR, stimulation. Together, these results support the view that the structure of the pre-TCR and alpha beta TCR directly influences their apoptosis-inducing capabilities by activating distinct signaling pathways. The Journal of Immunology, 2001.