Opposite Ability of Pre-TCR and αβTCR 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.

Impact of early expression of TCR α chain on thymocyte development

“…These results are therefore consistent with the notion that the § g TCR and pre-TCR elicit different signals for thymocyte development [12] despite the sharing of several signaling components [33]. However, it remains to be determined whether the difference between the § g TCR and pre-TCR results from the direct recruitment of distinct signaling molecules [34][35][36][37][38], or the differential abilities of pT § and TCR § chain to target the receptor complex to distinct cellular locations [9,11,39], or both.…”

Prostaglandin A2 Acts as a Transactivator for NOR1 (NR4A3) within the Nuclear Receptor Superfamily

“…4,9,[11][12][13][14][15] Similarly, PGA derivatives are reported to be involved in cell cycle regulation, apoptosis and growth inhibition, not via cytosolic proliferative signaling pathways. 27) While the target molecules or receptors for PGA 2 have not yet been identified, previous reports have shown that PGA 2 induced p21…”

“…[11][12][13][14] PGA 2 was also shown to induce apoptotic cell death and affect the expression levels of cyclin D1 and p21…”

“…NOR1 is implicated in oncogenesis as part of the EWS fusion protein, resulting from chromosomal translocation found in human extraskeletal myxoid chondrosarcoma tumors. 10) In addition, NOR1, as well as Nur77, play a key role in apoptosis of T lymphocytes, eosinophils, and various cell types, [11][12][13][14][15] and thus may be implicated in disorders related to genetically-or environmentally-induced defects of activation-induced apoptosis, including autoimmune diseases and allergic diseases. As such, transactivators for NOR1 represent potential agents for therapeutic intervention to combat human disorders associated with dysfunctional NR4A signaling.…”

The NR4A nuclear receptor family in eosinophils

“…Recently, Nurr1 has emerged as a possible target gene in Parkinson's disease (Kim et al 2002), a condition known to be related to differentiation of dopaminergic neurons (Zetterstrom et al 1996b;Saucedo-Cardenas et al 1998); however, roles for Nurr1 in blood cells are almost unknown. On the contrary, there is evidence that Nur77 and NOR1 appear to function similarly in cells, because both molecules reportedly have apoptotic characteristics in immune cells (Cheng et al 1997;Steff et al 2001;He 2002;Winoto and Littman 2002). It follows that they may be implicated in disorders related to genetically or environmentally induced defects of activation-induced cell death (AICD), such as autoimmune diseases.…”