title: Opposite ability of pre-TCR and alpha beta TCR 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 alphabetaTCR 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 alphabetaTCR 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 alphabetaTCR to induce apoptosis in a CD4(-)CD8(-) thymoma cell line following receptor cross-linking with mAbs. Cross-linking of alphabetaTCR 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 TCRzeta chain, since TCRs containing alpha-pTalpha chimeric chains, binding weakly to TCRzeta, were still able to induce apoptosis. Although similar tyrosine phosphorylation and calcium influx were induced after either pre-TCR or alphabetaTCR 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 alphabetaTCR, but not pre-TCR, stimulation. Together, these results support the view that the structure of the pre-TCR and alphabetaTCR directly influences their apoptosis-inducing capabilities by activating distinct signaling pathways.
authors: Division of Research and Development, PROCREA BioSciences, Montreal, Quebec, Canada.
authors: A M
authors: AM
authors: Steff
authors: S
authors: S
authors: Trop
authors: M
authors: M
authors: Maira
authors: J
authors: J
authors: Drouin
authors: P
authors: P
authors: Hugo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053222:Fas Ligand Protein; D008024:Ligands; D008223:Lymphoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D013953:Thymus Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; C539818:Nr4a1 protein, mouse; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015534:Trans-Activators; D014157:Transcription Factors; C054979:antigen T cell receptor, zeta chain; D019014:fas Receptor; C090377:pre-T cell receptor alpha