Apoptosis of nur77/N10-transgenic thymocytes involves the Fas/Fas ligand pathway.
The orphan nuclear receptor Nur77/N10 has recently been demonstrated to be involved in apoptosis of T cell hybridomas. We report here that chronic expression of Nur77/N10 in thymocytes of transgenic mice results in a dramatic reduction of CD4+CD8+ double-positive as well as CD4+CD8- and CD4-CD8+ single-positive cell populations due to an early onset of apoptosis. CD4-CD8- double-negative and CD25+ precursor cells, however, are unaffected. Moreover, nur77/N10-transgenic thymocytes show increased expression of Fas ligand (FasL), while the levels of the Fas receptor (Fas) are not increased. The mouse spontaneous mutant gld (generalized lymphoproliferative disease) carries a point mutation in the extracellular domain of the FasL gene that abolishes the ability of FasL to bind to Fas. Thymuses from nur77/N10-transgenic mice on a gld/gld background have increased cellularity and an almost normal profile of thymocyte subpopulations. Our results demonstrate that one pathway of apoptosis triggered by Nur77/N10 in double-positive thymocytes occurs through the upregulation of FasL expression resulting in increased signaling through Fas.
Weih
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F
Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Ryseck
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RP
Chen
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L
Bravo
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R
D000818:Animals; D017209:Apoptosis; D001284:Atrophy; D001483:Base Sequence; D018801:CD2 Antigens / Q000096:biosynthesis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D013006:Growth Hormone / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000276:immunology; D011987:Receptors, Steroid; D013601:T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D014158:Transcription, Genetic; D019014:fas Receptor / Q000276:immunology*
D018801:CD2 Antigens; D017931:DNA Primers; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D019014:fas Receptor; D013006:Growth Hormone