Abstract
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.
MeSH terms
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Animals
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Apoptosis*
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Atrophy
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Base Sequence
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CD2 Antigens / biosynthesis
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CD2 Antigens / genetics
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CD4-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / immunology
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DNA Primers
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / physiology*
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Fas Ligand Protein
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Flow Cytometry
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Growth Hormone / biosynthesis
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Growth Hormone / genetics
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Humans
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Ligands
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Membrane Glycoproteins / immunology*
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Nuclear Receptor Subfamily 4, Group A, Member 1
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Polymerase Chain Reaction
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RNA, Messenger / biosynthesis
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / immunology
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Receptors, Steroid
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T-Lymphocytes / immunology*
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T-Lymphocytes / physiology
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Thymus Gland / immunology
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Thymus Gland / pathology
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Transcription Factors / biosynthesis
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Transcription Factors / physiology*
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Transcription, Genetic
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fas Receptor / immunology*
Substances
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CD2 Antigens
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DNA Primers
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DNA-Binding Proteins
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Ligands
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Membrane Glycoproteins
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NR4A1 protein, human
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Nr4a1 protein, mouse
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Nuclear Receptor Subfamily 4, Group A, Member 1
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Receptors, Steroid
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Transcription Factors
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fas Receptor
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Growth Hormone