Ligation of retinoic acid receptor alpha regulates negative selection of thymocytes by inhibiting both DNA binding of nur77 and synthesis of bim.
Negative selection refers to the selective deletion of autoreactive thymocytes. Its molecular mechanisms have not been well defined. Previous studies in our laboratory have demonstrated that retinoic acids, physiological ligands for the nuclear retinoid receptors, selectively inhibit TCR-mediated death under in vitro conditions, and the inhibition is mediated via the retinoic acid receptor (RAR) alpha. The present studies were undertaken to investigate whether ligation of RARalpha leads to inhibition of TCR-mediated death in vivo and to identify the molecular mechanisms involved. Three models of TCR-mediated death were studied: anti-CD3-mediated death of thymocytes in wild-type mice, and Ag- and bacterial superantigen-driven thymocyte death in TCR-transgenic mice expressing a receptor specific for a fragment of pigeon cytochrome c in the context of the E(k) (class II MHC) molecule. Our data demonstrate that the molecular program of both anti-CD3- and Ag-driven, but not that of superantigen-mediated apoptosis involves up-regulation of nur77, an orphan nuclear receptor, and bim, a BH3-only member of the proapoptotic bcl-2 protein family, proteins previously implicated to participate in the negative selection. Ligation of RARalpha by the synthetic agonist CD336 inhibited apoptosis, DNA binding of nur77, and synthesis of bim induced by anti-CD3 or the specific Ag, but had no effect on the superantigen-driven cell death. Our data imply that retinoids are able to inhibit negative selection in vivo as well, and they interfere with multiple steps of the T cell selection signal pathway.
Szegezdi
Eva
E
Department of Biochemistry and Molecular Biology,University of Debrecen, Debrecen, Hungary.
Kiss
Ildikó
I
Simon
Agnes
A
Blaskó
Bernadett
B
Reichert
Uwe
U
Michel
Serge
S
Sándor
Mátyás
M
Fésüs
László
L
Szondy
Zsuzsa
Z
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D001565:Benzoates / Q000008:administration & dosage; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D017637:Clonal Deletion / Q000187:drug effects / Q000276:immunology; D010856:Columbidae; D003574:Cytochrome c Group / Q000008:administration & dosage / Q000276:immunology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D004768:Enterotoxins / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000378:metabolism / Q000502:physiology*; D011987:Receptors, Steroid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism
D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001565:Benzoates; D017252:CD3 Complex; D002352:Carrier Proteins; D003574:Cytochrome c Group; D004268:DNA-Binding Proteins; D004768:Enterotoxins; D008024:Ligands; D008565:Membrane Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011518:Proto-Oncogene Proteins; C000607072:Rara protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D018089:Superantigens; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C068073:Am 580; C026066:enterotoxin A, Staphylococcal