Ligation of retinoic acid receptor α regulates negative selection of thymocytes by inhibiting both DNA binding of nur77 and synthesis of bim

Éva Szegezdi, Ildikó Kiss, A. Simon, B. Blaskó, Uwe Reichert, Serge Michel, Mátyás Sándor, L. Fésüs, Z. Szondy

Research output: Contribution to journalArticle

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Abstract

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) α. The present studies were undertaken to investigate whether ligation of RARα 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 Ek (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 RARα 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.

Original languageEnglish
Pages (from-to)3577-3584
Number of pages8
JournalJournal of Immunology
Volume170
Issue number7
Publication statusPublished - Apr 1 2003

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Retinoic Acid Receptors
Thymocytes
Ligation
Superantigens
DNA
Retinoids
Nuclear Receptor Subfamily 4, Group A, Member 1
Apoptosis
Columbidae
Cytoplasmic and Nuclear Receptors
Cytochromes c
Tretinoin
Transgenic Mice
Signal Transduction
Proteins
Cell Death
Up-Regulation
Ligands
T-Lymphocytes

ASJC Scopus subject areas

  • Immunology

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Ligation of retinoic acid receptor α regulates negative selection of thymocytes by inhibiting both DNA binding of nur77 and synthesis of bim. / Szegezdi, Éva; Kiss, Ildikó; Simon, A.; Blaskó, B.; Reichert, Uwe; Michel, Serge; Sándor, Mátyás; Fésüs, L.; Szondy, Z.

In: Journal of Immunology, Vol. 170, No. 7, 01.04.2003, p. 3577-3584.

Research output: Contribution to journalArticle

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