Positive and negative thymic selection in T cell receptor-transgenic mice correlate with Nur77 mRNA expression.

The orphan nuclear receptor Nur77 has been implicated in thymic negative selection. We studied the effect of two T cell receptor (TCR) transgenes on positive selction and Nur77 mRNA expression in thymus. DO11.10 mice, expressing a transgenic TCR specific for an ovalbumin (OVA) 323-339 peptide presented by I-A(d), were found to have an enlarged thymus with a reduced apoptotic activity, measured by flow cytometry, reduced mitochondrial membrane potential and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) techniques. In contrast, in F5 mice expressing a transgenic TCR recognizing the influenza virus nucleoprotein (NP) 366-374 peptide restricted by D-b, this positive selection effect was much less pronounced. Positive thymic selection in DO11.10 TCR+ mice correlated with a reduced level of Nur77 mRNA expression shown by Northern blot. F5 mice expressed levels close to those expressed by the wild type. Both transgenic mouse strains responded with extensive cortical apoptosis, and with up-regulation of Nur77 mRNA, to injection of cognate peptides. As 9-cis-Retinoic acid (9-cis-RA) inhibits Nu77-dependent apoptosis in T cell hybridomas in vitro, mice were pretreated with the drug to investigate a similar effect in vivo. However, the drug itself, at saturating concentrations. caused extensive apoptosis in immature CD4(+)/CD8(+) thymocytes, The result demonstrates a correlation between Nur77 expression and thymic apoptotic activity, both during positive and negative selection events.