THYMIC EXPRESSION OF THE TRANSCRIPTION FACTOR NUR77 RESCUES THE T-CELL BUT NOT THE B-CELL ABNORMALITY OF GLD GLD MICE/

Fas and Fas ligand are critical regulators of lymphocyte homeostasis. Disruption of this pathway in the spontaneous mouse mutant gld Beads t o autoimmunity characterized by the appearance of a population of CD4( -)8(-)B220(+) T cells and the production of autoantibodies. Nur77 is a transcription factor that is induced upon TCR signaling, Constitutive thymic expression of Nur77 leads to apoptosis. We have previously sho wn that introduction of this Nur77 transgene can eliminate the accumul ation of abnormal T cells in the periphery of gld/gld mice. In this re port, we further characterized the effects of the Nur77 transgene on t he gld phenotype. Nur77-mediated apoptosis is evident in the thymuses of mice with either a gld/gld homozygous or gld/+ heterozygous backgro und. Consequently, few mature T cells are generated in these mice. In addition, mature T cells exhibit a diminished response to proliferativ e signals through CD3. Interestingly, the Nur77 transgene failed to re duce serum levels of Igs and anti-DNA Abs to wild-type levels, These d ata suggest that the rescue of the T cell lymphoproliferative syndrome in gld/gld mice by the Nur77 transgene is mediated by events in the t hymus and that B cell autoimmune disease associated with the gld mutat ion can develop independently of the T cell abnormality,