Thymic Expression of the Transcription Factor Nur77 Rescues the T Cell But Not the B Cell Abnormality of gld/gld Mice

Abstract

Fas and Fas ligand are critical regulators of lymphocyte homeostasis. Disruption of this pathway in the spontaneous mouse mutant gld leads to 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 shown that introduction of this Nur77 transgene can eliminate the accumulation of abnormal T cells in the periphery of gld/gld mice. In this report, we further characterized the effects of the Nur77 transgene on the gld phenotype. Nur77-mediated apoptosis is evident in the thymuses of mice with either a gld/gld homozygous or gld/+ heterozygous background. Consequently, few mature T cells are generated in these mice. In addition, mature T cells exhibit a diminished response to proliferative signals through CD3. Interestingly, the Nur77 transgene failed to reduce serum levels of Igs and anti-DNA Abs to wild-type levels. These data suggest that the rescue of the T cell lymphoproliferative syndrome in gld/gld mice by the Nur77 transgene is mediated by events in the thymus and that B cell autoimmune disease associated with the gld mutation can develop independently of the T cell abnormality.