Functional distinctions between MRL-lpr and MRL-gld lymphocytes: Normal cells reverse the gld but not lpr immunoregulatory defect

Homozygosity for either of the autosomal recessive mutations, lpr or gld, confers an autoimmune syndrome characterized by massive lymphoid hyperplasia and extensive autoantibody production. Despite the similarities in disease progression, functional distinctions in these genetic defects have been observed in bone marrow transplantation studies. To elucidate the mechanisms responsible for the aberrant immune phenotype of these strains, we analyzed interactions between normal T cells and T cells from the two autoimmune strains with regard to their in vitro responses to autologous and allogeneic stimuli and in an in vivo bone marrow transplantation model. Despite similar propensities for lpr and gld T cells to spontaneously proliferate in vitro in response to autologous class II Ag, a dramatic difference in their immunoregulatory properties was found when mixtures of normal and autoimmune CD4⁺ responder cells were challenged with an allogeneic stimulus. T cells from the lpr, but not gld, mice blocked the normal T cell component of the response. In vivo, the ability of lpr stem cells to trigger a wasting syndrome when transplanted into normal irradiated recipients could not be prevented by including normal stem cells in the inoculum; however, the ability of gld stem cells to transfer the gld-lymphoproliferative syndrome to normal recipients could be prevented with the addition of normal stem cells. These results support a model whereby the lpr and gld strains are defective in reciprocal components of a down-regulatory signaling pathway; failure to express either the functional receptor or ligand leads to a dysregulated immune system resulting in systemic autoimmunity. Based on the linkage between the lpr locus and Fas Ag expression, we propose that the failure of lpr mice to express Fas results in overproduction of Fas-ligand, whereas gld mice fail to make either the Fas-ligand or a functionally related protein, presumably belonging to the TNF family.