Mice homozygous for lpr (a defect at the Fas locus) or gld (a defect at the FasL locus) develop autoimmunity and profound lymphadenopathy characterized by the accumulation of two functionally anergic T cell subsets, a predominant B220+ DN T cell population and a minor CD4+B220+ population. Enlarged LN also contain increased numbers of memory CD4+ and CD8+ T cells capable of secreting high levels of proinflammatory cytokines. In the past year we continued to investigate the origins of the B220+ T cell subsets and the effects of defective Fas/FasL function on T cell deletion in the periphery. In addition, we investigated exon utilization in the activation- associated high MW CD45 isoforms recognized by the mcAb RA36B2 and initiated a survey of tumor incidence in aging lpr and gld mice. Studies of lpr and gld mice with inactivated beta-2 microglobulin genes revealed that 1) the majority of B220+ DN T cells are derived from CD8+ precursors selected on MHC class I, 2) CD4+B220+ T cells are a separate lineage that undergo normal negative selection in the thymus and develop independently of CD8+ T cells or MHC class I expression, and 3) CD8+ T cells may regulate the accumulation of CD4+ T cells by Fas-independent mechanisms. Using superantigen-treated lpr and gld mice, we demonstrated that 1) Fas-mediated deletion is not an absolute requirement for the elimination of activated T cells and may be more important for eliminating CD8+ T cells than CD4+ T cells, 2) B220+ DN T cells are unlikely to accumulate by proliferating to Ag, and 3) potent mitogenic stimuli do not induce the conversion of CD8+ lpr and gld T cells into B220+ DN T cells. Studies of the expression of activation-associated CD45 isoforms on CD8+ T cells showed that the RA36B2 mAb recognized CD45 isoforms in addition to the 220 kD species and that the expression of these is regulated by IL-4. Finally, approximately 34% of 10-18 mon old lpr and gld mice were shown to have B cell neoplasms. These studies and others indicate that Fas/FasL- mediated deletion mechanisms play an important role in regulating the survival of peripheral T cells, especially those selected on MHC class I and in eliminating autoreactive and transformed B cells in the periphery.
