A specific intercellular pathway of apoptotic cell death is defective in the mature peripheral T cells of autoimmune lpr and gld mice

Homozygosity for either of the unlinked murine autosomal recessive mutations lpr or gld leads to autoimmunity characterized by peripheral accumulation of CD4−/CD8− “double‐negative” T cells, autoantibodies and various forms of tissue pathology. Recently, the gene affected by lpr was identified as fas, whose product acts as a trigger for programmed cell death or apoptosis. Data reported here indicate that the Fas receptor and its ligand, the wild‐type form of the gld gene product, are essential for antigen‐stimulated peripheral T cell apoptosis. Furthermore, the wild‐type gld gene product is a non‐cell‐autonomous protein that is produced by activated T cells. Apoptotic elimination of antigen‐receptor‐triggered peripheral T cells appears to be abnormal in lpr and gld mice, and this deficiency causes peripheral T cells to accumulate resulting in lymphadenopathy. These findings support the importance of apoptotic regulation of lymphocyte persistence after antigen encounter in vivo.