Dysregulation of CD95/CD95 ligand apoptotic pathway in CD3(+) large granular lymphocyte leukemia

CD95 (Fas)-induced apoptosis plays a critical role in the elimination of ac tivated lymphocytes and induction of peripheral tolerance. Defects in CD95/ CD95L (Fas-Ligand)-apoptotic pathway have been recognized in autoimmune lym phoproliferative diseases (ALPS) and lpr or gld mice and attributed to CD95 and CD95L gene mutations, respectively. Large granular lymphocyte (LGL) le ukemia is a chronic disease characterized by a proliferation of antigen-act ivated cytotoxic T lymphocytes. Autoimmune features such as hypergammaglobu linemia, rheumatoid factor, and circulating immune complexes are common fea tures in LGL leukemia and ALPS. Therefore, we hypothesize that expansion of leukemic LGL may be secondary to a defective CD95 apoptotic pathway. In th is study, we investigated expression of CD95 and CD95L in 11 patients with CD3(+) LGL leukemia and explored the apoptotic response to agonistic CD95 m onoclonal antibody (MoAb). We found that leukemic LGL from each patient exp ressed constitutively high levels of CD95/CD95L, similar to those seen in n ormal activated T cells. However, cells from 9 of these 11 patients were to tally resistant to anti-CD95-induced apoptosis. Similarly, cells were resis tant to anti-CD3-MoAb-triggered cell death. Lack of anti-CD95-induced apopt osis was not due to mutations in the CD95 antigen. Leukemic LGL were not in trinsically resistant to CD95-dependent death, because LGL from all but 1 p atient underwent apoptosis after phytohemagglutinin/interleukin-1. activati on. The patient whose leukemic LGL were intrinsically resistant to CD95 had an aggressive form of LGL leukemia that was resistant to combination chemo therapy. These findings that leukemic LGL are resistant to CD95-dependent a poptosis despite expressing high levels of CD95 are similar to observations made in CD95L transgenic mice. These data suggest that LGL leukemia may be a useful model of dysregulated apoptosis causing human malignancy and auto immune disease. (C) 1998 by The American Society of Hematology.