Antigen Activation and Impaired Fas-Induced Death-Inducing Signaling Complex (DISC) Formation in Large Granular Lymphocyte Leukemaia.

Clonal T-cell expansion in patients with T-Large-Granular Lymphocyte (LGL) Leukemia occurs by an undefined mechanism that may be related to Fas apoptosis resistance. Here we demonstrate polarized expansion of CD8+ terminal-memory differentiation in such patients, as demonstrated by CD45RA expression and absence of CD62L expression, suggesting repeated stimulation by antigen in vivo. Elimination of antigen-stimulated T-cells normally occurs through Fas-mediated apoptosis. We show that cells from LGL leukemia patients express c-FLIP and display resistance to Fas-mediated apoptosis and abridged recruitment of proteins that comprise the Death Inducing Signaling Complex (DISC) including the Fas-associated death-domain (FADD) protein and caspase-8. Exposure to interleukin-2 (IL-2) for only 24 hours sensitized leukemic LGL to Fas-mediated apoptosis with enhanced formation of the DISC, and increased caspase-8 and caspase-3 activities; a process that required antigen stimulation in normal T-cells. Our results demonstrate that expanded T-cells in patients with LGL leukemia display both functional and phenotypic characteristics of prior antigen activation in vivo and display reduced capacity for Fas-mediated DISC formation.