Submitted June 11, 2007
Accepted October 31, 2007
Antigen activation and impaired Fas-induced DISC formation in LGL leukemia
Jun Yang*, P.K. Epling-Burnette, Jeffrey S. Painter, JianXiang Zou, Fanqi Bai, Sheng Wei, and Thomas P. Loughran Jr.
Department of Medicine, Penn State Cancer Institute, College of Medicine, Penn State University, Hershey, PA, United States
Department of Interdisciplinary Oncology, Immunology Program and Malignant Hematology Division, H Lee Moffitt Cancer Center and Research Inst., Univ of South Florida Veteran's Admin. Hospital, Tampa, FL, United States
* Corresponding author; email: jyang{at}psu.edu.
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 increased levels of 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 protein with death-domain (FADD) 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. We observed dysregulation of c-FLIP by IL-2 in leukemic LGL, suggesting a role in Fas resistance. 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.
