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 Blood, 1 February 2008, Vol. 111, No. 3, pp. 1610-1616.
Prepublished online as a Blood First Edition Paper on November 9, 2007; DOI 10.1182/blood-2007-06-093823.

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NEOPLASIA

Antigen activation and impaired Fas-induced death-inducing signaling complex formation in T-large-granular lymphocyte leukemia

Jun Yang1, P. K. Epling-Burnette2, Jeffrey S. Painter2, JianXiang Zou2, Fanqi Bai2, Sheng Wei2, and Thomas P. Loughran, Jr1

1 Penn State Cancer Institute, Department of Medicine, College of Medicine, Penn State University, Hershey, PA; and 2 Immunology Program and Malignant Hematology Division, H. Lee Moffitt Cancer Center and Research Institute, Department of Interdisciplinary Oncology at the University of South Florida and Veterans' Administration (VA) Hospital, Tampa, FL

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.


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