title: Antigen activation and impaired Fas-induced death-inducing signaling complex formation in T-large-granular lymphocyte leukemia.
abstract: 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.
authors.affiliation: Penn State Cancer Institute, Department of Medicine, College of Medicine, Penn State University, Hershey, PA 17033, USA. jyang@psu.edu
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: P K
authors.initials: PK
authors.lastname: Epling-Burnette
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Painter
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Zou
authors.forename: Fanqi
authors.initials: F
authors.lastname: Bai
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D016827:CD8 Antigens / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology; D054066:Leukemia, Large Granular Lymphocytic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D016827:CD8 Antigens; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor