title: Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis.
abstract: Peripheral T-cell lymphoma (PTCL) is a biologically diverse lymphoid malignancy. The clinical aggressiveness associated with hemophagocytic syndrome (HS) is a characteristic of PTCL, being more distinctive in CD8(+) PTCL. However, the underlying mechanism of PTCL-associated HS has not yet been fully investigated. We newly established a novel IL-2-dependent CD8(+) PTCL lymphoma cell line (T8ML-1) from a patient with CD8(+) PTCL who suffered recurrent HS accompanying disease flare-up. Focusing on the lymphoma cell T-cell receptor (TCR), we examined the lymphoma cell functions responsible for such clinical manifestations. First, T8ML-1.1 in which endogenous TCR-α/β chains were silenced by siRNAs, and T8ML-1.2 in which endogenous TCR-α/β chains were replaced with HLA-A*24:02-restricted and WT1(235-243)-specific TCR-α/β, were established. T8ML-1 exerted phytohemagglutinin (PHA)-dependent cytotoxicity via granular exocytosis. Additionally, soluble factors produced by PHA-stimulated T8ML-1, which included INF-γ and TNF-α, but not by simple-cultured T8ML-1, caused human monocytes to exhibit erythrophagocytosis and thrombophagocytosis in vitro. PHA binding induced phosphorylation of CD3ζ chain. Furthermore, both cytotoxicity and hemophagocytosis were completely inhibited by T8ML-1.1, but eventually restored by T8ML-1.2. These data suggest that exogenous activation of TCR signaling in PTCL cells might play an important role in the formation of PTCL-associated HS.
authors.affiliation: Department of Bioregulatory Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: An
authors.affiliation: Department of Bioregulatory Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan. yunarief@m.ehime-u.ac.jp.|Department of Cell Growth and Cancer Regulation, Ehime University Proteomedicine Research Center, Shitsukawa, Toon, Ehime, 791-0295, Japan. yunarief@m.ehime-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Department of Bioregulatory Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Suemori
authors.affiliation: Division of Clinical Laboratory, Ehime University Hospital, Toon, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Niiya
authors.affiliation: Department of Bioregulatory Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Azuma
authors.affiliation: Department of Bioregulatory Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Tanimoto
authors.affiliation: Department of Bioregulatory Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Ochi
authors.affiliation: Aichi Cancer Center, Nagoya, Aichi, Japan.|Department of Hematology, Fujita Health University, Toyoake, Aichi, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Akatsuka
authors.affiliation: Takara Bio Inc., Ohtsu, Shiga, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Mineno
authors.affiliation: Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Ozawa
authors.affiliation: Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ishikawa
authors.affiliation: Aichi Cancer Center, Nagoya, Aichi, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Kuzushima
authors.affiliation: Department of Bioregulatory Medicine, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.|Department of Cell Growth and Cancer Regulation, Ehime University Proteomedicine Research Center, Shitsukawa, Toon, Ehime, 791-0295, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
mesh_terms: D001773:Blood Cells / Q000473:pathology*; D045744:Cell Line, Tumor; D057899:Cytophagocytosis; D006801:Humans; D016411:Lymphoma, T-Cell, Peripheral / Q000473:pathology / Q000503:physiopathology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011948:Receptors, Antigen, T-Cell