Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis

Jun An, Hiroshi Fujiwara, Koichiro Suemori, Toshiyuki Niiya, Taichi Azuma, Kazushi Tanimoto, Toshiki Ochi, Yoshiki Akatsuka, Junichi Mineno, Hidetoshi Ozawa, Fumihiko Ishikawa, Kiyotaka Kuzushima, Masaki Yasukawa

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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 WT1235-243-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.

Original languageEnglish
Pages (from-to)176-185
Number of pages10
JournalInternational Journal of Hematology
Volume93
Issue number2
DOIs
Publication statusPublished - 01-02-2011

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Peripheral T-Cell Lymphoma
T-Cell Antigen Receptor
Lymphoma
Hemophagocytic Lymphohistiocytosis
Phytohemagglutinins
Exocytosis
Interleukin-2
Monocytes
Phosphorylation
Cell Line

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

An, Jun ; Fujiwara, Hiroshi ; Suemori, Koichiro ; Niiya, Toshiyuki ; Azuma, Taichi ; Tanimoto, Kazushi ; Ochi, Toshiki ; Akatsuka, Yoshiki ; Mineno, Junichi ; Ozawa, Hidetoshi ; Ishikawa, Fumihiko ; Kuzushima, Kiyotaka ; Yasukawa, Masaki. / Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis. In: International Journal of Hematology. 2011 ; Vol. 93, No. 2. pp. 176-185.
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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 WT1235-243-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.",
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An, J, Fujiwara, H, Suemori, K, Niiya, T, Azuma, T, Tanimoto, K, Ochi, T, Akatsuka, Y, Mineno, J, Ozawa, H, Ishikawa, F, Kuzushima, K & Yasukawa, M 2011, 'Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis', International Journal of Hematology, vol. 93, no. 2, pp. 176-185. https://doi.org/10.1007/s12185-010-0758-7

Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis. / An, Jun; Fujiwara, Hiroshi; Suemori, Koichiro; Niiya, Toshiyuki; Azuma, Taichi; Tanimoto, Kazushi; Ochi, Toshiki; Akatsuka, Yoshiki; Mineno, Junichi; Ozawa, Hidetoshi; Ishikawa, Fumihiko; Kuzushima, Kiyotaka; Yasukawa, Masaki.

In: International Journal of Hematology, Vol. 93, No. 2, 01.02.2011, p. 176-185.

Research output: Contribution to journalArticle

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T1 - Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis

AU - An, Jun

AU - Fujiwara, Hiroshi

AU - Suemori, Koichiro

AU - Niiya, Toshiyuki

AU - Azuma, Taichi

AU - Tanimoto, Kazushi

AU - Ochi, Toshiki

AU - Akatsuka, Yoshiki

AU - Mineno, Junichi

AU - Ozawa, Hidetoshi

AU - Ishikawa, Fumihiko

AU - Kuzushima, Kiyotaka

AU - Yasukawa, Masaki

PY - 2011/2/1

Y1 - 2011/2/1

N2 - 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 WT1235-243-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.

AB - 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 WT1235-243-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.

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