Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis
Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis
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DOI：
10.1007/s12185-010-0758-7
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发表时间：
2011-02-01
影响因子：
2.1
通讯作者：
Yasukawa, Masaki
中科院分区：
文献类型：
--
作者：
An, Jun;Fujiwara, Hiroshi;Yasukawa, Masaki
外周T细胞淋巴瘤(PTCL)是一种生物多样性的淋巴系统恶性肿瘤。与噬血细胞综合征(HS)相关的临床侵袭性是PTCL的一个特征，在CD8(+)PTCL中更为明显。然而，PTCL相关HS的潜在机制尚未得到充分的研究。我们新建立了一种新的IL-2依赖的CD8(+)PTCL淋巴瘤细胞系(T8ML-1)，该细胞系来源于一例复发的HS伴发疾病的CD8(+)PTCL患者。聚焦于淋巴瘤细胞T细胞受体(TCR)，我们检测了导致这种临床表现的淋巴瘤细胞功能。首先，建立了T8ML-1.1和T8ML-1.2，T8ML-1.1内源性TCR-α/β链被SIR-Nas沉默，T8ML-1.2内源性TCR-α/β链被HLA-A*24：02限制性和WT1(235-243)特异性TCR-α/β取代。T8ML-1通过颗粒胞吐作用发挥植物血凝素(PHA)依赖的细胞毒作用。此外，由PHA刺激的T8ML-1产生的可溶性因子，包括干扰素-γ和肿瘤坏死因子-α，但不是由简单培养的T8ML-1产生的，在体外可导致人单核细胞表现出红细胞吞噬和血小板吞噬功能。PHA结合诱导CD3 Zeta链磷酸化。此外，T8ML-1.1完全抑制细胞毒性和吞噬血细胞功能，但最终被T8ML-1.2恢复。这些结果提示，PTCL细胞中TCR信号的外源性激活可能在PTCL相关HS的形成中起重要作用。
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-alpha/beta chains were silenced by siR-NAs, and T8ML-1.2 in which endogenous TCR-alpha/beta chains were replaced with HLA-A*24:02-restricted and WT1(235-243)-specific TCR-alpha/beta, were established. T8ML-1 exerted phytohemagglutinin (PHA)-dependent cytotoxicity via granular exocytosis. Additionally, soluble factors produced by PHA-stimulated T8ML-1, which included INF-gamma and TNF-alpha, but not by simple-cultured T8ML-1, caused human monocytes to exhibit erythrophagocytosis and thrombophagocytosis in vitro. PHA binding induced phosphorylation of CD3 zeta 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.