Institute for Biotechnology of Infectious Disease, and Department of Medical and Molecular Biosciences, University of Technology, Sydney.
Blood. 2010 Apr 22;115(16):3258-68. doi: 10.1182/blood-2009-11-255497. Epub 2010 Feb 25.
To delineate the relative roles of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand in lymphocyte biology and lymphoproliferative disease, we generated mice defective in both molecules. B6.GT mice develop severe polyclonal lymphoproliferative disease because of accumulating CD3(+)CD4(-)CD8(-)B220(+) T cells, CD4(+) and CD8(+) T cells, and follicular B cells, and mice die prematurely from extreme lymphocytosis, thrombocytopenia, and hemorrhage. Accumulating lymphocytes resembled antigen-experienced lymphocytes, consistent with the maximal resistance of B6.GT CD4(+) and CD8(+) T cell to activation-induced cell death. More specifically, we show that TRAIL contributes to Fas ligand-mediated activation-induced cell death and controls lymphocyte apoptosis in the presence of interferon-gamma once antigen stimulation is removed. Furthermore, dysregulated lymphocyte homeostasis results in the production of anti-DNA and rheumatoid factor autoantibodies, as well as antiplatelet IgM and IgG causing thrombocytopenia. Thus, B6.GT mice reveal new roles for TRAIL in lymphocyte homeostasis and autoimmune lymphoproliferative syndromes and are a model of spontaneous idiopathic thrombocytopenia purpura secondary to lymphoproliferative disease.
为了阐明肿瘤坏死因子相关凋亡诱导配体（TRAIL）和 Fas 配体在淋巴细胞生物学和淋巴增生性疾病中的相对作用，我们生成了这两种分子均缺失的小鼠。B6.GT 小鼠由于积累了 CD3(+)CD4(-)CD8(-)B220(+)T 细胞、CD4(+)和 CD8(+)T 细胞以及滤泡 B 细胞，因此会发展出严重的多克隆淋巴增生性疾病，并且小鼠会因极度淋巴细胞增多、血小板减少和出血而过早死亡。积累的淋巴细胞类似于抗原经历的淋巴细胞，这与 B6.GT CD4(+)和 CD8(+)T 细胞对激活诱导细胞死亡的最大抗性一致。更具体地说，我们表明 TRAIL 有助于 Fas 配体介导的激活诱导细胞死亡，并在干扰素-γ存在的情况下控制淋巴细胞凋亡，一旦抗原刺激被去除。此外，失调的淋巴细胞稳态导致产生抗 DNA 和类风湿因子自身抗体，以及导致血小板减少症的抗血小板 IgM 和 IgG。因此，B6.GT 小鼠揭示了 TRAIL 在淋巴细胞稳态和自身免疫性淋巴增生性综合征中的新作用，并且是继发于淋巴增生性疾病的自发性特发性血小板减少性紫癜的模型。
