Lamy T, Liu J H, Landowski T H, Dalton W S, Loughran T P
H. Lee Moffitt Cancer Center and Research Institute, the Veterans's Administration Hospital, University of South Florida Medical School, Tampa, FL, USA.
Blood. 1998 Dec 15;92(12):4771-7.
CD95 (Fas)-induced apoptosis plays a critical role in the elimination of activated lymphocytes and induction of peripheral tolerance. Defects in CD95/CD95L (Fas-Ligand)-apoptotic pathway have been recognized in autoimmune lymphoproliferative diseases (ALPS) and lpr or gld mice and attributed to CD95 and CD95L gene mutations, respectively. Large granular lymphocyte (LGL) leukemia is a chronic disease characterized by a proliferation of antigen-activated cytotoxic T lymphocytes. Autoimmune features such as hypergammaglobulinemia, rheumatoid factor, and circulating immune complexes are common features in LGL leukemia and ALPS. Therefore, we hypothesize that expansion of leukemic LGL may be secondary to a defective CD95 apoptotic pathway. In this study, we investigated expression of CD95 and CD95L in 11 patients with CD3(+) LGL leukemia and explored the apoptotic response to agonistic CD95 monoclonal antibody (MoAb). We found that leukemic LGL from each patient expressed constitutively high levels of CD95/CD95L, similar to those seen in normal activated T cells. However, cells from 9 of these 11 patients were totally resistant to anti-CD95-induced apoptosis. Similarly, cells were resistant to anti-CD3-MoAb-triggered cell death. Lack of anti-CD95-induced apoptosis was not due to mutations in the CD95 antigen. Leukemic LGL were not intrinsically resistant to CD95-dependent death, because LGL from all but 1 patient underwent apoptosis after phytohemagglutinin/interleukin-2 activation. The patient whose leukemic LGL were intrinsically resistant to CD95 had an aggressive form of LGL leukemia that was resistant to combination chemotherapy. These findings that leukemic LGL are resistant to CD95-dependent apoptosis despite expressing high levels of CD95 are similar to observations made in CD95L transgenic mice. These data suggest that LGL leukemia may be a useful model of dysregulated apoptosis causing human malignancy and autoimmune disease.
CD95（Fas）诱导的细胞凋亡在清除活化淋巴细胞和诱导外周耐受中起关键作用。自身免疫性淋巴增殖性疾病（ALPS）以及lpr或gld小鼠中已发现CD95/CD95L（Fas配体）凋亡途径存在缺陷，分别归因于CD95和CD95L基因突变。大颗粒淋巴细胞（LGL）白血病是一种以抗原活化的细胞毒性T淋巴细胞增殖为特征的慢性疾病。高球蛋白血症、类风湿因子和循环免疫复合物等自身免疫特征是LGL白血病和ALPS的常见特征。因此，我们推测白血病性LGL的扩增可能继发于有缺陷的CD95凋亡途径。在本研究中，我们调查了11例CD3（+）LGL白血病患者中CD95和CD95L的表达，并探讨了对激动性CD95单克隆抗体（MoAb）的凋亡反应。我们发现，每位患者的白血病性LGL均组成性高表达CD95/CD95L，类似于正常活化T细胞中的情况。然而，这11例患者中有9例的细胞对抗CD95诱导的细胞凋亡完全耐药。同样，细胞对抗CD3 - MoAb触发的细胞死亡也耐药。抗CD95诱导的细胞凋亡缺失并非由于CD95抗原的突变。白血病性LGL并非固有地对CD95依赖性死亡耐药，因为除1例患者外，所有患者的LGL在植物血凝素/白细胞介素 - 2激活后均发生凋亡。其白血病性LGL对CD95固有耐药的患者患有侵袭性LGL白血病，对联合化疗耐药。这些白血病性LGL尽管高表达CD95但对CD95依赖性凋亡耐药的发现与在CD95L转基因小鼠中的观察结果相似。这些数据表明，LGL白血病可能是凋亡失调导致人类恶性肿瘤和自身免疫性疾病的有用模型。
