Loss of T cell receptor-induced Bmi-1 in the KLRG1+ senescent CD8+ T lymphocyte
Loss of T cell receptor-induced Bmi-1 in the KLRG1+ senescent CD8+ T lymphocyte
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DOI：
10.1073/pnas.0706040104
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发表时间：
2007-08-14
影响因子：
11.1
通讯作者：
Fearon, Douglas T.
中科院分区：
文献类型：
--
作者：
Heffner, Maike;Fearon, Douglas T.
对病毒抗原特异的CD 8（+）T细胞克隆必须避免复制性衰老，以在慢性病毒感染期间维持新效应细胞的持续产生。在本研究中，我们已经确定了这种能力是否可能与Bmi-1有关，一种转录抑制物，维持造血干细胞和某些神经干细胞所需，通过抑制lnk 4a/Arf肿瘤抑制基因座的转录。T细胞受体的连接增加了原代CD 8（+）T细胞中Bmi-1 mRNA和蛋白的水平。增加的表达在去除抗原后是可逆的，但可以通过使用IL-2受体刺激来维持。通过使用慢病毒编码的短发夹RNA特异性抑制Bmi-1抑制IL-2刺激的CTLL-2细胞毒性T细胞和原代CD 8（+）T细胞的增殖。异位表达的Bmi-1在体外增强了IL-2和IL-7刺激的原代CD 8（+）T细胞的扩增，在体内增强了稳态信号刺激的原代CD 8（+）T细胞的扩增。综上所述，这些发现表明Bmi-1是CD 8（+）T细胞克隆扩增所必需的，并且受到介导这种反应的受体的正调控。因此，观察到T细胞受体诱导Bmi-1的能力在具有复制能力的、经历抗原的CD 8（+）T细胞亚群中得以维持，所述CD 8（+）T细胞不表达杀伤细胞凝集素样受体G1（KLRG 1），但在衰老过程中发育关闭，KLRG 1+亚群表明Bmi-1是CD 8（+）T细胞克隆在慢性病毒感染期间持续存在的能力的分子决定因素。
Clones of CD8(+) T cells specific for viral antigens must avoid replicative senescence to maintain continuous production of new effector cells during chronic viral infections in the present study, we have determined whether this capability may be related to Bmi-1, a transcriptional repressor that is required for the maintenance of hematopoietic stem cells and certain neural stem cells and that mediates its antisenescence function by inhibiting transcription of the lnk4a/Arf tumor suppressor locus. Ligation of the T cell receptor increased the levels of Bmi-1 mRNA and protein in primary CD8(+) T cells. The increased expression was reversible upon removal of antigen but could be maintained by using stimulation with the IL-2 receptor. Specific suppression of Bmi-1 by using a lentivirally encoded short hairpin RNA inhibited the proliferation of IL-2-stimulated CTLL-2 cytotoxic T cells and primary CD8(+) T cells. Ectopically expressed Bmi-1 enhanced the expansion of primary CD8(+) T cells stimulated by IL-2 and IL-7 in vitro and by homeostatic signals in vivo. Taken together, these findings indicate that Bmi-1 is required for CD8(+) T cell clonal expansion and is positively regulated by receptors that mediate this response. Therefore, the observation that the ability of the T cell receptor to induce Bmi-1 is maintained in the subset of replication-competent, antigenexperienced CD8(+) T cells that do not express the killer cell lectin-like receptor G1 (KLRG1) but is developmentally switched off in the senescent, KLRG1+ subset suggests that Bmi-1 is a molecular determinant of the capacity of a CD8(+) T cell clone to persist during chronic viral infections.