The BTG/TOB family protein TIS21 regulates stage-specific proliferation of developing thymocytes
The BTG/TOB family protein TIS21 regulates stage-specific proliferation of developing thymocytes
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DOI：
10.1002/eji.200526345
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发表时间：
2005-10-01
影响因子：
5.4
通讯作者：
Zúñiga-Pflücker, JC
中科院分区：
文献类型：
--
作者：
Konrad, MAP;Zúñiga-Pflücker, JC
随着胸腺细胞在胸腺中进行分化，它们经历静止和增殖的不同阶段。确定维持胸腺细胞处于非分裂状态的细胞机制对于充分理解T细胞发育至关重要。抗增殖蛋白的B细胞易位基因/Erb B-2（BTG/TO B）家族的成员被鉴定为外周无能和未刺激的T细胞中的静止状态的关键介质。在这里，我们证明了BTG/TOB家族成员TPA诱导序列21（TIS 21）在TCR β选择之前在静止的CD 44（+）CD 25（-）早期祖胸腺细胞和CD 44（-）CD 25（+）细胞中表达。然而，在增殖的CD 25（+）CD 44（+）祖胸腺细胞和CD 25（低）CD 44（-）β选择性细胞中，TIS 21表达降低，表明其调节的表达可能使胸腺细胞在没有促有丝分裂信号的情况下保持静止。我们通过在发育中的胸腺细胞和造血祖细胞中异位表达TIS 21来解决TIS 21在调节胸腺细胞阶段特异性扩增中的作用。即使在内源性促有丝分裂信号的存在下，TIS 21的表达失调也会抑制胸腺细胞的扩增，而胸腺细胞的分化则不受阻碍。这些研究结果表明，细胞内机制调节胸腺细胞的分化和增殖，这是诱导下游的发展线索，功能独立的早期T细胞的发展。
As thymocytes undergo differentiation in the thymus, they progress through distinct phases of quiescence and proliferation. Identifying cellular mechanisms that maintain thymocytes in a non-dividing state is critical to fully understand T cell development. A member of the B cell translocation gene/transducer of ErbB-2 (BTG/TOB) family of anti-proliferative proteins was identified as a key mediator of the quiescent state in peripheral anergic and unstimulated T cells. Here, we demonstrate that the BTG/TOB family member TPA-inducible sequence 21 (TIS21) is expressed in quiescent CD44(+)CD25(-) early progenitor thymocytes and CD44(-)CD25(+) cells prior to TCR beta-selection. However, TIS21 expression is decreased in proliferating CD25(+)CD44(+) progenitor thymocytes and CD25(low)CD44(-) beta-selected cells, suggesting that its regulated expression may enable thymocytes to remain quiescent in the absence of mitogenic signals. We addressed the role of TIS21 in regulating thymocyte stage-specific expansion by ectopically expressing TIS21 in developing thymocytes and hematopoietic progenitors. Dysregulated expression of TIS21 inhibited the expansion of thymocytes even in the presence of endogenous mitogenic signals, while thymocyte differentiation was unimpeded. These findings imply that the intracellular mechanisms regulating thymocyte differentiation and proliferation, which are induced downstream of developmental cues, function independently during early T cell development.