Successive expression and activation of NFAT family members during thymocyte differentiation
Successive expression and activation of NFAT family members during thymocyte differentiation
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DOI：
10.1074/jbc.275.19.14708
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发表时间：
2000-05-12
影响因子：
4.8
通讯作者：
Iwata, M
中科院分区：
文献类型：
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作者：
Adachi, S;Amasaki, Y;Iwata, M
未成熟的CD 4（+）CD 8（+）胸腺细胞向成熟的CD 4（+）或CD 8（+）T细胞的分化是由阳性选择诱导的，并且似乎涉及钙调神经磷酸酶依赖的NFAT（转录因子家族）活化。NFATx主要在CD 4（+）CD 8（+）胸腺细胞中表达，而NFATp和NFATc在胸腺中的表达水平远低于成熟T细胞。然而，每个NFAT成员如何或何时参与分化途径尚不清楚。使用体外模型系统，分离的CD 4（+）CD 8（+）胸腺细胞可以存活并分化为半成熟的CD 4-谱系T细胞，我们认为，低钙调磷酸酶活性持续约20小时是细胞存活和分化所必需的。相应地，NFAT的DNA结合活性在刺激20 h诱导分化期间缓慢增加。NFATx显著促进了早期升高，但晚期升高主要是由于NFATc激活。同时，NFATx mRNA表达下降，NFATc mRNA表达升高。NFATp的DNA结合活性是可检测的，但在整个刺激过程中很低。在半成熟T细胞分化为成熟和活化的CD 4 T细胞后，NFATp变得占主导地位。这些发现表明，NFATx和NFATc相继在T细胞发育中发挥作用。
Differentiation of immature CD4(+)CD8(+) thymocytes to mature CD4(+) or CD8(+) T cells is induced by positive selection and appears to involve calcineurin-dependent activation of NFAT, a family of transcription factors. NFATx is predominantly expressed in CD4(+)CD8(+) thymocytes, whereas NFATp and NFATc are expressed at much lower levels in the thymus than in mature T cells. However, how or when each NFAT member is involved in the differentiation pathway is unclear. Using an in vitro model system where isolated CD4(+)CD8(+) thymocytes can survive and differentiate into semi-mature CD4-lineage T cells, we suggest that low calcineurin activity sustained for approximately 20 h is required for cell survival and differentiation. Accordingly, the DNA binding activity of NFAT slowly increased during the stimulation of 20 h to induce the differentiation. NFATx significantly contributed to the early rise, but the late increase was mostly due to NFATc activation. Meanwhile, the expression of NFATx mRNA decreased and that of NFATc mRNA increased. The DNA-binding activity of NFATp was detectable but low throughout the stimulation. NFATp became dominantly active after the semi-mature T cells differentiated into mature and activated CD4 T cells. These findings suggest that NFATx and NFATc successively play roles in T cell development.