Constitutive Nuclear Localization of NFAT in Foxp3+ Regulatory T Cells Independent of Calcineurin Activity
Constitutive Nuclear Localization of NFAT in Foxp3+ Regulatory T Cells Independent of Calcineurin Activity
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DOI：
10.4049/jimmunol.1102376
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发表时间：
2012-05-01
影响因子：
4.4
通讯作者：
Chen, Xinjian
中科院分区：
文献类型：
--
作者：
Li, Qiuxia;Shakya, Arvind;Chen, Xinjian
Foxp 3在赋予CD 4（+）/Foxp 3（+）调节性T细胞（T细胞）抑制功能中起重要作用。虽然研究表明Foxp 3必须与NFAT形成合作复合物才能与靶基因结合，但目前尚不清楚NFAT是否存在于原代胸腺细胞核中以供Foxp 3进入。一般认为，静息细胞中的NFAT位于细胞质中，其核转位依赖于钙调神经磷酸酶（CN）的激活。我们报告说，一部分NFAT蛋白组成性定位于原代Treg的细胞核中，在那里它选择性地结合Foxp 3靶基因。用CN抑制剂处理TCFs不诱导NFAT从细胞核输出，表明其核转位不依赖于CN活性。一致地，在IL-2的存在下，TcB对CN抑制剂具有抗性，并且响应于抗CD 3刺激而继续增殖，而非TcB的增殖被CN抑制剂消除。此外，激活T细胞活化所需的其他转录因子而不是NFAT的PMA在不存在离子霉素的情况下选择性地诱导Treg增殖。PMA诱导的Treg增殖不需要TCR与自身MHC II类相互作用。通过PMA或在CN抑制剂存在下扩增的Treg维持Treg表型和功能性。这些发现揭示了Treg生物学，为选择性激活TcG的策略铺平了道路。免疫学杂志，2012，188：4268-4277。
Foxp3 plays an essential role in conferring suppressive functionality to CD4(+)/Foxp3(+) regulatory T cells (Tregs). Although studies showed that Foxp3 has to form cooperative complexes with NFAT to bind to target genes, it remains unclear whether NFAT is available in the nucleus of primary Tregs for Foxp3 access. It is generally believed that NFAT in resting cells resides in the cytoplasm, and its nuclear translocation depends on calcineurin (CN) activation. We report that a fraction of NFAT protein constitutively localizes in the nucleus of primary Tregs, where it selectively binds to Foxp3 target genes. Treating Tregs with CN inhibitor does not induce export of NFAT from the nucleus, indicating that its nuclear translocation is independent of CN activity. Consistently, Tregs are resistant to CN inhibitors in the presence of IL-2 and continue to proliferate in response to anti-CD3 stimulation, whereas proliferation of non-Tregs is abrogated by CN inhibitors. In addition, PMA, which activates other transcription factors required for T cell activation but not NFAT, selectively induces Treg proliferation in the absence of ionomycin. TCR interaction with self-MHC class II is not required for PMA-induced Treg proliferation. Tregs expanded by PMA or in the presence of CN inhibitors maintain Treg phenotype and functionality. These findings shed light on Treg biology, paving the way for strategies to selectively activate Tregs. The Journal of Immunology, 2012, 188: 4268-4277.