Enhanced NFATc1 nuclear occupancy causes T cell activation independent of CD28 costimulation
Enhanced NFATc1 nuclear occupancy causes T cell activation independent of CD28 costimulation
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DOI：
10.4049/jimmunol.178.7.4315
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发表时间：
2007-04-01
影响因子：
4.4
通讯作者：
Crabtree, Gerald R.
中科院分区：
文献类型：
--
作者：
Pan, Minggui;Winslow, Monte M.;Crabtree, Gerald R.
TCR信号诱导NFATc蛋白的核定位，NFATc蛋白被糖原合成酶激酶3和其他激酶再磷酸化后从细胞核中移除。快速核输出可能允许持续监测受体占用，使转录反应与TCR/CD28信号传导的持续时间成正比。为了研究这种可能性，我们分析了T细胞表达NFATc1变体（NFATc1(nuc)）的小鼠，在糖原合成酶激酶3磷酸化位点发生丝氨酸到丙氨酸的变化。NFATc1(nuc) T细胞在体内具有组成核NFATc1，增强的T细胞活化，在体外具有不依赖钙调磷酸酶的增殖。NFATc1(nuc) T细胞对TCR/CD3刺激超敏感，导致增殖和细胞因子产生增强，而不依赖于CD28共刺激。这些结果支持了CD28抑制NFATc转录因子核输出的观点。此外，NFATc1（nuc）破坏了一个正反馈环的稳定性，在这个正反馈环中，NFATc1激活其自身的转录以及它的靶标，如CD40配体和Th1/Th2细胞因子。
TCR signals induce the nuclear localization of NFATc proteins, which are removed from the nucleus after rephosphorylation by glycogen synthase kinase 3 and other kinases. Rapid nuclear export might allow continuous monitoring of receptor occupancy, making the transcriptional response proportional to the duration of TCR/CD28 signaling. To investigate this possibility, we analyzed mice in which T cells express a NFATc1 variant (NFATc1(nuc)) with serine-to-alanine changes at the glycogen synthase kinase 3 phosphorylation sites. NFATc1(nuc) T cells have constitutively nuclear NFATc1, enhanced T cell activation in vivo, and calcineurin-independent proliferation in vitro. NFATc1(nuc) T cells are hypersensitive to TCR/CD3 stimulation, resulting in enhanced proliferation and cytokine production that is independent of CD28 costimulation. These results support the notion that CD28 inhibits nuclear export of NFATc transcription factors. In addition, NFATc1(nuc) destabilizes a positive feedback loop in which NFATc1 activates its own transcription as well as its targets, such as CD40 ligand and Th1/Th2 cytokines.