Downregulation of NFAT3 Due to Lack of T-Box Transcription Factor TBX5 Is Crucial for Cytokine Expression in T Cells
Downregulation of NFAT3 Due to Lack of T-Box Transcription Factor TBX5 Is Crucial for Cytokine Expression in T Cells
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DOI：
10.4049/jimmunol.1602113
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发表时间：
2018-01-01
影响因子：
4.4
通讯作者：
Hiroi, Takachika
中科院分区：
文献类型：
--
作者：
Kaminuma, Osamu;Kitamura, Noriko;Hiroi, Takachika
NFAT家族转录因子在免疫学和其他生物学活动中起着至关重要的作用。NFAT 3很少在T细胞中表达，并且在T细胞中特异性NFAT 3下调的机制和意义一直是未知的。在人CD 4（+）T细胞中，NFAT 1和NFAT 3的过表达分别增强和抑制IL-2的表达。使用RNA干扰技术在Jurkat细胞中下调NFAT 3可增强IL-2的表达，而敲低NFAT 1、NFAT 2和NFAT 4则可抑制IL-2的表达。一项采用NFAT 1/NFAT 3嵌合分子的研究显示，NFAT 3中负责NFAT启动子活性抑制的区域位于其N端反式激活结构域、Ca 2+调节结构域和DNA结合结构域内。与表达内源性NFAT 3的主动脉平滑肌细胞相比，T细胞中NFAT 3表达的下调由其启动子中较低的染色质可及性和增强子活性介导。T-box转录因子TBX 5和NK-2转录因子相关位点5 Nkx2.5在主动脉平滑肌细胞中的表达水平高于T细胞，其结合位点位于2387至+ 97 NFAT 3启动子区域内，表现出最大的增强子活性。TBX 5的结合位点突变而非Nkx2.5的突变降低了NFAT 3启动子的活性，而TBX 5的过表达增强了NFAT 3的活性。TBX 5缺陷介导的NFAT 3的下调对于T细胞的高精氨酸产生活性至关重要。
The NFAT family transcription factors play crucial roles in immunological and other biological activities. NFAT3 is rarely expressed in T cells, and the mechanisms and significance of the specific NFAT3 downregulation in T cells have been unknown. In human CD4(+) T cells, overexpression of NFAT1 and NFAT3 enhanced and suppressed IL-2 expression, respectively. NFAT3 downregulation in Jurkat cells using RNA interference technology augmented IL-2 expression, whereas a knockdown of NFAT1, NFAT2, and NFAT4 suppressed it. The promoter/enhancer activity of the NFAT-binding site in the IL-2 gene was upregulated and downregulated by NFAT1 and NFAT3, respectively. A study employing NFAT1/NFAT3 chimeric molecules revealed that the region in NFAT3 responsible for NFAT promoter activity inhibition was located within its N-terminal transactivation domain, Ca2+-regulatory domain, and DNA-binding domain. Downregulation of NFAT3 expression in T cells is mediated by lower chromatin accessibility and enhancer activity in its promoter in comparison with aortic smooth muscle cells expressing endogenous NFAT3. The binding sites of T-box transcription factor TBX5 and NK-2 transcription factor-related locus 5 Nkx2.5, which were expressed at higher levels in aortic smooth muscle cells than in T cells, were located within the 2387 to + 97 NFAT3 promoter region, exhibiting the maximum enhancer activity. Mutating the binding site of TBX5 but not Nkx2.5 diminished the NFAT3 promoter activity, whereas the overexpression of TBX5 enhanced it. Introduction of TBX5 into CD4(+) T cells enhanced the expression of NFAT3 and suppressed that of IL-2. TBX5 deficiency- mediated downregulation of NFAT3 is crucial for the high cytokine-producing activity of T cells.