NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment
NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment
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DOI：
10.1073/pnas.0403139101
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发表时间：
2004-07-20
影响因子：
11.1
通讯作者：
Ho, SN
中科院分区：
文献类型：
--
作者：
Go, WY;Liu, XB;Ho, SN
渗透应激反应不仅对单细胞生物的生存至关重要，而且对哺乳动物肾脏的正常功能也至关重要。然而，肾外细胞在体内依赖渗透应激反应的程度仍然未知。活化 T 细胞核因子 5 (NFAT5)/张力增强剂结合蛋白 (TonEBP) 是唯一已知的渗透敏感哺乳动物转录因子，在胸腺中表达最丰富，并在淋巴细胞激活时被诱导。在这里，我们报告 NFAT5/TonEBP 不仅对于高渗条件下的正常细胞增殖至关重要，而且对于最佳适应性免疫也是必需的。 Nfat5基因的外显子6和7（编码DNA结合结构域的关键区域）的靶向删除导致纯合状态下功能完全丧失和杂合状态下部分功能丧失。功能完全丧失导致妊娠晚期死亡。此外，高渗诱导的 NFAT5/TonEBP 转录活性和 hsp70.1 启动子功能被完全消除，高渗培养条件下的细胞增殖明显受损。 NFAT5/TonEBP 功能的部分丧失导致活杂合动物中淋巴细胞减少和抗原特异性抗体反应受损。此外，在高渗而非等渗培养条件下，离体淋巴细胞增殖减少。组织渗透压的直接测量进一步揭示淋巴组织是高渗透压的。这些结果表明淋巴细胞介导的免疫取决于对生理渗透应激的适应，从而深入了解淋巴微环境以及 NFAT5/TonEBP 体内渗透应激反应途径的重要性。
Osmotic stress responses are critical not only to the survival of unicellular organisms but also to the normal function of the mammalian kidney. However, the extent to which cells outside the kidney rely on osmotic stress responses in vivo remains unknown. Nuclear factor of activated T cells 5 (NFAT5)/tonicity enhancer binding protein (TonEBP), the only known osmosensitive mammalian transcription factor, is expressed most abundantly in the thymus and is induced upon lymphocyte activation. Here we report that NFAT5/TonEBP is not only essential for normal cell proliferation under hyperosmotic conditions but also necessary for optimal adaptive immunity. Targeted deletion of exons 6 and 7 of the Nfat5 gene, which encode a critical region of the DNA-binding domain, gave rise to a complete loss of function in the homozygous state and a partial loss of function in the heterozygous state. Complete loss of function resulted in late gestational lethality. Furthermore, hypertonicity-induced NFAT5/TonEBP transcriptional activity and hsp70.1 promoter function were completely eliminated, and cell proliferation under hyperosmotic culture conditions was markedly impaired. Partial loss of NFAT5/TonEBP function resulted in lymphoid hypocellularity and impaired antigen-specific antibody responses in viable heterozygous animals. In addition, lymphocyte proliferation ex vivo was reduced under hypertonic, but not isotonic, culture conditions. Direct measurement of tissue osmolality further revealed lymphoid tissues to be hyperosmolar. These results indicate that lymphocyte-mediated immunity is contingent on adaptation to physiologic osmotic stress, thus providing insight into the lymphoid microenvironment and the importance of the NFAT5/TonEBP osmotic stress response pathway in vivo.