Impaired GATA3-dependent chromatin remodeling and Th2 cell differentiation leading to attenuated allergic airway inflammation in aging mice
Impaired GATA3-dependent chromatin remodeling and Th2 cell differentiation leading to attenuated allergic airway inflammation in aging mice
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DOI：
10.4049/jimmunol.176.4.2546
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发表时间：
2006-02-15
影响因子：
4.4
通讯作者：
Nakayama, T
中科院分区：
文献类型：
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作者：
Hasegawa, A;Miki, T;Nakayama, T
淋巴细胞中与年龄相关的变化在 T 细胞区室中最为突出。关于老年小鼠和人类 T 细胞功能，例如 Th1 和 Th2 细胞因子的产生，已有大量报道，但结果显示出相当大的差异和矛盾。在本研究中，我们使用8至12个月大的衰老小鼠和成熟的体外Th1/Th2细胞分化培养系统来识别可在衰老相对早期阶段检测到的Th1/Th2细胞分化的分子缺陷。衰老小鼠 CD4(+) T 细胞分化为 Th2 细胞的能力降低。在衰老小鼠CD4+T细胞中观察到TCR刺激后ERK MAPK级联的激活减少，但细胞内游离钙离子浓度动员和正常IL-4诱导的STAT6激活正常。此外，在发育中的 Th2 细胞中检测到 GATA3 表达降低。 Th2 细胞因子基因座的染色质重塑被发现受损。与年轻成年小鼠相比，衰老小鼠的 Th2 依赖性过敏性气道炎症较轻。这些结果表明，衰老过程中，由于 ERK MAPK 级联激活、GATA3 蛋白表达和 Th2 细胞因子基因座的 GATA3 依赖性染色质重塑缺陷，Th2 细胞分化水平和由此产生的 Th2 依赖性免疫反应（包括过敏性气道炎症）水平下降。在本研究中，我们提供了第一个证据，表明 T 细胞中的染色质重塑事件因衰老而受损。
Age-related changes in lymphocytes are most prominent in the T cell compartment. There have been substantial numbers of reports on T cell function in aged mice and humans, such as on the production of Th1 and Th2 cytokines, but the results show considerable variation and contradictions. In the present study, we used 8- to 12-mo-old aging mice and a well-established in vitro Th1/Th2 cell differentiation culture system to identify molecular defects in Th1/Th2 cell differentiation that can be detected in the relatively early stages of aging. The capability to differentiate into Th2 cells is reduced in aging mouse CD4(+) T cells. Decreased activation of the ERK MAPK cascade upon TCR stimulation, but normal intracellular-free calcium ion concentration mobilization and normal IL-4-induced STAT6 activation were observed in aging mouse CD4(+) T cells. In addition, reduced expression of GATA3 was detected in developing Th2 cells. Chromatin remodeling of the Th2 cytokine gene locus was found to be impaired. Th2-dependent allergic airway inflammation was milder in aging mice compared with in young adult mice. These results suggest that the levels of Th2 cell differentiation and resulting Th2-dependent immune responses, including allergic airway inflammation, decline during aging through defects in the activation of the ERK MAPK cascade, expression of GATA3 protein and GATA3-dependent chromatin remodeling of the Th2 cytokine gene locus. In the present study, we provide the first evidence indicating that a chromatin-remodeling event in T cells is impaired by aging.