Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection.
Zfat-deficiency results in a loss of CD3ζ phosphorylation with dysregulation of ERK and Egr activities leading to impaired positive selection.
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DOI：
10.1371/journal.pone.0076254
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Shirasawa S
中科院分区：
文献类型：
--
作者：
Ogawa M;Okamura T;Ishikura S;Doi K;Matsuzaki H;Tanaka Y;Ota T;Hayakawa K;Suzuki H;Tsunoda T;Sasazuki T;Shirasawa S
人类ZFAT基因最初被鉴定为自身免疫性甲状腺疾病的易感基因。小鼠 Zfat 是原始造血的关键转录调节因子，也是外周 T 细胞稳态所必需的。然而，其在 T 细胞发育中的生理作用仍知之甚少。在这里，我们生成了 Zfat f/f-LckCre 小鼠，并证明 Zfat f/f-LckCre 小鼠中 T 细胞特异性 Zfat 缺失导致 CD4+CD8+双阳性 (DP) 细胞、CD4+单阳性细胞和 CD8+单阳性细胞数量减少。事实上，在 Zfat f/f-LckCre DP 细胞中，正选择受到严重损害。使用 TCR 转基因小鼠，在外源 TCR 存在的情况下，Zfat 缺陷型胸腺细胞的正选择缺陷并未得到恢复。此外，Zfat缺陷的DP细胞在响应T细胞抗原受体（TCR）刺激时表现出CD3δ磷酸化的丧失，同时伴有细胞外信号相关激酶（ERK）和早期生长反应蛋白（Egr）活性的失调。这些结果表明，Zfat 是正确调节 TCR 近端信号传导所必需的，并且是通过 ERK 和 Egr 活性进行正选择的关键分子，因此表明充分了解 Zfat 的精确分子机制将为 T 细胞发育和免疫调节提供更深入的了解。
The human ZFAT gene was originally identified as a susceptibility gene for autoimmune thyroid disease. Mouse Zfat is a critical transcriptional regulator for primitive hematopoiesis and required for peripheral T cell homeostasis. However, its physiological roles in T cell development remain poorly understood. Here, we generated Zfat f/f-LckCre mice and demonstrated that T cell-specific Zfat-deletion in Zfat f/f-LckCre mice resulted in a reduction in the number of CD4+CD8+double-positive (DP) cells, CD4+single positive cells and CD8+single positive cells. Indeed, in Zfat f/f-LckCre DP cells, positive selection was severely impaired. Defects of positive selection in Zfat-deficient thymocytes were not restored in the presence of the exogenous TCR by using TCR-transgenic mice. Furthermore, Zfat-deficient DP cells showed a loss of CD3ζ phosphorylation in response to T cell antigen receptor (TCR)-stimulation concomitant with dysregulation of extracellular signal-related kinase (ERK) and early growth response protein (Egr) activities. These results demonstrate that Zfat is required for proper regulation of the TCR-proximal signalings, and is a crucial molecule for positive selection through ERK and Egr activities, thus suggesting that a full understanding of the precise molecular mechanisms of Zfat will provide deeper insight into T cell development and immune regulation.
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DOI：
10.4049/jimmunol.181.11.7778
发表时间：
2008-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lauritsen JP;Kurella S;Lee SY;Lefebvre JM;Rhodes M;Alberola-Ila J;Wiest DL
通讯作者：
Wiest DL
影响因子：
56.9
作者：
Lee, KM;Chuang, E;Bluestone, JA
通讯作者：
Bluestone, JA
影响因子：
4.4
作者：
Bettini, M;Xi, HK;Kersh, GJ
通讯作者：
Kersh, GJ
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
64.8
作者：
Anand, Paras K.;Malireddi, R. K. Subbarao;Lukens, John R.;Vogel, Peter;Bertin, John;Lamkanfi, Mohamed;Kanneganti, Thirumala-Devi
通讯作者：
Kanneganti, Thirumala-Devi