Cytoskeletal protein 4.1R negatively regulates T-cell activation by inhibiting the phosphorylation of LAT
Cytoskeletal protein 4.1R negatively regulates T-cell activation by inhibiting the phosphorylation of LAT
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DOI：
10.1182/blood-2008-10-182329
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发表时间：
2009-06-11
期刊：
影响因子：
20.3
通讯作者：
An, Xiuli
中科院分区：
文献类型：
--
作者：
Kang, Qiaozhen;Yu, Yu;An, Xiuli
蛋白4.1R（4.1R）首先在红细胞中被鉴定，在维持红细胞膜的机械稳定性中起重要作用。4.1R也被证明在T细胞中表达，但其功能尚不清楚。在本研究中，我们使用4.1R缺陷小鼠来探索4.1R在T细胞中的作用。我们发现，4.1R被招募到免疫突触后T细胞抗原受体（TCR）刺激。我们进一步表明，4.1R（-/）-小鼠的CD 4（+）T细胞被过度激活，它们表现出过度增殖和白细胞介素-2（IL-2）和干扰素γ（IFN γ）的产生增加。这种过度活化是由于LAT及其下游信号分子ERK磷酸化增强所致。4.1R通过直接结合LAT发挥作用，从而抑制ZAP-70对其的磷酸化。此外，4.1R缺陷的小鼠显示对T细胞依赖性抗原免疫的体液应答升高。因此，我们已经确定了一个迄今尚未认识的作用，4.1R在负调节T细胞活化，通过调节细胞内信号转导。（血。2009; 113：6128-6137）
Protein 4.1R (4.1R) was first identified in red cells where it plays an important role in maintaining mechanical stability of red cell membrane. 4.1R has also been shown to be expressed in T cells, but its function has been unclear. In the present study, we use 4.1R-deficient mice to explore the role of 4.1R in T cells. We show that 4.1R is recruited to the immunologic synapse after T cell-antigen receptor (TCR) stimulation. We show further that CD4(+) T cells of 4.1R(-/)-mice are hyperactivated and that they displayed hyperproliferation and increased production of interleukin-2 (IL-2) and interferon gamma (IFN gamma). The hyperactivation results from enhanced phosphorylation of LAT and its downstream signaling molecule ERK. The 4.1R exerts its effect by binding directly to LAT, and thereby inhibiting its phosphorylation by ZAP-70. Moreover, mice deficient in 4.1R display an elevated humoral response to immunization with T cell-dependent antigen. Thus, we have defined a hitherto unrecognized role for 4.1R in negatively regulating T-cell activation by modulating intracellular signal transduction. (Blood. 2009; 113: 6128-6137)