The ERM Protein Moesin Regulates CD8+ Regulatory T Cell Homeostasis and Self-Tolerance
The ERM Protein Moesin Regulates CD8+ Regulatory T Cell Homeostasis and Self-Tolerance
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DOI：
10.4049/jimmunol.1700074
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发表时间：
2017-11
期刊：
影响因子：
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通讯作者：
Hiroki Satooka;D. Nagakubo;Tomomi Sato;T. Hirata
中科院分区：
文献类型：
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作者：
Hiroki Satooka;D. Nagakubo;Tomomi Sato;T. Hirata
ERM （ezrin-radixin-moesin）蛋白是一个膜相关蛋白家族，它将膜蛋白与细胞皮层的肌动蛋白丝连接起来，并调节许多细胞过程，包括细胞形状决定、膜运输和信号转导。淋巴细胞主要表达两种ERM成员，ezrin和moesin。人类moesin基因的突变与原发性免疫缺陷与深度淋巴细胞减少有关，moesin缺陷小鼠表现出类似的淋巴细胞减少表型。在这项研究中，我们发现衰老moesin缺陷小鼠产生系统性红斑狼疮样自身免疫表型，其特征是血清自身抗体水平升高和肾小球肾炎。年轻的moesin缺陷小鼠在免疫后表现出几种Ig同种型的基础水平升高和Ab亲和力成熟增强。生发中心B细胞和滤泡辅助性T细胞在未免疫小鼠体内自发积累，抑制滤泡辅助性T细胞扩增的CD8+CD44+CD122+Ly49+调节性T细胞（CD8+ Tregs）在未免疫小鼠体内严重减少。moesin缺失小鼠的CD8+ Treg细胞在IL-15作用下增殖受损，同时伴有STAT5激活和IL-15Rα内化缺陷，提示moesin在IL-15介导的信号传导中起关键作用。这些发现强调了moesin在il -15依赖性CD8+ Treg细胞稳态中的重要性，从而控制了自我耐受。
The ezrin–radixin–moesin (ERM) proteins are a family of membrane-associated proteins that link membrane proteins with actin filaments in the cell cortex and regulate many cellular processes, including cell shape determination, membrane transport, and signal transduction. Lymphocytes predominantly express two ERM members, ezrin and moesin. Mutations in the moesin gene in humans are associated with primary immunodeficiency with profound lymphopenia, and moesin-deficient mice exhibit a similar lymphopenia phenotype. In this study, we show that aging moesin-deficient mice develop a systemic lupus erythematosus–like autoimmune phenotype, which is characterized by elevated serum autoantibody levels and glomerulonephritis. Younger moesin-deficient mice exhibited elevated basal levels of several Ig isotypes and enhanced Ab affinity maturation upon immunization. Germinal center B cells and follicular helper T cells spontaneously accumulated in unimmunized mice, and CD8+CD44+CD122+Ly49+ regulatory T (CD8+ Tregs) cells, which inhibit the expansion of follicular helper T cells, were severely reduced in these mice. Isolated CD8+ Treg cells from moesin-deficient mice showed impaired proliferation in response to IL-15, which was accompanied by defects in STAT5 activation and IL-15Rα internalization, suggesting that moesin plays a key role in IL-15–mediated signaling. These findings underscore the importance of moesin in IL-15–dependent CD8+ Treg cell homeostasis and, thus, the control of self-tolerance.