Satooka Hiroki, Nagakubo Daisuke, Sato Tomomi, Hirata Takako
Department of Fundamental Biosciences, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan; and.
Department of Pediatrics, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
J Immunol. 2017 Nov 15;199(10):3418-3426. doi: 10.4049/jimmunol.1700074. Epub 2017 Oct 4.
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 CD8CD44CD122Ly49 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.
埃兹蛋白-根蛋白-膜突蛋白（ERM）家族是一类膜相关蛋白，它们将膜蛋白与细胞皮层中的肌动蛋白丝相连，并调节许多细胞过程，包括细胞形状确定、膜运输和信号转导。淋巴细胞主要表达两种ERM家族成员，即埃兹蛋白和膜突蛋白。人类膜突蛋白基因的突变与伴有严重淋巴细胞减少的原发性免疫缺陷有关，膜突蛋白缺陷小鼠表现出类似的淋巴细胞减少表型。在本研究中，我们发现衰老的膜突蛋白缺陷小鼠会出现系统性红斑狼疮样自身免疫表型，其特征为血清自身抗体水平升高和肾小球肾炎。年轻的膜突蛋白缺陷小鼠表现出几种免疫球蛋白同种型的基础水平升高，且免疫后抗体亲和力成熟增强。生发中心B细胞和滤泡辅助性T细胞在未免疫小鼠中自发积累，而抑制滤泡辅助性T细胞扩增的CD8CD44CD122Ly49调节性T（CD8 Tregs）细胞在这些小鼠中严重减少。从膜突蛋白缺陷小鼠分离出的CD8 Treg细胞对白细胞介素-15（IL-15）的反应性增殖受损，同时伴有信号转导及转录激活因子5（STAT5）激活和IL-15Rα内化缺陷，这表明膜突蛋白在IL-15介导的信号传导中起关键作用。这些发现强调了膜突蛋白在依赖IL-15的CD8 Treg细胞稳态维持以及自身耐受性控制中的重要性。
