Lyn Signaling To Upregulate GANP Is Critical for the Survival of High-Affinity B Cells in Germinal Centers of Lymphoid Organs
Lyn Signaling To Upregulate GANP Is Critical for the Survival of High-Affinity B Cells in Germinal Centers of Lymphoid Organs
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DOI：
10.4049/jimmunol.1200649
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发表时间：
2012-10-01
影响因子：
4.4
通讯作者：
Sakaguchi, Nobuo
中科院分区：
文献类型：
--
作者：
Kuwahara, Kazuhiko;Nakaya, Teruo;Sakaguchi, Nobuo
通过BCR和共刺激分子的信号在外周淋巴器官的生发中心（GC）中选择具有IG V区突变的高亲和力B细胞中起重要作用。Lyn-deficient（林恩（-/-））小鼠表现出受损的BCR信号触发细胞增殖和GC形成，引起高IgM，并在衰老后表现出自身免疫。在这项研究中，我们证明，林恩介导的信号上调GANP是必不可少的成熟GC样（mGC）B细胞的生存与高亲和力型BCR突变后，抗原免疫。转基因ganp表达入林恩（-/-）小鼠在用硝基苯基鸡γ-球蛋白免疫后，在B细胞分化、血清Ig和脾中受损的GC形成方面没有恢复Lyn-deficient表型，但它通过抑制DNA损伤显著挽救了mGC B细胞的细胞存活，从而增加IgV（H）-186.2区域中Trp（33）-至-Leu突变的频率和硝基苯结合B细胞的亲和力成熟。GANP可能在淋巴细胞介导的外周淋巴器官高亲和力B细胞选择信号中起关键作用。免疫学杂志，2012，189：3472-3479。
Signals through BCR and costimulatory molecules play essential roles in selecting high-affinity B cells with Ig V-region mutations in the germinal centers (GCs) of peripheral lymphoid organs. Lyn-deficient (lyn(-/-)) mice show impaired BCR signal triggering for cell proliferation and GC formation, causing hyper-IgM, and display autoimmunity after aging. In this study, we demonstrate that Lyn-mediated signaling to upregulate GANP is essential for the survival of mature GC-like (mGC) B cells with high-affinity type BCR mutations upon Ag immunization. Transgenic ganp expression into lyn(-/-) mice did not recover the Lyn-deficient phenotype with regard to B cell differentiation, serum Igs, and impaired GC formation in spleens after immunization with nitrophenylchicken gamma-globulin, but it markedly rescued cell survival of mGC B cells by suppressing DNA damage, thereby increasing the frequency of the Trp(33)-to-Leu mutation in the IgV(H)-186.2 region and affinity maturation of nitrophenyl-binding B cells. GANP may play a critical role in Lyn-mediated signaling for the selection of high-affinity B cells in peripheral lymphoid organs. The Journal of Immunology, 2012, 189: 3472-3479.