Phosphoinositide 3-Kinase p110δ Regulates Natural Antibody Production, Marginal Zone and B-1 B Cell Function, and Autoantibody Responses
Phosphoinositide 3-Kinase p110δ Regulates Natural Antibody Production, Marginal Zone and B-1 B Cell Function, and Autoantibody Responses
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DOI：
10.4049/jimmunol.0900432
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发表时间：
2009-11-01
影响因子：
4.4
通讯作者：
Gold, Michael R.
中科院分区：
文献类型：
--
作者：
Durand, Caylib A.;Hartvigsen, Karsten;Gold, Michael R.
B-1和边缘区（MZ）B细胞产生天然抗体，对微生物病原体产生抗体应答，并促进自身免疫。尽管PI 3 K p110催化亚基的δ同种型对于这些先天样B细胞的发育是必需的，但其在正常B-1和MZ B细胞的定位、活化和功能中的作用尚不清楚。使用IC 87114，一种高度选择性的p110 delta酶活性抑制剂，我们发现p110 delta对于小鼠B-1和MZ B细胞对BCR聚集、TLR配体LPS和CpG DNA以及趋化剂CXCL 13和1-磷酸鞘氨醇的反应是重要的。在这些先天样B细胞中，p110 δ活性介导BCR、TLR和趋化因子诱导的Akt促生存激酶活化、趋化因子诱导的迁移和TLR诱导的增殖。此外，我们发现，TLR刺激的抗体反应的B-1和MZ B细胞，以及MZ B细胞在脾脏中的定位，依赖于p110 δ活性。最后，我们表明，在体内生产的天然抗体需要p110 δ和p110 δ抑制剂可以减少体内自身抗体反应。因此，靶向p110 δ可能是调节先天性B细胞和治疗Ab介导的自身免疫性疾病的新方法。免疫学杂志，2009，183：5673-5684.
B-1 and marginal zone (MZ) B cells produce natural Abs, make Ab responses to microbial pathogens, and contribute to autoimmunity. Although the delta isoform of the PI3K p110 catalytic subunit is essential for development of these innate-like B cells, its role in the localization, activation, and function of normal B-1 and MZ B cells is not known. Using IC87114, a highly selective inhibitor of p110 delta enzymatic activity, we show that p110 delta is important for murine B-1 and MZ B cells to respond to BCR clustering, the TLR ligands LPS and CpG DNA, and the chemoattractants CXCL13 and sphingosine 1-phosphate. In these innate-like B cells, p110 delta activity mediates BCR-, TLR- and chemoattractant-induced activation of the Akt prosurvival kinase, chemoattractant-induced migration, and TLR-induced proliferation. Moreover, we found that TLR-stimulated Ab responses by B-1 and MZ B cells, as well as the localization of MZ B cells in the spleen, depend on p110 delta activity. Finally, we show that the in vivo production of natural Abs requires p110 delta and that p110 delta inhibitors can reduce in vivo autoantibody responses. Thus, targeting p110 delta may be a novel approach for regulating innate-like B cells and for treating Ab-mediated autoimmune diseases. The Journal of Immunology, 2009, 183: 5673-5684.