Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Exp Med. 2010 May 10;207(5):1113-24. doi: 10.1084/jem.20092210. Epub 2010 Apr 19.
S1P1 receptor expression is required for the egress of newly formed T cells from the thymus and exit of mature T and B cells from secondary lymphoid organs. In this study, we deleted the expression of the S1P1 receptor gene (S1pr1) in developing B cells in the bone marrow. Although B cell maturation within the bone marrow was largely normal in the B cell-specific S1pr1 knockout (B-S1pr1KO) mice, their newly generated immature B cells appeared in the blood at abnormally low numbers as compared with control mice. In the bone marrow of B-S1pr1KO mice, immature B cells in contact with the vascular compartment displayed increased apoptosis as compared with control mice. Forced expression of CD69, a negative regulator of S1P1 receptor expression, in developing bone marrow B cells also reduced the number of immature B cells in the blood. Attenuation of CXCR4 signaling, which is required for the proper retention of developing B cells in bone marrow, did not release immature B cells into the blood of B-S1pr1KO mice as effectively as in control mice. Our results indicate that the S1P1 receptor provides a signal necessary for the efficient transfer of newly generated immature B cells from the bone marrow to the blood.
S1P1 受体表达对于新形成的 T 细胞从胸腺中迁出以及成熟的 T 和 B 细胞从次级淋巴器官中迁出是必需的。在这项研究中，我们在骨髓中的发育 B 细胞中删除了 S1P1 受体基因（S1pr1）的表达。尽管 B 细胞特异性 S1pr1 敲除（B-S1pr1KO）小鼠中的 B 细胞在骨髓中的成熟过程基本正常，但与对照小鼠相比，其新生成的未成熟 B 细胞在血液中的数量异常低。在 B-S1pr1KO 小鼠的骨髓中，与血管腔接触的未成熟 B 细胞与对照小鼠相比凋亡增加。在发育中的骨髓 B 细胞中强制表达 CD69，S1P1 受体表达的负调节剂，也会减少血液中未成熟 B 细胞的数量。减弱 CXCR4 信号传导，这是适当保留骨髓中发育中的 B 细胞所必需的，并没有像对照小鼠那样有效地将未成熟 B 细胞从 B-S1pr1KO 小鼠的血液中释放出来。我们的结果表明，S1P1 受体提供了一个信号，对于从骨髓中有效转移新生成的未成熟 B 细胞到血液中是必需的。
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