Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, Research Triangle Park, NC 27709.
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, U.S. Department of Health and Human Services, Research Triangle Park, NC 27709
J Immunol. 2020 Aug 1;205(3):619-629. doi: 10.4049/jimmunol.1901135. Epub 2020 Jun 22.
Glucocorticoids promote CXCR4 expression by T cells, monocytes, macrophages, and eosinophils, but it is not known if glucocorticoids regulate CXCR4 in B cells. Considering the important contributions of CXCR4 to B cell development and function, we investigated the glucocorticoid/CXCR4 axis in mice. We demonstrate that glucocorticoids upregulate CXCR4 mRNA and protein in mouse B cells. Using a novel strain of mice lacking glucocorticoid receptors (GRs) specifically in B cells, we show that reduced CXCR4 expression associated with GR deficiency results in impaired homing of mature B cells to bone marrow, whereas migration to other lymphoid tissues is independent of B cell GRs. The exchange of mature B cells between blood and bone marrow is sensitive to small, physiologic changes in glucocorticoid activity, as evidenced by the lack of circadian rhythmicity in GR-deficient B cell counts normally associated with diurnal patterns of glucocorticoid secretion. B cell mice mounted normal humoral responses to immunizations with T-dependent and T-independent (Type 1) Ags, but Ab responses to a multivalent T-independent (Type 2) Ag were impaired, a surprise finding considering the immunosuppressive properties commonly attributed to glucocorticoids. We propose that endogenous glucocorticoids regulate a dynamic mode of B cell migration specialized for rapid exchange between bone marrow and blood, perhaps as a means to optimize humoral immunity during diurnal periods of activity.
糖皮质激素通过 T 细胞、单核细胞、巨噬细胞和嗜酸性粒细胞促进 CXCR4 的表达，但尚不清楚糖皮质激素是否调节 B 细胞中的 CXCR4。鉴于 CXCR4 对 B 细胞发育和功能的重要贡献，我们研究了小鼠中的糖皮质激素/CXCR4 轴。我们证明糖皮质激素可上调小鼠 B 细胞中 CXCR4 的 mRNA 和蛋白。使用一种新型缺乏 B 细胞中糖皮质激素受体 (GR) 的小鼠品系，我们表明与 GR 缺乏相关的 CXCR4 表达减少导致成熟 B 细胞向骨髓的归巢受损，而向其他淋巴组织的迁移则不依赖于 B 细胞 GR。成熟 B 细胞在血液和骨髓之间的交换对糖皮质激素活性的微小生理变化敏感，这可以从 GR 缺陷型 B 细胞计数缺乏与糖皮质激素分泌的昼夜节律相关的昼夜节律性中得到证明。B 细胞小鼠对 T 依赖性和 T 非依赖性 (1 型) 抗原的免疫产生正常的体液反应，但对多价 T 非依赖性 (2 型) 抗原的 Ab 反应受损，这是一个令人惊讶的发现，考虑到通常归因于糖皮质激素的免疫抑制特性。我们提出内源性糖皮质激素调节 B 细胞迁移的动态模式，专门用于骨髓和血液之间的快速交换，这也许是在活动的昼夜周期中优化体液免疫的一种手段。
