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N-Glycan Branching Is Required for Development of Mature B Cells
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-26 , DOI: 10.4049/jimmunol.2000101
Christie-Lynn Mortales 1 , Sung-Uk Lee 2 , Michael Demetriou 2, 3
Affiliation  

Key Points N-glycan branching is required for generation of mature B cells. N-glycan branching inhibits development of pre-, immature, and T2 B cells. N-glycan branching promotes CD19 surface expression to inhibit death by neglect. Galectins have been implicated in inhibiting BCR signaling in mature B cells but promoting pre-BCR signaling during early development. Galectins bind to branched N-glycans attached to cell surface glycoproteins to control the distribution, clustering, endocytosis, and signaling of surface glycoproteins. During T cell development, N-glycan branching is required for positive selection of thymocytes, inhibiting both death by neglect and negative selection via enhanced surface retention of the CD4/CD8 coreceptors and limiting TCR clustering/signaling, respectively. The role of N-glycan branching in B cell development is unknown. In this study, we report that N-glycan branching is absolutely required for development of mature B cells in mice. Elimination of branched N-glycans in developing B cells via targeted deletion of N-acetylglucosaminyl transferase I (Mgat1) markedly reduced cellularity in the bone marrow and/or spleen and inhibited maturation of pre-, immature, and transitional stage 2 B cells. Branching deficiency markedly reduced surface expression of the pre-BCR/BCR coreceptor CD19 and promoted spontaneous death of pre-B cells and immature B cells in vitro. Death was rescued by low-dose pre-BCR/BCR stimulation but exacerbated by high-dose pre-BCR/BCR stimulation as well as antiapoptotic BclxL overexpression in pre-B cells. Branching deficiency also enhanced Nur77 induction, a marker of negative selection. Together, these data suggest that, as in T cells, N-glycan branching promotes positive selection of B cells by augmenting pre-BCR/BCR signaling via CD19 surface retention, whereas limiting negative selection from excessive BCR engagement.

中文翻译:

N-聚糖分支是成熟 B 细胞发育所必需的

关键点 N-聚糖分支是成熟 B 细胞生成所必需的。N-聚糖分支抑制前、未成熟和 T2 B 细胞的发育。N-聚糖分支促进 CD19 表面表达以抑制因忽视而死亡。半乳糖凝集素参与抑制成熟 B 细胞中的 BCR 信号传导,但在早期发育过程中促进前 BCR 信号传导。半乳糖凝集素与附着在细胞表面糖蛋白上的分支 N-聚糖结合,以控制表面糖蛋白的分布、聚集、内吞作用和信号传导。在 T 细胞发育期间,胸腺细胞的正选择需要 N-聚糖分支,分别通过增强 CD4/CD8 辅助受体的表面保留和限制 TCR 聚集/信号传导来抑制因忽视和负选择而导致的死亡。N-聚糖分支在 B 细胞发育中的作用尚不清楚。在这项研究中,我们报告了 N-聚糖分支对于小鼠成熟 B 细胞的发育是绝对需要的。通过靶向缺失 N-乙酰葡糖胺基转移酶 I (Mgat1) 在发育中的 B 细胞中消除分支 N-聚糖显着降低了骨髓和/或脾脏中的细胞结构,并抑制了前、未成熟和过渡期 2 B 细胞的成熟。分支缺陷显着降低了前 BCR/BCR 辅助受体 CD19 的表面表达,并促进了体外前 B 细胞和未成熟 B 细胞的自发死亡。低剂量 pre-BCR/BCR 刺激挽救了死亡,但高剂量 pre-BCR/BCR 刺激以及 pre-B 细胞中的抗凋亡 BclxL 过度表达加剧了死亡。分枝缺陷也增强了 Nur77 诱导,负选择的标志。总之,这些数据表明,与在 T 细胞中一样,N-聚糖分支通过 CD19 表面保留增强前 BCR/BCR 信号,促进 B 细胞的正选择,同时限制过度 BCR 参与的负选择。
更新日期:2020-06-26
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