In antibody responses, mutated germinal center B (B GC ) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of B GC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (T FH ) cell–derived signals, in particular costimulation through CD40. Here, we demonstrate that the T FH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting B GC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. B GC cells, compared with non-B GC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)–mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in B GC cells and up-regulated in ASC precursors, suggesting selective desensitization to IL-21 in B GC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.

中文翻译：

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硫酸乙酰肝素调节控制生发中心 B 细胞选择和分化的 IL-21 生物利用度和信号强度

在抗体反应中，突变的生发中心 B (BGC) 细胞被积极选择用于再进入或分化。作为 GCs 的产物，记忆 B 细胞和抗体分泌细胞 (ASCs) 支持高亲和力和持久的免疫力。正选BGC细胞受 B 细胞受体 (BCR) 和滤泡辅助 T (T跳频) 细胞衍生信号，特别是通过 CD40 的共刺激。在这里，我们证明了 T跳频细胞效应细胞因子白细胞介素 21 (IL-21) 与 BCR 和 CD40 一起支持 BGC选择并揭示强 IL-21 信号传导优先考虑体内 ASC 分化。乙GC细胞，与非B相比GC细胞，显示出显着降低的 IL-21 结合和减弱的信号传导，这是由低细胞硫酸乙酰肝素 (HS) 硫酸化介导的。从机制上讲，N-脱乙酰酶和 N-磺基转移酶 1 (Ndst1) 介导的 B 细胞中 HS 的 N-硫酸化可促进 IL-21 结合和信号强度。Ndst1 在 B 中下调GC细胞并在 ASC 前体中上调，表明 B 中对 IL-21 的选择性脱敏GC细胞。因此，IL-21 生物利用度和信号强度的专门生化调节在 GC 选择的严格性和效率之间建立了平衡。