Key Points BAFF-silenced DCs exhibited an immature and tolerogenic phenotype. BAFF-silenced DCs alleviated mouse CIA by modulating the Th17/Treg balance. BAFF might be a promising genetic target to generate tolDCs for RA treatment. Tolerogenic dendritic cells (tolDCs) have received much attention because of their capacity to restore immune homeostasis. RNA interference techniques have been used in several studies to generate tolDCs by inactivating certain molecules that regulate DC maturation and immunologic function. BAFF is a key B cell survival factor that is not only essential for B cell function but also T cell costimulation, and DCs are the major source of BAFF. In this study, we determined whether BAFF gene silencing in mature DCs could lead to a tolerogenic phenotype as well as the potential therapeutic effect of BAFF-silenced DCs on collagen-induced arthritis (CIA) in mice. Meanwhile, CRISPR/Cas9-mediated BAFF−/− DC2.4 cells were generated to verify the role of BAFF in DC maturation and functionality. BAFF-silenced DCs and BAFF−/− DC2.4 cells exhibited an immature phenotype and functional state. Further, the transplantation of BAFF-silenced DCs significantly alleviated CIA severity in mice, which correlated with a reduction in Th17 populations and increased regulatory T cells. In vitro, BAFF-silenced DCs promoted Foxp3 mRNA and IL-10 expression but inhibited ROR-γt mRNA and IL-17A expression in CD4+ T cells. Together, BAFF-silenced DCs can alleviate CIA, partly by inducing Foxp3+ regulatory T cells and suppressing Th17 subsets. Collectively, BAFF plays an important role in interactions between DCs and T cells, which might be a promising genetic target to generate tolDCs for autoimmune arthritis treatment.

中文翻译：

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BAFF 产生的致耐受性树突细胞通过调节 Th17/调节性 T 细胞平衡来抑制胶原诱导的关节炎

关键点 BAFF 沉默的 DCs 表现出不成熟和耐受性的表型。BAFF 沉默的 DCs 通过调节 Th17/Treg 平衡减轻小鼠 CIA。BAFF 可能是产生用于 RA 治疗的 tolDC 的有希望的遗传靶点。致耐受性树突状细胞 (tolDC) 因其恢复免疫稳态的能力而备受关注。RNA 干扰技术已用于多项研究，通过灭活某些调节 DC 成熟和免疫功能的分子来产生 tolDC。BAFF 是关键的 B 细胞存活因子，不仅对 B 细胞功能而且对 T 细胞共刺激至关重要，DC 是 BAFF 的主要来源。在这项研究中，我们确定了成熟 DC 中的 BAFF 基因沉默是否会导致耐受性表型以及 BAFF 沉默的 DC 对小鼠胶原诱导性关节炎 (CIA) 的潜在治疗作用。同时，生成 CRISPR/Cas9 介导的 BAFF-/- DC2.4 细胞以验证 BAFF 在 DC 成熟和功能中的作用。BAFF 沉默的 DC 和 BAFF-/- DC2.4 细胞表现出未成熟的表型和功能状态。此外，BAFF 沉默的 DC 的移植显着减轻了小鼠的 CIA 严重程度，这与 Th17 种群的减少和调节性 T 细胞的增加有关。在体外，BAFF 沉默的 DCs 促进 Foxp3 mRNA 和 IL-10 表达，但抑制 CD4+ T 细胞中的 ROR-γt mRNA 和 IL-17A 表达。总之，BAFF 沉默的 DC 可以减轻 CIA，部分通过诱导 Foxp3+ 调节性 T 细胞和抑制 Th17 亚群。总的来说，BAFF 在 DCs 和 T 细胞之间的相互作用中起着重要作用，这可能是产生用于自身免疫性关节炎治疗的 tolDCs 的有希望的遗传靶点。