Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Nature. 2012 Nov 8;491(7423):264-8. doi: 10.1038/nature11501. Epub 2012 Oct 14.
B cells regulate immune responses by producing antigen-specific antibodies. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.
B 细胞通过产生抗原特异性抗体来调节免疫反应。然而，特定的 B 细胞亚群也可以负调控 T 细胞免疫反应，这些 B 细胞被称为调节性 B 细胞。已经鉴定出具有表达抑制性细胞因子白细胞介素-10（IL-10）能力的人类和小鼠调节性 B 细胞（B10 细胞）。尽管 B10 细胞很少，但它们是小鼠中抗原特异性炎症和 T 细胞依赖性自身免疫性疾病的有效负调控因子。在不诱导全身免疫抑制的情况下，体内如何控制 B10 细胞 IL-10 的产生和抗原特异性免疫反应的调节尚不清楚。在这里，我们使用多发性硬化症的小鼠模型表明，B10 细胞成熟为具有抑制体内自身免疫疾病功能的 IL-10 分泌效应细胞需要 IL-21 和 CD40 依赖性与 T 细胞的同源相互作用。此外，体外提供 CD40 和 IL-21 受体信号可以通过四百万倍的倍数驱动 B10 细胞的发育和扩增，并产生 B10 效应细胞产生 IL-10，当转移到患有已建立的自身免疫性疾病的小鼠中时，可显著抑制疾病症状。自体 B10 细胞的体外扩增和再输注可能为对当前治疗方法有抗性的严重自身免疫性疾病提供一种新的有效体内治疗方法。
