Division of Medicine, Centre for Rheumatology Research, University College London, London W1T 4JF, United Kingdom.
J Immunol. 2011 May 15;186(10):5569-79. doi: 10.4049/jimmunol.1100284. Epub 2011 Apr 4.
IL-10-producing B cells, also known as regulatory B cells (Bregs), play a key role in controlling autoimmunity. In this study, we report that chimeric mice specifically lacking IL-10-producing B cells (IL-10(-/-)B cell) developed an exacerbated arthritis compared with chimeric wild-type (WT) B cell mice. A significant decrease in the absolute numbers of Foxp3 regulatory T cells (Tregs), in their expression level of Foxp3, and a marked increase in inflammatory Th1 and Th17 cells were detected in IL-10(-/-) B cell mice compared with WT B cell mice. Reconstitution of arthritic B cell deficient (μMT) mice with different B cell subsets revealed that the ability to modulate Treg frequencies in vivo is exclusively restricted to transitional 2 marginal zone precursor Bregs. Moreover, transfer of WT transitional 2 marginal zone precursor Bregs to arthritic IL-10(-/-) mice increased Foxp3(+) Tregs and reduced Th1 and Th17 cell frequencies to levels measured in arthritic WT mice and inhibited inflammation. In vitro, IL-10(+/+) B cells established longer contact times with arthritogenic CD4(+)CD25(-) T cells compared with IL-10(-/-) B cells in response to Ag stimulation, and using the same culture conditions, we observed upregulation of Foxp3 on CD4(+) T cells. Thus, IL-10-producing B cells restrain inflammation by promoting differentiation of immunoregulatory over proinflammatory T cells.
产生白介素-10 的 B 细胞，也称为调节性 B 细胞（Bregs），在控制自身免疫中发挥关键作用。在这项研究中，我们报告称，特异性缺乏产生白介素-10 的 B 细胞（IL-10(-/-)B 细胞）的嵌合小鼠与嵌合野生型（WT）B 细胞小鼠相比，发生了更为严重的关节炎。与 WT B 细胞小鼠相比，IL-10(-/-)B 细胞小鼠中 Foxp3 调节性 T 细胞（Tregs）的绝对数量显著减少，Foxp3 的表达水平降低，炎症性 Th1 和 Th17 细胞明显增加。与 WT B 细胞小鼠相比，IL-10(-/-)B 细胞小鼠中不同 B 细胞亚群的 Foxp3 调节性 T 细胞（Tregs）的绝对数量显著减少，其表达水平降低，炎症性 Th1 和 Th17 细胞明显增加。用不同的 B 细胞亚群重建关节炎 B 细胞缺陷（μMT）小鼠表明，体内调节 Treg 频率的能力仅局限于过渡 2 边缘区前体 Bregs。此外，将 WT 过渡 2 边缘区前体 Bregs 转移到关节炎 IL-10(-/-)小鼠中，增加了 Foxp3(+)Tregs，降低了 Th1 和 Th17 细胞频率，使其达到关节炎 WT 小鼠的水平，并抑制了炎症。体外，与 IL-10(-/-)B 细胞相比，IL-10(+/+)B 细胞在抗原刺激下与致关节炎性 CD4(+)CD25(-)T 细胞建立了更长的接触时间，并且在相同的培养条件下，我们观察到 CD4(+)T 细胞上 Foxp3 的上调。因此，产生白介素-10 的 B 细胞通过促进免疫调节性 T 细胞而非促炎性 T 细胞的分化来抑制炎症。
