Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
J Immunol. 2013 Sep 15;191(6):2948-55. doi: 10.4049/jimmunol.1301173. Epub 2013 Aug 19.
IL-21 is a pluripotent cytokine that regulates B cell and plasma cell differentiation and is thought be an autocrine factor for follicular helper T cell (T(FH)) and Th17 differentiation. Although IL-21 has been implicated in autoimmune diseases, its relevant cellular source and target cells have not been well characterized. We investigated this issue in the K/BxN mouse model of autoimmune arthritis. Adoptive transfer of KRN-transgenic CD4⁺ T cells into appropriate hosts drives germinal center (GC) formation and autoantibody production against glucose-6-phosphate isomerase, leading to joint inflammation and destruction. By comparing transfer of T or B cells deficient in IL-21 or IL-21R, we were able to dissect the contribution of each cell type. T cells deficient in IL-21 did not induce GC formation or autoantibody production, but they went through normal T(FH) differentiation. However, T cells lacking IL-21R induced Ab titers, GC B cell frequency, and arthritis development similar to wild-type T cells, suggesting that IL-21 is not required for T(FH) differentiation and function. IL-21 acts on B cells, because IL-21R expression on B cells was required to induce disease. In contrast, Th17 cells, a T cell subset that also produces IL-21 and can provide help to B cells, are not required for the GC response and arthritis. These data have implications in developing effective therapies for rheumatoid arthritis and other Ab-mediated autoimmune diseases.
白细胞介素 21（IL-21）是一种多能细胞因子，可调节 B 细胞和浆细胞分化，被认为是滤泡辅助 T 细胞（T(FH)）和 Th17 分化的自分泌因子。尽管 IL-21 已被牵涉到自身免疫性疾病中，但它的相关细胞来源和靶细胞尚未得到很好的描述。我们在自身免疫性关节炎的 K/BxN 小鼠模型中研究了这个问题。将 KRN 转基因 CD4⁺T 细胞过继转移到合适的宿主中，可驱动生发中心（GC）的形成和针对葡萄糖-6-磷酸异构酶的自身抗体的产生，导致关节炎症和破坏。通过比较缺乏 IL-21 或 IL-21R 的 T 或 B 细胞的转移，我们能够剖析每种细胞类型的贡献。缺乏 IL-21 的 T 细胞不会诱导 GC 的形成或自身抗体的产生，但它们经历了正常的 T(FH)分化。然而，缺乏 IL-21R 的 T 细胞诱导的 Ab 滴度、GC B 细胞频率和关节炎发展与野生型 T 细胞相似，表明 IL-21 对于 T(FH)分化和功能不是必需的。IL-21 作用于 B 细胞，因为 B 细胞上需要表达 IL-21R 才能诱导疾病。相比之下，Th17 细胞，一种也能产生 IL-21 并能为 B 细胞提供帮助的 T 细胞亚群，对于 GC 反应和关节炎不是必需的。这些数据对于开发类风湿关节炎和其他 Ab 介导的自身免疫性疾病的有效治疗方法具有重要意义。
