Autoimmunity and Tolerance Laboratory, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
J Immunol. 2011 Feb 1;186(3):1512-20. doi: 10.4049/jimmunol.1002373. Epub 2011 Jan 5.
Autoantibody production is a hallmark of autoimmune diseases, such as lupus and rheumatoid arthritis. Accumulating evidence suggests a role of invariant NKT (iNKT) cells in their pathogenesis. Mechanisms underlying the role of iNKT cells in these diseases, however, remain unclear. In this study, we show that iNKT cells suppress IgG anti-DNA Ab and rheumatoid factor production and reduce IL-10-secreting B cells in a contact-dependent manner, but increase total IgG production and enhance activation markers on B cells via soluble factors. In vivo reconstitution with iNKT cells also reduces autoantibody production in iNKT-deficient mice and in SCID mice implanted with B cells. Using an anti-DNA transgenic model, we found that autoreactive B cells spontaneously produce IL-10 and are activated in vivo. In the presence of activated iNKT cells, these autoreactive B cells are selectively reduced, whereas nonautoreactive B cells are markedly activated. Because iNKTs recognize CD1d, we reasoned that CD1d might play a role in the differential regulation of autoreactive versus nonautoreactive B cells by iNKT cells. Indeed, autoreactive B cells express more CD1d than nonautoreactive B cells, and CD1d deficiency in lupus mice exacerbates autoantibody production and enhances Ab response to a self-peptide but not to a foreign peptide. Importantly, iNKT cells fail to inhibit autoantibody production by CD1d-deficient B cells. Thus, iNKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner but activate nonautoreactive B cells via cytokines. Such ability of iNKTs to suppress autoantibody production, without causing global suppression of B cells, has important implications for the development of iNKT-based therapy for autoimmune diseases.
自身抗体的产生是自身免疫性疾病（如狼疮和类风湿关节炎）的一个标志。越来越多的证据表明，不变自然杀伤 T(iNKT)细胞在其发病机制中起作用。然而，iNKT 细胞在这些疾病中的作用机制仍不清楚。在这项研究中，我们表明 iNKT 细胞以接触依赖性方式抑制 IgG 抗 DNA Ab 和类风湿因子的产生，并减少产生 IL-10 的 B 细胞，但通过可溶性因子增加总 IgG 产生并增强 B 细胞的激活标志物。体内重建 iNKT 细胞也可减少 iNKT 缺陷小鼠和植入 B 细胞的 SCID 小鼠中的自身抗体产生。使用抗 DNA 转基因模型，我们发现自身反应性 B 细胞自发产生 IL-10 并在体内被激活。在活化的 iNKT 细胞存在下，这些自身反应性 B 细胞被选择性减少，而非自身反应性 B 细胞则被显著激活。由于 iNKT 细胞识别 CD1d，我们推断 CD1d 可能在 iNKT 细胞对自身反应性和非自身反应性 B 细胞的差异调节中起作用。事实上，自身反应性 B 细胞比非自身反应性 B 细胞表达更多的 CD1d，狼疮小鼠中 CD1d 的缺乏会加剧自身抗体的产生，并增强对自身肽的 Ab 反应，但对外国肽无反应。重要的是，iNKT 细胞无法抑制 CD1d 缺陷 B 细胞的自身抗体产生。因此，iNKT 细胞以接触和 CD1d 依赖的方式抑制自身反应性 B 细胞，但通过细胞因子激活非自身反应性 B 细胞。iNKT 细胞具有抑制自身抗体产生而不引起 B 细胞全面抑制的这种能力，对开发基于 iNKT 的自身免疫性疾病治疗方法具有重要意义。
