Good Kim L, Bryant Vanessa L, Tangye Stuart G
Centenary Institute of Cancer Medicine and Cell Biology, New South Wales, Australia.
J Immunol. 2006 Oct 15;177(8):5236-47. doi: 10.4049/jimmunol.177.8.5236.
Although recent studies indicated that IL-21 is an important regulator of human B cell activation, detailed comparison of the effects of IL-21 on distinct B cell subsets have not been performed. Our studies revealed that IL-21R is expressed by naive and germinal center B cells, but not memory or plasma cells. IL-21R was increased on naive and memory B cells following in vitro activation. Investigation into the kinetics and magnitude of responses of human B cells to IL-21 revealed that IL-21 potently augmented proliferation of CD40L-stimulated neonatal, splenic naive, and memory and tonsil germinal center B cells. This response exceeded that induced by IL-4, IL-10, and IL-13, cytokines that also induce B cell proliferation. Remarkably, CD40L/IL-21-stimulated naive B cells underwent the same number of divisions as memory cells and exhibited a greater enhancement in their response compared with CD40L alone than memory B cells. Therefore, IL-21 is a powerful growth factor for naive B cells. This may result from the higher expression of IL-21R on naive, compared with memory, B cells. Stimulation of human B cells with CD40L/IL-21 also induced IL-10 production and activation of STAT3. We propose that IL-21 may have therapeutic application in conditions of immunodeficiency where it could expand naive B cells, the predominant B cell subset in such patients. Conversely, because IL-21 is increased in murine models of lupus, dysregulated IL-21 production may contribute to perturbed B cell homeostasis observed in systemic lupus erythematosus. Thus, antagonizing IL-21 may be a novel strategy for treating Ab-mediated autoimmune diseases.
尽管最近的研究表明白细胞介素-21（IL-21）是人类B细胞活化的重要调节因子，但尚未对IL-21对不同B细胞亚群的作用进行详细比较。我们的研究表明，IL-21受体（IL-21R）在初始B细胞和生发中心B细胞中表达，但在记忆B细胞或浆细胞中不表达。体外活化后，初始B细胞和记忆B细胞上的IL-21R表达增加。对人类B细胞对IL-21反应的动力学和强度进行研究发现，IL-21能有力地增强CD40L刺激的新生儿、脾脏初始、记忆和扁桃体生发中心B细胞的增殖。这种反应超过了由IL-4、IL-10和IL-13诱导的反应，这几种细胞因子也能诱导B细胞增殖。值得注意的是，CD40L/IL-21刺激的初始B细胞经历的分裂次数与记忆B细胞相同，并且与单独使用CD40L相比，其反应增强程度比记忆B细胞更大。因此，IL-21是初始B细胞的强大生长因子。这可能是由于与记忆B细胞相比，初始B细胞上IL-21R的表达更高。用CD40L/IL-21刺激人类B细胞还能诱导IL-10的产生和信号转导及转录激活因子3（STAT3）的活化。我们提出，IL-21在免疫缺陷状态下可能具有治疗应用价值，因为它可以扩增初始B细胞，而初始B细胞是此类患者中主要的B细胞亚群。相反，由于在狼疮小鼠模型中IL-21水平升高，IL-21产生失调可能导致系统性红斑狼疮中观察到的B细胞内环境稳态紊乱。因此，拮抗IL-21可能是治疗抗体介导的自身免疫性疾病的一种新策略。
