Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21
Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21
复制标题
DOI：
10.4049/jimmunol.177.8.5236
复制
发表时间：
2006-10-15
影响因子：
4.4
通讯作者：
Tangye, Stuart G.
中科院分区：
文献类型：
--
作者：
Good, Kim L.;Bryant, Vanessa L.;Tangye, Stuart G.
尽管近期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。我们的研究显示，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。在体外活化后，初始B细胞和记忆B细胞上的IL - 21R增加。对人类B细胞对IL - 21反应的动力学和强度的研究表明，IL - 21能显著增强CD40配体（CD40L）刺激的新生儿B细胞、脾脏初始B细胞、记忆B细胞以及扁桃体生发中心B细胞的增殖。这种反应超过了由白细胞介素 - 4（IL - 4）、白细胞介素 - 10（IL - 10）和白细胞介素 - 13（IL - 13）诱导的反应，这些细胞因子也能诱导B细胞增殖。值得注意的是，CD40L/IL - 21刺激的初始B细胞分裂次数与记忆B细胞相同，且与单独使用CD40L相比，其反应增强程度大于记忆B细胞。因此，IL - 21是初始B细胞的一种强大生长因子。这可能是由于初始B细胞上的IL - 21R表达高于记忆B细胞。用CD40L/IL - 21刺激人类B细胞还能诱导白细胞介素 - 10（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在免疫缺陷疾病中可能具有治疗应用，它可以扩增此类患者中占主导的初始B细胞亚群。相反，由于在狼疮小鼠模型中IL - 21增加，IL - 21产生失调可能导致系统性红斑狼疮中观察到的B细胞内稳态紊乱。因此，拮抗IL - 21可能是治疗抗体介导的自身免疫疾病的一种新策略。
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.