Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan, USA.
PLoS One. 2013 Aug 5;8(8):e70131. doi: 10.1371/journal.pone.0070131. Print 2013.
Beyond their critical role in humoral immunity, B lymphocytes can employ a variety of immunomodulatory mechanisms including expression of the apoptosis-inducing molecule Fas ligand (FasL; CD178). Here, we extensively characterized the surface phenotype of FasL(+) killer B cells, showing they are enriched in the IgM(high)CD5(+)CD1d(high) B cell subset previously reported to contain a higher frequency of B cells producing interleukin-10 (IL-10). A rare population of B cells expressing IL-10 was present among FasL(+) B cells, but most FasL(+) B cells did not produce IL-10. We also identify interleukin-5 (IL-5) as a novel inducer of killer B cell function. Constitutively FasL(+) B cells expressed higher levels of the IL-5 receptor, and treating B cells with IL-5 and CD40L resulted in the expansion of a B cell population enriched for FasL(+) cells. B cells stimulated with IL-5 and CD40L were potent inducers of apoptosis in activated primary CD4(+) T cells, and this killing function was antigen-specific and dependent upon FasL. IL-5 also enhanced IL-10 secretion in B cells stimulated with CD40L. Taken together these findings elucidate the relationship of FasL(+) B cells and IL-10-producing B cells and demonstrate that IL-5 can induce or enhance both killer B cell activity and IL-10 secretion in B cells. Finally, we found that the killer B cell activity induced by IL-5 was completely blocked by IL-4, suggesting the existence of a previously unknown antagonistic relationship between these type-2 cytokines in modulating the activity of killer B cells. Targeting this IL-5/IL-4 signaling axis may therefore represent a novel area of drug discovery in inflammatory disorders.
除了在体液免疫中发挥关键作用外，B 淋巴细胞还可以采用多种免疫调节机制，包括表达凋亡诱导分子 Fas 配体 (FasL; CD178)。在这里，我们广泛表征了 FasL(+)杀伤性 B 细胞的表面表型，表明它们富含 IgM(高)CD5(+)CD1d(高)B 细胞亚群，该亚群先前报道含有更高频率产生白细胞介素-10 (IL-10)的 B 细胞。FasL(+)B 细胞中存在表达 IL-10 的罕见 B 细胞群体，但大多数 FasL(+)B 细胞不产生 IL-10。我们还确定白细胞介素-5 (IL-5) 是一种新型杀伤性 B 细胞功能诱导剂。组成性 FasL(+)B 细胞表达更高水平的 IL-5 受体，用 IL-5 和 CD40L 处理 B 细胞可导致 FasL(+)细胞丰富的 B 细胞群体扩增。用 IL-5 和 CD40L 刺激的 B 细胞是激活的原代 CD4(+)T 细胞凋亡的有力诱导剂，这种杀伤功能是抗原特异性的，依赖于 FasL。IL-5 还增强了 CD40L 刺激的 B 细胞中 IL-10 的分泌。这些发现阐明了 FasL(+)B 细胞和产生 IL-10 的 B 细胞之间的关系，并表明 IL-5 可以诱导或增强 B 细胞中的杀伤性 B 细胞活性和 IL-10 分泌。最后，我们发现 IL-5 诱导的杀伤性 B 细胞活性被 IL-4 完全阻断，这表明在调节杀伤性 B 细胞活性方面，这两种 2 型细胞因子之间存在以前未知的拮抗关系。因此，靶向该 IL-5/IL-4 信号轴可能代表炎症性疾病药物发现的一个新领域。
