Interleukin-5 Supports the Expansion of Fas Ligand-Expressing Killer B Cells that Induce Antigen-Specific Apoptosis of CD4⁺ T Cells and Secrete Interleukin-10

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 IgMhighCD5+CD1dhigh 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（humoral immunity）中发挥关键作用之外，B淋巴细胞（B lymphocytes）还可通过多种免疫调节机制行使功能，其中包括表达凋亡诱导分子Fas配体（Fas ligand, FasL; CD178）。本研究对FasL+杀伤性B细胞的表面表型（surface phenotype）进行了全面表征，结果显示其富集于此前报道的、分泌白细胞介素10（interleukin-10, IL-10）的B细胞频率更高的IgMhighCD5+CD1dhigh B细胞亚群中。FasL+ B细胞中存在少量表达IL-10的B细胞群体，但大多数FasL+ B细胞并不分泌IL-10。本研究还鉴定出白细胞介素5（interleukin-5, IL-5）是杀伤性B细胞功能的新型诱导剂。组成性表达FasL的B细胞其IL-5受体的表达水平更高；采用IL-5与CD40配体（CD40 ligand, CD40L）处理B细胞，可使以FasL+细胞为主的B细胞群体发生扩增。经IL-5与CD40L刺激的B细胞可有效诱导活化原代CD4+ T细胞发生凋亡，该杀伤功能具有抗原特异性且依赖于FasL。此外，IL-5还可增强CD40L刺激下B细胞的IL-10分泌能力。综合上述研究结果，本研究阐明了FasL+ B细胞与分泌IL-10的B细胞之间的关联，并证实IL-5可诱导或增强B细胞的杀伤性B细胞活性以及IL-10分泌能力。最后，本研究发现IL-4可完全阻断IL-5诱导的杀伤性B细胞活性，这提示在调节杀伤性B细胞活性的过程中，这两种2型细胞因子（type-2 cytokines）之间存在此前未被发现的拮抗关系。因此，靶向该IL-5/IL-4信号轴（signaling axis）或可成为炎症性疾病（inflammatory disorders）药物研发的全新方向。