The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions.

白细胞介素 6 (IL-6) 膜受体及其循环可溶性形式 sIL-6R 可以通过抗体疗法进行靶向，以减少由促炎细胞因子 IL-6 的慢性过度表达引起的有害免疫信号。这种策略也可能有望治疗急性过度炎症，例如在 2019 年冠状病毒病 (COVID-19) 中观察到的情况，这凸显了定义 IL-6 稳态调节剂的必要性。我们发现传统的树突状细胞 (cDC)，通过表达转录因子Zbtb46在小鼠中定义, 是循环 sIL-6R 的主要来源，因此系统调节 IL-6 信号。这是通过鉴定依赖于 cDC 但不依赖于 T 细胞的方式发现的，这种方式自然地促进浆细胞分化和对蛋白质抗原的抗体反应。然后将该途径揭示为更广泛的生物缓冲系统的一部分，其中 cDC 衍生的 sIL-6R 设置 IL-6 在溶液中的持久性。该控制轴可以进一步告知治疗剂的开发以调节促炎免疫反应。