Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced by antigen-presenting cells to regulate the activation and differentiation of lymphocytes, and they share IL-12Rβ1 as a receptor signaling subunit. We present a crystal structure of the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12Rβ1 complex, together with cryoelectron microscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12Rβ2/IL-12Rβ1 and IL-23 receptor (IL-23R) complexes, which reveal “non-canonical” topologies where IL-12Rβ1 directly engages the common p40 subunit. We targeted the shared IL-12Rβ1/p40 interface to design a panel of IL-12 partial agonists that preserved interferon gamma (IFNγ) induction by CD8⁺ T cells but impaired cytokine production from natural killer (NK) cells in vitro. These cell-biased properties were recapitulated in vivo, where IL-12 partial agonists elicited anti-tumor immunity to MC-38 murine adenocarcinoma absent the NK-cell-mediated toxicity seen with wild-type IL-12. Thus, the structural mechanism of receptor sharing used by IL-12 family cytokines provides a protein interface blueprint for tuning this cytokine axis for therapeutics.

白细胞介素12（IL-12）和IL-23是由抗原呈递细胞产生以调节淋巴细胞活化和分化的异二聚体细胞因子，它们共享IL-12Rβ1作为受体信号亚基。我们展示了四元 IL-23 (IL-23p19/p40)/IL-23R/IL-12Rβ1 复合物的晶体结构，以及完整 IL-12 (IL-12p35/p40) 的低温电子显微镜 (cryo-EM) 图)/IL-12Rβ2/IL-12Rβ1 和 IL-23 受体 (IL-23R) 复合物，揭示了 IL-12Rβ1 直接与常见 p40 亚基结合的“非规范”拓扑。^{我们针对共享的 IL-12Rβ1/p40 界面设计了一组 IL-12 部分激动剂，这些激动剂保留了 CD8 +} T 细胞对干扰素 γ (IFNγ) 的诱导作用，但在体外损害了自然杀伤 (NK) 细胞的细胞因子产生. 这些细胞偏向特性在体内得到了概括，其中 IL-12 部分激动剂引发了对 MC-38 鼠腺癌的抗肿瘤免疫，而没有野生型 IL-12 所见的 NK 细胞介导的毒性。因此，IL-12 家族细胞因子使用的受体共享结构机制为调整该细胞因子轴以进行治疗提供了蛋白质界面蓝图。