Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell. 2021 Feb 18;184(4):983-999.e24. doi: 10.1016/j.cell.2021.01.018.
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）和白细胞介素-23（IL-23）是异源二聚体细胞因子，由抗原呈递细胞产生，以调节淋巴细胞的激活和分化，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，以及完整的 IL-12（IL-12p35/p40）/IL-12Rβ2/IL-12Rβ1 和 IL-23 受体（IL-23R）复合物的 cryo-EM 图谱，揭示了“非典型”拓扑结构，其中 IL-12Rβ1 直接与共同的 p40 亚基结合。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 细胞诱导干扰素γ（IFNγ）的能力，但损害了自然杀伤（NK）细胞在体外的细胞因子产生。这些细胞偏向性特性在体内得到了重现，其中 IL-12 部分激动剂在没有野生型 IL-12 引起的 NK 细胞介导的毒性的情况下，引发了对 MC-38 小鼠腺癌的抗肿瘤免疫。因此，白细胞介素-12 家族细胞因子共享受体的结构机制为调节该细胞因子轴的治疗提供了一个蛋白质界面蓝图。
