美国斯坦福大学医学院K. Christopher Garcia研究团队在研究中取得进展。他们探明白介素12（IL-12）和IL-23受体共享的结构基础揭示了靶向T细胞与NK细胞形成作用的途径。2021年2月18日出版的国际知名学术期刊《细胞》杂志发表了这一成果。
他们提出了四级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）的冷冻电镜（cryo-EM）图）/IL-12Rβ2/IL-12Rβ1和IL-23受体（IL-23R）复合物，它们揭示了“非规范”拓扑结构，其中IL-12Rβ1直接与常见的p40亚基结合。他们靶向共享的IL-12Rβ1/ p40界面设计了一组IL-12部分激动剂，这些激动剂可保留CD8 + T细胞对干扰素γ（IFNγ）的诱导作用，但会削弱体外自然杀伤（NK）细胞产生的细胞因子。
这些细胞偏好特性在体内得到了概括，其中IL-12部分激动剂引发了靶向MC-38鼠腺癌的抗肿瘤免疫力，而没有野生型IL-12所见的NK细胞介导的毒性。因此，IL-12家族细胞因子所使用的受体共享的结构机制为调节该细胞因子轴提供了治疗所需的蛋白质界面蓝图。
据了解，IL-12和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。
附：英文原文
Title: Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells
Author: Caleb R. Glassman, Yamuna Kalyani Mathiharan, Kevin M. Jude, Leon Su, Ouliana Panova, Patrick J. Lupardus, Jamie B. Spangler, Lauren K. Ely, Christoph Thomas, Georgios Skiniotis, K. Christopher Garcia
Issue&Volume: 2021/02/18
Abstract: Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines that are produced byantigen-presenting cells to regulate the activation and differentiation of lymphocytes,and they share IL-12Rβ1 as a receptor signaling subunit. We present a crystal structureof the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12Rβ1 complex, together with cryoelectronmicroscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12Rβ2/IL-12Rβ1 andIL-23 receptor (IL-23R) complexes, which reveal “non-canonical” topologies where IL-12Rβ1directly engages the common p40 subunit. We targeted the shared IL-12Rβ1/p40 interfaceto 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 adenocarcinomaabsent the NK-cell-mediated toxicity seen with wild-type IL-12. Thus, the structuralmechanism of receptor sharing used by IL-12 family cytokines provides a protein interfaceblueprint for tuning this cytokine axis for therapeutics.
DOI: 10.1016/j.cell.2021.01.018
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00061-1