Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells

We present a crystal structure of the quaternary IL-23 /IL-23R/IL-12Rβ1 complex, together with cryoelectron microscopy maps of the complete IL-12 /IL-12Rβ2/IL-12Rβ1 and IL-23 receptor complexes, which reveal “non-canonical” topologies where IL-12Rβ1 directly engages the common p40 subunit

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

2021

Scholarcy highlights

  • Interleukin-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-23R/IL-12Rβ1 complex, together with cryoelectron microscopy maps of the complete IL-12/IL-12Rβ2/IL-12Rβ1 and IL-23 receptor 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 induction by CD8+ T cells but impaired cytokine production from natural killer 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
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