Structural basis for IL-12 and IL-23 shared receptor usage reveals a gateway for shaping actions on T versus NK cells
By C. Glassman, Y. K. Mathiharan, K. Jude, L. Su, O. Panova, P. Lupardus, Jamie B. Spangler, L. K. Ely, C. Thomas, G. Skiniotis and 1 more. 2021
151 citations recorded by the source corpus.
Summary: Interleukin-12 (IL-12) and IL-23 are heterodimeric cytokines produced by antigen presenting cells to regulate the activation and differentiation of lymphocytes and which 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 cryo-EM maps of the complete IL-12(IL-12p35/p40)/IL-12Rβ2/IL-12Rβ1 and IL-23 receptor complexes, which reveal ‘non-canonical’ topologies whereby 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.
Subfields: Immunology, Oncology, Computational Biology & Bioinformatics
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Citations in the corpus
- Accurate prediction of protein structures and interactions using a 3-track neural network (2021, positive): “Such an understanding is important for dissecting the specific actions of IL-12 and IL-23 and generating inhibitors that block IL-12 without affecting IL-23 signaling.”
- Structural insights into the assembly and activation of the IL‐27 signaling complex (2022, unknown): “GP130 binds a range of cytokines to elicit diverse cellular responses (Grotzinger et al , 1997; Hunter & Jones, 2015).”