Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells
Open accessAbstract
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.
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A central crevice extends into the membrane and is lined with residues required for activity (His182 and Asp213) or conserved (W298), as well as a pathogenic mutation (H183Q) found in progressive myoclonus epilepsy and dementia that decreases ceramide levels.
“A central crevice extends into the membrane and is lined with residues required for activity (His182 and Asp213) (30) or conserved (W298), as well as a pathogenic mutation (H183Q) found in progressive myoclonus epilepsy and dementia that decreases ceramide levels (31).”
From Accurate prediction of protein structures and interactions using a 3-track network (2021) · cites this paper as [30]
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References 92 · Cited by 181
- Authors
- Glassman, C. R., Mathiharan, Y. K., Jude, K. M., Su, L., Panova, O., Lupardus, P. J., Spangler, J. B., Ely, L. K., Thomas, C., Skiniotis, G., & Garcia, K. C.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 184
- Issue
- 4
- Pages
- 983-999.e24
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7899134
- OpenAlex
- W3133025128
- Cited by
- 181
- References
- 92
- Citations by year
- 2026: 27 · 2025: 49 · 2024: 34 · 2023: 31 · 2022: 29 · 2021: 11
- FWCI
- 9.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- IL-12, IL-23, IL-12 receptor, IL23R, T cells, natural killer cells, antitumor immunity, NK cell cytotoxicity
- MeSH terms
- Amino Acid Sequence, Animals, Epitopes, Binding Sites, Female, Humans, Immunity, Killer Cells, Natural, Mice, Inbred C57BL, Models, Molecular, Neoplasms, Structure-Activity Relationship, T-Lymphocytes, Signal Transduction, Receptors, Interleukin, Crystallography, X-Ray, Interleukin-12, Cryoelectron Microscopy, Protein Structure, Quaternary, Mice, Receptors, Interleukin-12, Interleukin-12 Subunit p40, HEK293 Cells
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