Journal
CELL
Volume 184, Issue 4, Pages 983-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2021.01.018
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Funding
- National Institutes of Health [R01-AI51321]
- Mathers Foundation
- Ludwig Foundation
- National Science Foundation Graduate Research Fellowship Program [DGE-1656518]
- Department of Energy Office of Science User Facility [DE-AC02-05CH11231]
- US Department of Energy Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- Department of Energy, Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
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The structural mechanism of receptor sharing used by IL-12 family cytokines can be utilized to tune the cytokine axis for therapeutics, as demonstrated by the design of IL-12 partial agonists that elicited anti-tumor immunity in vivo.
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-12R beta 1 as a receptor signaling subunit. We present a crystal structure of the quaternary IL-23 (IL-23p19/p40)/IL-23R/IL-12R beta 1 complex, together with cryoelectron microscopy (cryo-EM) maps of the complete IL-12 (IL-12p35/p40)/IL-12R beta 2/IL-12R beta 1 and IL-23 receptor (IL-23R) complexes, which reveal non-canonical'' topologies where IL-12R beta 1 directly engages the common p40 subunit. We targeted the shared IL-12R beta 1/p40 interface to design a panel of IL-12 partial agonists that preserved interferon gamma (IFN gamma) 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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