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

Cell. 2021 Feb 18;184(4):983-999.e24. doi: 10.1016/j.cell.2021.01.018.


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.

Keywords: IL-12; IL-23; immunology; receptor biology; signaling; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • Epitopes / immunology
  • Female
  • HEK293 Cells
  • Humans
  • Immunity
  • Interleukin-12 / agonists
  • Interleukin-12 / chemistry*
  • Interleukin-12 / metabolism*
  • Interleukin-12 Subunit p40 / chemistry
  • Interleukin-12 Subunit p40 / metabolism
  • Killer Cells, Natural / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Protein Structure, Quaternary
  • Receptors, Interleukin / chemistry*
  • Receptors, Interleukin / metabolism*
  • Receptors, Interleukin / ultrastructure
  • Receptors, Interleukin-12 / metabolism
  • Signal Transduction
  • Structure-Activity Relationship
  • T-Lymphocytes / metabolism*


  • Epitopes
  • IL23R protein, human
  • Interleukin-12 Subunit p40
  • Receptors, Interleukin
  • Receptors, Interleukin-12
  • Interleukin-12