Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10

Science. 2021 Mar 19;371(6535):eabc8433. doi: 10.1126/science.abc8433.


Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo-electron microscopy at a resolution of 3.5 angstroms. The hexameric structure shows how IL-10 and IL-10Rα form a composite surface to engage the shared signaling receptor IL-10Rβ, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rβ binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity. Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8+ T cells, thereby uncoupling the major opposing functions of IL-10. These results provide a mechanistic blueprint for tuning the pleiotropic actions of IL-10.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line
  • Cryoelectron Microscopy
  • Cytokines / metabolism
  • Directed Molecular Evolution
  • Humans
  • Inflammation
  • Interleukin-10 / agonists
  • Interleukin-10 / chemistry*
  • Interleukin-10 / metabolism*
  • Interleukin-10 Receptor alpha Subunit / chemistry
  • Interleukin-10 Receptor alpha Subunit / metabolism
  • Interleukin-10 Receptor beta Subunit / chemistry
  • Interleukin-10 Receptor beta Subunit / metabolism
  • Macrophage Activation
  • Mice
  • Models, Molecular
  • Monocytes / immunology
  • Monocytes / metabolism
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Protein Binding
  • Protein Engineering
  • Protein Interaction Domains and Motifs
  • Protein Multimerization
  • STAT3 Transcription Factor / metabolism
  • Sepsis / immunology
  • Signal Transduction


  • Cytokines
  • IL10 protein, human
  • Interleukin-10 Receptor alpha Subunit
  • Interleukin-10 Receptor beta Subunit
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Interleukin-10