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

Robert A. Saxton, Naotaka Tsutsumi, Leon L. Su, Gita C. Abhiraman, Kritika Mohan, Lukas T. Henneberg, Nanda G. Aduri, Cornelius Gati, K. Christopher Garcia

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

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-10Ra form a composite surface to engage the shared signaling receptor IL-10Rb, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rb 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.

Original languageEnglish
Article numbereabc8433
JournalScience
Volume371
Issue number6535
DOIs
Publication statusPublished - Mar 19 2021
Externally publishedYes

ASJC Scopus subject areas

  • General

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