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

Science (New York, N.Y.) 2021 Mar 19

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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. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Citation

Robert A Saxton, Naotaka Tsutsumi, Leon L Su, Gita C Abhiraman, Kritika Mohan, Lukas T Henneberg, Nanda G Aduri, Cornelius Gati, K Christopher Garcia. Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10. Science (New York, N.Y.). 2021 Mar 19;371(6535)