期刊
SCIENCE
卷 371, 期 6535, 页码 1222-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abc8433
关键词
-
资金
- NIH [5R01CA177684, R37-AI51321, U54CA244711]
- Department of Energy, Laboratory Directed Research and Development program at SLAC National Accelerator Laboratory [DE-AC02-76SF00515]
- Stanford Medical Scientist Training Program [T32GM007365]
By determining the structure of the IL-10 receptor complex and uncovering differences in IL-10 response thresholds across immune cell populations, this study provides a mechanistic blueprint for manipulating the pleiotropic actions of IL-10. Some IL-10 variants displayed myeloid-biased activity, suppressing macrophage activation without stimulating inflammatory CD8(+) T cells, thus uncoupling the major opposing functions of IL-10.
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-10R alpha form a composite surface to engage the shared signaling receptor IL-10R beta, enabling the design of partial agonists. IL-10 variants with a range of IL-10R beta 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.
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