期刊
SCIENCE SIGNALING
卷 13, 期 649, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.abc0653
关键词
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资金
- Wellcome Trust [203752/Z/16/Z, 202323/Z/16/Z]
- ERC-206-STG grant
- EMBO [454-2017]
- Deutsche Forschungsgemeinschaft [SFB 944]
- NIH [R01 AI143554]
- Projects Fondation ARC 2019
- La Ligue Contre le Cancer grants
- Wellcome Trust [202323/Z/16/Z, 203752/Z/16/Z] Funding Source: Wellcome Trust
Interleukin-10 (IL-10) is a dimeric cytokine with both immunosuppressive and immunostimulatory activities; however, IL-10-based therapies have shown only marginal clinical benefits. Here, we explored whether the stability of the IL-10 receptor complex contributes to the immunomodulatory potency of IL-10. We generated an IL-10 mutant with enhanced affinity for its IL-10R. receptor using yeast surface display. Compared to the wild-type cytokine, the affinity-enhanced IL-10 variants recruited IL-10R. more efficiently into active cell surface signaling complexes and triggered greater STAT1 and STAT3 activation in human monocytes and CD8(+) T cells. These effects, in turn, led to more robust induction of IL-10-mediated gene expression programs at low ligand concentrations in both human cell subsets. IL-10-regulated genes are involved in monocyte energy homeostasis, migration, and trafficking and in CD8(+) T cell exhaustion. At nonsaturating doses, IL-10 did not induce key components of its gene expression program, which may explain its lack of efficacy in clinical settings. Our engineered IL-10 variant showed a more robust bioactivity profile than that of wild-type IL-10 at low doses in monocytes and CD8(+) T cells. Moreover, CAR-modified T cells expanded with the engineered IL-10 variant displayed superior cytolytic activity than those expanded with wild-type IL-10. Our study provides insights into how IL-10 receptor complex stability fine-tunes IL-10 biology and opens new opportunities to revitalize failed IL-10 therapies.
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