Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses
Autor(en): | Gorby, Claire Bellon, Junel Sotolongo Wilmes, Stephan Warda, Walid Pohler, Elizabeth Fyfe, Paul K. Cozzani, Adeline Ferrand, Christophe Walter, Mark R. Mitra, Suman Piehler, Jacob Moraga, Ignacio |
Stichwörter: | ACTIVATION; Biochemistry & Molecular Biology; Cell Biology; CLASS-II; CYTOKINE PRODUCTION; EXPRESSION; IFN-GAMMA; INTERLEUKIN-10; MONOCYTES; STAT3; T-CELLS; TYROSINE PHOSPHORYLATION | Erscheinungsdatum: | 2020 | Herausgeber: | AMER ASSOC ADVANCEMENT SCIENCE | Journal: | SCIENCE SIGNALING | Volumen: | 13 | Ausgabe: | 649 | Zusammenfassung: | 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. |
ISSN: | 19450877 | DOI: | 10.1126/scisignal.abc0653 |
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geprüft am 15.05.2024