Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses
DC Element | Wert | Sprache |
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dc.contributor.author | Gorby, Claire | |
dc.contributor.author | Bellon, Junel Sotolongo | |
dc.contributor.author | Wilmes, Stephan | |
dc.contributor.author | Warda, Walid | |
dc.contributor.author | Pohler, Elizabeth | |
dc.contributor.author | Fyfe, Paul K. | |
dc.contributor.author | Cozzani, Adeline | |
dc.contributor.author | Ferrand, Christophe | |
dc.contributor.author | Walter, Mark R. | |
dc.contributor.author | Mitra, Suman | |
dc.contributor.author | Piehler, Jacob | |
dc.contributor.author | Moraga, Ignacio | |
dc.date.accessioned | 2021-12-23T16:22:17Z | - |
dc.date.available | 2021-12-23T16:22:17Z | - |
dc.date.issued | 2020 | |
dc.identifier.issn | 19450877 | |
dc.identifier.uri | https://osnascholar.ub.uni-osnabrueck.de/handle/unios/14246 | - |
dc.description.abstract | 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. | |
dc.description.sponsorship | Wellcome TrustWellcome TrustEuropean Commission [203752/Z/16/Z, 202323/Z/16/Z]; ERC-206-STG grant; EMBOEuropean Molecular Biology Organization (EMBO) [454-2017]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SFB 944]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 AI143554]; Projects Fondation ARC 2019; La Ligue Contre le Cancer grants; This work was supported by the Wellcome Trust 203752/Z/16/Z (to C.G.), by the Wellcome-Trust-202323/Z/16/Z and ERC-206-STG grant (to I.M.), by EMBO (454-2017; to S.W.), by the Deutsche Forschungsgemeinschaft (SFB 944 and P8/Z to J.P.), and NIH (R01 AI143554 to M.R.W.). The Mitra laboratory is supported by the Projects Fondation ARC 2019 and La Ligue Contre le Cancer grants. | |
dc.language.iso | en | |
dc.publisher | AMER ASSOC ADVANCEMENT SCIENCE | |
dc.relation.ispartof | SCIENCE SIGNALING | |
dc.subject | ACTIVATION | |
dc.subject | Biochemistry & Molecular Biology | |
dc.subject | Cell Biology | |
dc.subject | CLASS-II | |
dc.subject | CYTOKINE PRODUCTION | |
dc.subject | EXPRESSION | |
dc.subject | IFN-GAMMA | |
dc.subject | INTERLEUKIN-10 | |
dc.subject | MONOCYTES | |
dc.subject | STAT3 | |
dc.subject | T-CELLS | |
dc.subject | TYROSINE PHOSPHORYLATION | |
dc.title | Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses | |
dc.type | journal article | |
dc.identifier.doi | 10.1126/scisignal.abc0653 | |
dc.identifier.isi | ISI:000570555500003 | |
dc.description.volume | 13 | |
dc.description.issue | 649 | |
dc.contributor.orcid | 0000-0002-7171-9747 | |
dc.contributor.orcid | 0000-0001-5837-0459 | |
dc.contributor.orcid | 0000-0003-3541-2294 | |
dc.contributor.orcid | 0000-0003-3994-6744 | |
dc.contributor.orcid | 0000-0001-9909-0701 | |
dc.contributor.orcid | 0000-0002-9102-8847 | |
dc.contributor.orcid | 0000-0003-0119-3919 | |
dc.contributor.orcid | 0000-0002-4112-710X | |
dc.identifier.eissn | 19379145 | |
dc.publisher.place | 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA | |
dcterms.isPartOf.abbreviation | Sci. Signal. | |
dcterms.oaStatus | Green Submitted, Green Accepted | |
crisitem.author.dept | FB 05 - Biologie/Chemie | - |
crisitem.author.deptid | fb05 | - |
crisitem.author.orcid | 0000-0002-2143-2270 | - |
crisitem.author.parentorg | Universität Osnabrück | - |
crisitem.author.netid | PiJa938 | - |
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geprüft am 15.05.2024