Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses.

Autor:	Gorby C; Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK., Sotolongo Bellón J; Department of Biology and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, Barbarastraße 11, 49076 Osnabrück, Germany., Wilmes S; Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK., Warda W; Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France., Pohler E; Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK., Fyfe PK; Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK., Cozzani A; Université de Lille, INSERM UMR1277 CNRS UMR9020-CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France., Ferrand C; Université Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France., Walter MR; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35243, USA., Mitra S; Université de Lille, INSERM UMR1277 CNRS UMR9020-CANTHER and Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France., Piehler J; Department of Biology and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, Barbarastraße 11, 49076 Osnabrück, Germany., Moraga I; Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee DD15EH, UK. imoragagonzalez@dundee.ac.uk.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2020 Sep 15; Vol. 13 (649). Date of Electronic Publication: 2020 Sep 15.
DOI:	10.1126/scisignal.abc0653
Abstrakt:	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-10Rβ receptor using yeast surface display. Compared to the wild-type cytokine, the affinity-enhanced IL-10 variants recruited IL-10Rβ 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. (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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