Open AccessEngineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses
Author(s) -
Claire Gorby,
Junel Sotolongo Bellón,
Stephan Wilmes,
Walid Warda,
Elizabeth Pöhler,
Paul K. Fyfe,
Adeline Cozzani,
Christophe Ferrand,
Mark R. Walter,
Suman Mitra,
Jacob Piehler,
Ignacio Moraga
Publication year - 2020
Publication title -
science signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.659
H-Index - 154
eISSN - 1937-9145
pISSN - 1945-0877
DOI - 10.1126/scisignal.abc0653
Subject(s) - cd8 , cytokine , t cell , microbiology and biotechnology , receptor , biology , monocyte , ligand (biochemistry) , immune system , immunology , biochemistry
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.