Unknown

Dataset Information

0

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


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.

SUBMITTER: Gorby C 

PROVIDER: S-EPMC7685028 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications


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-10  ...[more]

Similar Datasets

2020-09-15 | GSE146438 | GEO
| PRJNA610578 | ENA
| S-EPMC10412504 | biostudies-literature
2021-10-28 | GSE160332 | GEO
| S-EPMC2796259 | biostudies-literature
| S-EPMC3795018 | biostudies-literature
| S-EPMC4025786 | biostudies-other
| S-EPMC10458264 | biostudies-literature
| S-EPMC1559766 | biostudies-literature
| S-EPMC3304096 | biostudies-literature