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Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist
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SYSNO ASEP 0543231 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist Author(s) Glassman, C. R. (US)
Su, L. (US)
Majri-Morrison, S. S. (US)
Winkelmann, H. (DE)
Mo, F. (US)
Li, P. (US)
Perez-Cruz, M. (US)
Ho, P. P. (US)
Koliesnik, I. (US)
Nagy, N. (US)
Hnízdilová, Tereza (MBU-M)
Picton, L.K. (US)
Kovář, Marek (MBU-M) RID, ORCID
Bollyky, P. (US)
Steinman, L. (GB)
Meyer, E. (US)
Piehler, J. (DE)
Leonard, W. J. (DE)
Garcia, K. C. (US)Number of authors 19 Article number e65777 Source Title eLife. - : eLife - ISSN 2050-084X
Roč. 10, MAY 18 2021 (2021)Number of pages 28 s. Language eng - English Country GB - United Kingdom Keywords il-2 receptor ; molecular-cloning ; gamma-chain ; alpha-chain ; beta-chain ; mice ; expression ; gene ; proliferation ; autoimmunity Subject RIV EE - Microbiology, Virology OECD category Microbiology R&D Projects GA18-12973S GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support MBU-M - RVO:61388971 UT WOS 000653615000001 EID SCOPUS 85106158874 DOI 10.7554/eLife.65777 Annotation Interleukin-2 is a pleiotropic cytokine that mediates both pro- and anti-inflammatory functions. Immune cells naturally differ in their sensitivity to IL-2 due to cell type and activation state-dependent expression of receptors and signaling pathway components. To probe differences in IL-2 signaling across cell types, we used structure-based design to create and profile a series of IL-2 variants with the capacity to titrate maximum signal strength in fine increments. One of these partial agonists, IL-2-REH, specifically expanded Foxp3+ regulatory T cells with reduced activity on CD8+ T cells due to cell type-intrinsic differences in IL-2 signaling. IL-2-REH elicited cell typedependent differences in gene expression and provided mixed therapeutic results: showing benefit in the in vivo mouse dextran sulfate sodium (DSS) model of colitis, but no therapeutic efficacy in a transfer colitis model. Our findings show that cytokine partial agonists can be used to calibrate intrinsic differences in response thresholds across responding cell types to narrow pleiotropic actions, which may be generalizable to other cytokine and growth factor systems. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2022 Electronic address https://elifesciences.org/articles/65777
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