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Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist

CR. Glassman, L. Su, SS. Majri-Morrison, H. Winkelmann, F. Mo, P. Li, M. Pérez-Cruz, PP. Ho, I. Koliesnik, N. Nagy, T. Hnizdilova, LK. Picton, M. Kovar, P. Bollyky, L. Steinman, E. Meyer, J. Piehler, WJ. Leonard, KC. Garcia

. 2021 ; 10 (-) : . [pub] 20210518

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem, Research Support, U.S. Gov't, Non-P.H.S.

Perzistentní odkaz   https://www.medvik.cz/link/bmc22019704

Grantová podpora
R01 AI051321 NIAID NIH HHS - United States
R37 AI051321 NIAID NIH HHS - United States
Howard Hughes Medical Institute - United States

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 type-dependent 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.

Citace poskytuje Crossref.org

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