Calibration of cell-intrinsic interleukin-2 response thresholds guides design of a regulatory T cell biased agonist
| Autor: | Everett Meyer, Leon Su, Nadine Nagy, Caleb R. Glassman, Magdiel Pérez-Cruz, Lora Picton, K. Christopher Garcia, Fei Mo, Peggy P. Ho, Lawrence Steinman, Paul L. Bollyky, Hauke Winkelmann, Jacob Piehler, Warren J. Leonard, Marek Kovar, Ievgen O. Koliesnik, Sonia S Majri-Morrison, Peng Li, Tereza Hnizdilova |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Interleukin 2 Cell type Mouse Regulatory T cell QH301-705.5 medicine.medical_treatment Science CD8-Positive T-Lymphocytes T-Lymphocytes Regulatory General Biochemistry Genetics and Molecular Biology Cell Line immunology 03 medical and health sciences Mice 0302 clinical medicine Immunology and Inflammation Biochemistry and Chemical Biology medicine Animals Biology (General) Receptor General Immunology and Microbiology Chemistry General Neuroscience IL-2 FOXP3 General Medicine Colitis Cell biology Mice Inbred C57BL Disease Models Animal 030104 developmental biology Cytokine medicine.anatomical_structure Medicine Cytokines Interleukin-2 Female cytokine signaling Signal transduction 030217 neurology & neurosurgery CD8 medicine.drug Signal Transduction Research Article Human |
| Zdroj: | eLife eLife, Vol 10 (2021) |
| ISSN: | 2050-084X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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