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.

Department of Biology University of Osnabrück Osnabrück Germany

Department of Molecular and Cellular Physiology Stanford University School of Medicine Stanford United States

Department of Neurology and Neurological Sciences Stanford University Stanford United States

Department of Pediatrics Stanford University Stanford United States

Department of Structural Biology Stanford University School of Medicine Stanford United States

Division of Blood and Marrow Transplantation Department of Medicine Stanford University School of Medicine Stanford United States

Division of Infectious Diseases and Geographic Medicine Department of Medicine Stanford University Stanford United States

Howard Hughes Medical Institute Stanford University School of Medicine Stanford United States

Immunology Graduate Program Stanford University School of Medicine Stanford United States

Laboratory of Molecular Immunology and Immunology Center National Heart Lung and Blood Institute NIH Bethesda United States

Laboratory of Tumor Immunology Institute of Microbiology of Czech Academy of Sciences Prague Czech Republic

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IL-2-driven CD8+ T cell phenotypes: implications for immunotherapy

Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection

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