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Calibration Of Cell-intrinsic Interleukin-2 Response Thresholds Guides Design Of A Regulatory T Cell Biased Agonist

Caleb R Glassman, Leon Su, Sonia S Majri-Morrison, Hauke Winkelmann, Fei Mo, Peng Li, Magdiel Pérez-Cruz, Peggy P Ho, Ievgen Koliesnik, Nadine Nagy, Tereza Hnizdilova, Lora K Picton, Marek Kovar, Paul Bollyky, Lawrence Steinman, Everett Meyer, Jacob Piehler, Warren J Leonard, K Christopher Garcia

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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.