GSE162928
Calibration of cell-intrinsic Interleukin-2 response thresholds guides design of a regulatory T cell biased agonist
Interleukin-2 (IL-2) is a pleotropic cytokine that mediates both pro- and anti-inflammatory functions. Immune cells natural 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 created through structure-based design, and then profiled, a series of IL-2 variants with the capacity to titrate signal strength in fine increments. One of these partial agonists, IL-2-REH, specifically expanded FoxP3+ regulatory T cells (Tregs) 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 therapeutic benefit in an in vivo model of mouse Colitis. 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. Overall design: RNA-Seq analyses using CD8+ T cells and Tregs that were treated with either no cytokine, or with IL-2 or IL-2-REH.