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.

白细胞介素-2（Interleukin-2, IL-2）是一种兼具促炎与抗炎功能的多效性细胞因子。免疫细胞对IL-2的敏感性天然存在差异，这源于其细胞类型及激活状态依赖的受体与信号通路组分表达模式不同。为探究不同细胞类型间IL-2信号通路的差异，我们通过基于结构的设计构建了一系列可精细梯度调节信号强度的IL-2变体，并对其开展了表征分析。其中一款部分激动剂IL-2-REH，可特异性扩增FoxP3+调节性T细胞（FoxP3+ regulatory T cells, Tregs），且由于IL-2信号通路的细胞内在差异，其对CD8+ T细胞的活性显著降低。IL-2-REH可诱导细胞类型依赖性的基因表达差异，并在小鼠结肠炎体内模型中展现出治疗益处。本研究结果表明，细胞因子部分激动剂可用于校准不同响应细胞类型间的应答阈值内在差异，从而缩窄其多效性作用范围，这一策略或可推广至其他细胞因子与生长因子系统。实验整体设计：对未施加细胞因子、或经IL-2或IL-2-REH处理的CD8+ T细胞与Tregs进行RNA测序（RNA-Seq）分析。