IL-2-based approaches to Treg enhancement

Abstract

Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients.

Keywords: autoimmunity; autoinflammatory disease; cytokines; immunotherapy; regulatory T cells.

Graphical Abstract

Figure 1.

IL-2 signaling and autoimmune disease susceptibility genes. IL-2 signals through receptor complexes composed of up to 3 subunits; the IL-2 receptor-α (CD25), IL-2 receptor-β (CD122), and the IL-2 receptor-γ (CD132; common-gamma chain). In conventional T cells, engagement with the intermediate affinity receptor or the high-affinity receptor initiates signal transduction through the STAT5, Ras/Raf/MAPK, and PI3K/Akt, mTOR signaling pathways leading to expression of IL-2 response genes. Regulatory T cells express high levels of PTEN which inhibits the PI3K/Akt/mTOR pathway, leaving Tregs relatively resistant to the effects of the immunosuppressant drug Rapamycin. Genome-wide association studies have identified single nucleotide polymorphisms in several elements of the IL-2 signaling pathway which increase the risk of autoimmune disease development (dashed boxes). Figure creating using BioRender.

Figure 2.

IL-2 engineering approaches. Several IL-2 technologies have been developed which act to increase the affinity of IL-2 to the high-affinity receptor complex, thus selectively expanding Tregs, and to increase its serum half-life in comparison to wild-type IL-2. Firstly, IL-2 can undergo PEGylation by attaching polyethyleneglycol chains to its surface. IL-2 muteins are generated by introducing point mutations into either the IL-2 protein or its receptor. IL-2 complexes are composed of IL-2 bound to either human or murine antibodies which act to block or conformationally alter binding sites for the IL-2 receptor-β (CD122). Finally, fusion proteins of IL-2 and the IL-2 receptor-α can also increase Treg selectivity and half-life. Figure created using BioRender.