A glimpse into the application of the immunomodulatory effect of IL-2 in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, which is mainly caused by the imbalance of immune cells. Current treatment regimens predominately rely on corticosteroids and immunosuppressive agents, accompanied by various side effects. Interleukin-2 (IL-2) is deemed an important cytokine for innate immune cells and adaptive immune cells, especially for the promotion of Treg cells. By combining IL-2/IL-2R system with engineered T cell-based immunotherapies to enhance the therapeutic efficacy of engineered T cells shows its potential in autoimmune diseases. But the pleiotropy of IL-2 may cause simultaneous stimulation and systemic toxicity, limiting its therapeutic use. There is a growing focus on using IL-2 in combination strategies for synergistic immune enhancement. In this article, we review the IL-2/IL-2R signaling, including IL-2 dependent signaling and IL-2 independent signaling, and discuss its functions in regulation of different immune cells. In addition, we summarize major clinical application of low-dose IL-2 treatment in SLE with or without other agents, such as rapamycin, tocilizumab and rituximab, present the IL-2 variants and fusion proteins designed for SLE, and highlight the future trends for research on these cytokine-based immunotherapies. It will help to design further optimized IL-2-based therapy for SLE.

Keywords: IL-2; SLE; engineered T cells; immunotherapy; interleukin-2.

FIGURE 1

IL-2/IL-2R signaling pathways. When IL-2 binds with intermediate-affinity IL-2R or high-affinity IL-2R, the formation of cytokine-receptor complex leads to the activation of JAK1 next to IL-2Rβ and JAK3 next to γc. Although the binding affinity can be increased by IL-2Rα, IL-2Rα does not work as the signaling subunit. Downstream signaling pathways are presented as (a–c). (a) IL- 2 promotes the phosphorylation of STAT5 affecting the expression of Foxp3, Blimp1, Bcl-1 and Bcl-6 to regulate the differentiation and maturation of T cell subsets. (b) IL- 2 promotes the activation of PI3K-AKT-mTOR pathway to regulate T cell growth, survival, exhaustion and metabolism. (c) IL- 2 promotes the activation of MAPK pathways to regulate T cell proliferation and function.