Therapeutic window of interleukin-2 for autoimmune diseases.

Abstract

An uncontrolled immune system threatens human health as much as a defective one. Autoimmune diseases, such as type 1 diabetes (T1D), result from destruction of healthy tissues by a rogue immune system. Much of the self-policing of the immune system can be attributed to one subset of T cells called regulatory T cells (Tregs) (1). Patients with congenital defects in Tregs develop fatal multiorgan autoimmune diseases early in life (2). Tregs can be identified by the cell surface phenotype of CD4+CD25+CD127lo. CD25 is not merely a marker for Tregs but important for the maintenance and function of these cells as well. It associates with CD122 and CD132 to form the high-affinity receptor for interleukin (IL)-2, a growth factor for T cells. CD25 is constitutively expressed on Tregs, whereas its expression on other T cells is induced only after activation. Therefore, Tregs can better respond to IL-2 than other T cells in the steady state, prompting the consideration of using IL-2 therapeutically to expand Tregs for restoration of immune homeostasis. One challenge to this approach is that other T cells and natural killer (NK) cells constitutively express CD122 and CD132 that can respond to high-dose IL-2, leading to their activation and tissue destruction. In fact, the current U.S. Food and Drug Administration–approved use of IL-2 is for enhancing immunity …