Abstract
Regulatory T cells (Treg) are crucial for the maintenance of peripheral tolerance and for the control of ongoing inflammation and autoimmunity. The cytokine interleukin-2 (IL-2) is essentially required for the growth and survival of Treg in the peripheral lymphatic tissues and thus plays a vital role in the biology of Treg. Most autoimmune and rheumatic diseases exhibit disturbances in Treg biology either at a numerical or functional level resulting in an imbalance between protective and pathogenic immune cells. In addition, in some autoimmune diseases, a relative deficiency of IL-2 develops during disease pathogenesis leading to a disturbance of Treg homeostasis, which further amplifies the vicious cycle of tolerance breach and chronic inflammation. Low-dose IL-2 therapy aims either to compensate for this IL-2 deficiency to restore a physiological state or to strengthen the Treg population in order to be more effective in counter-regulating inflammation while avoiding global immunosuppression. Here we highlight key findings and summarize recent advances in the clinical translation of low-dose IL-2 therapy for the treatment of autoimmune and rheumatic diseases.
Highlights
Since the 1970s, when the cytokine interleukin-2 (IL 2) was first discovered and cloned, the view on its function and role in the immune system has changed fundamentally [1, 2]
Later studies could clearly link IL-2 with immune tolerance by showing that IL-2 is essentially required for the growth and survival of regulatory T cells (Treg) in the peripheral lymphatic organs and for their thymic development and differentiation, highlighting the fundamental importance of IL-2 in Treg biology [9,10,11]
But probably less likely because of the quite universal response pattern to low-dose IL-2 therapy reported so far, disease-related alterations in IL-2 signaling pathways and associated molecules leading to differences in the biological responsiveness to IL-2 therapy could affect clinical efficacy
Summary
Since the 1970s, when the cytokine interleukin-2 (IL 2) was first discovered and cloned, the view on its function and role in the immune system has changed fundamentally [1, 2]. The in vitro suppressive function of Treg from SLE patients was not impaired suggesting that expansion of the endogenous Treg population by low-dose IL-2 therapy is a feasible approach to strengthen immune tolerance Together, these studies demonstrated the pathophysiological importance of a disturbed Treg-IL-2 axis in SLE and constituted the scientific basis for the clinical introduction of low-dose IL-2 therapy in SLE. The findings here are less clear compared to those in SLE and in part even inconsistent, it appears justified to suppose, in consideration of the immune pathogenesis of these diseases, that expansion of the Treg population or inhibition of Tfh and Th17 cell differentiation by low-dose IL-2 therapy could be a potential treatment option for a large variety of autoimmune and rheumatic diseases
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