IL-2 immunotherapy for targeting regulatory T cells in autoimmunity

Abstract

FOXP3+ regulatory T cells (Treg) are indispensable for immune homoeostasis and for the prevention of autoimmune diseases. Interleukin-2 (IL-2) signalling is critical in all aspects of Treg biology. Consequences of defective IL-2 signalling are insufficient numbers or dysfunction of Treg and hence autoimmune disorders in human and mouse. The restoration and maintenance of immune homoeostasis remain central therapeutic aims in the field of autoimmunity. Historically, broadly immunosuppressive drugs with serious side-effects have been used for the treatment of autoimmune diseases or prevention of organ-transplant rejection. More recently, ex vivo expanded or in vivo stimulated Treg have been shown to induce effective tolerance in clinical trials supporting the clinical benefit of targeting natural immunosuppressive mechanisms. Given the central role of exogenous IL-2 in Treg homoeostasis, a new and promising focus in drug development are IL-2-based approaches for in vivo targeted expansion of Treg or for enhancement of their suppressive activity. In this review, we summarise the role of IL-2 in Treg biology and consequences of dysfunctional IL-2 signalling pathways. We then examine evidence of efficacy of IL-2-based biological drugs targeting Treg with specific focus on therapeutic candidates in clinical trials and discuss their limitations.

Causal effects of immune cell surface antigens and functional outcome after ischemic stroke: a Mendelian randomization study

“…CD25 (α-chain), together with CD122 (β-chain) and CD132 (γ-chain), forms the functional IL-2 receptor (IL-2R), and of these three receptor chains, the binding affinity of CD25 for IL-2 is the highest ( 38 ). IL-2 signalling can affect Treg peripheral induction, lineage commitment, stability sustainability, and homeostasis, and CD25 expression is critical for IL-2 signalling to Treg ( 39 , 40 ). Thus, the expression status of CD25 influences, to some extent, the immunomodulatory functions of Treg involved in re-establishing immune homeostasis and regulating inflammatory response after ischemic stroke.…”

The combination of IL-2 nanoparticles and Palbociclib enhances the anti-tumor immune response for colon cancer therapy

“…IL-2 was identified as an early potent immunotherapeutic agent against cancer ( 22 ), demonstrating different affinities to various receptors ( 23 ). At low doses, it binds to high-affinity receptors, activating regulatory T cells and exerting immunosuppressive effects suitable for treating autoimmune diseases ( 24 ). At high doses, IL-2 binds to medium-affinity receptors, activating effector T cells and exerting immune-activating effects, which are employed in anti-tumor therapy ( 25 ).…”

The potential protective role of peripheral immunophenotypes in Alzheimer’s disease: a Mendelian randomization study

“…Our findings indicate that the Treg cell immunophenotypes contributing to protection in AD are predominantly characterized by the secreting and activated types. Activated Treg cells are generated largely from resting Tregs after exposure to self-antigens and express high levels of CD25 ( Lykhopiy et al, 2023 ). CD25, encoded by the gene interleukin (IL)2 receptor alpha, is the α-chain of the IL-2 receptor, a component of the receptor complex.…”