The IL-2 - IL-2 receptor pathway: Key to understanding multiple sclerosis

Abstract

The development, progression, diagnosis and treatment of autoimmune diseases, such as multiple sclerosis (MS), are convoluted processes which remain incompletely understood. Multiple studies demonstrated that the interleukin (IL)-2 - IL-2 receptor (IL-2R) pathway plays a pivotal role within these processes. The most striking functions of the IL-2 - IL-2R pathway are the differential induction of autoimmune responses and tolerance. This paradoxical function of the IL-2 - IL-2R pathway may be an attractive therapeutic target for autoimmune diseases such as MS. However, the exact mechanisms that lead to autoimmunity or tolerance remain to be elucidated. Furthermore, another factor of this pathway, the soluble form of the IL-2R (sIL-2R), further complicates understanding the role of the IL-2 - IL-2R pathway in MS. The challenge is to unravel these mechanisms to prevent, diagnose and recover MS. In this review, first, the current knowledge of MS and the IL-2 - IL-2R pathway are summarized. Second, the key findings of the relation between the IL-2 - IL-2R pathway and MS have been highlighted. Eventually, this review may launch broad interest in the IL-2 - IL-2R pathway propelling further research in autoimmune diseases, including MS.

Keywords: Interleukin 2; Interleukin 2 receptor; Multiple sclerosis; Soluble interleukin 2 receptor.

Fig. 1

The IL-2R classification and the IL-2 – IL-2R signalling pathway. IL-2 binds to the monomeric (low binding affinity: K_d of $\sim$10⁻⁸ M), dimeric (intermediate binding affinity: K_d of $\sim$10⁻⁹ M), trimeric (high binding affinity: K_d of $\sim$10⁻¹¹ M) and soluble (binding affinity: K_d of $\sim$10⁻¹⁰ M, sIL-2R) IL-2R. The monomeric IL-2R consists of only the IL-2Rα-chain. The heterodimeric receptor is composed of the combination of the IL-2Rβ and -γ forms, while the trimeric receptor combines all three subunits. The trimeric IL-2R can be constructed by the cis-presentation of IL-2Rα on T-cells and the trans-presentation of IL-2Rα on antigen presenting cells (e.g., dendritic cells, DCs). The IL-2Rα-chain can be shed off, generating the sIL-2R. Only the binding of IL-2 to the dimeric and trimeric IL-2Rs results in downstream signalling via three main pathways: PI3K-AKT, STAT5 and MAPK. These pathways activate the transcription of target genes such as the IL2RA gene.

Fig. 2

The interleukin (IL-)2 – IL-2 receptor (IL-2R) pathway in multiple sclerosis (MS). The role of the IL-2 – IL-2R pathway in MS is influenced by genetic and environmental factors. This can lead to immune homeostasis (balance of regulatory, helper and cytotoxic T-cells (T_reg, T_h and T_c, respectively) and natural killer cells (NK-cells)) or immune disturbance, less NK-cells and T_reg and more T_h- and T_c-cells. Subsequently, a balanced immune homeostasis enables prevention and recovering of MS, while disturbed immune responses enable development and worsening of MS. Furthermore, the soluble form of the IL-2R (sIL-2R) also seems to play an important role within these outcomes. However, the exact function remains to be elucidated.