Abstract
For many years, the role of interleukin-2 (IL-2) in autoimmune responses was established as a cytokine possessing strong pro-inflammatory activity. Studies of the past few years have changed our knowledge on IL-2 in autoimmune chronic inflammation, suggesting its protective role, when administered at low-doses. The disrupted balance between regulatory and effector T cells (Tregs and Teffs, respectively) is a characteristic of autoimmune diseases, and is dependent on homeostatic cytokines, including IL-2. Actually, inherent defects in the IL-2 signaling pathway and/or levels leading to Treg compromised function and numbers as well as Th17 expansion have been attributed to autoimmune disorders. In this review, we discuss the role of IL-2 in the pathogenesis of autoimmune diseases. In particular, we highlight the impact of the dysregulated IL-2 pathway on disruption of the Treg/Th17 balance, reversal of which appears to be a possible mechanism of the low-dose IL-2 treatment. The negative effects of IL-2 on the differentiation of follicular helper T cells (Tfh) and pathogenic Th17 cells, both of which contribute to autoimmunity, is emphasized in the paper as well. We also compare the current IL-2-based therapies of animal and human subjects with immune-mediated diseases aimed at boosting the Treg population, which is the most IL-2-dependent cell subset desirable for sufficient control of autoimmunity. New perspectives of therapeutic approaches focused on selective delivery of IL-2 to inflamed tissues, thus allowing local activity of IL-2 to be combined with its reduced systemic and pleiotropic toxicity, are also proposed in this paper.
Highlights
Autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or type-1 diabetes (T1D), are examples of the lost tolerance to self antigens, in which one’s own immune system is able to destroy particular cells of the host
We report the significance of IL-2 in eliminating either the Tfh cells, which promote autoantibody production, or the pathogenic Th17 cells, both of which play a major role in the development of autoimmune diseases
We consistently reported a correlation between irreversible IL-2 deficit in peripheral blood (PB)
Summary
Autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or type-1 diabetes (T1D), are examples of the lost tolerance to self antigens, in which one’s own immune system is able to destroy particular cells of the host. Anti-inflammatory activity of IL-2 in autoimmunity has been generally accepted, since inherent defects in the IL-2 pathway, decreased response to IL-2, and/or reduced IL-2 availability, resulting in the impairment of Treg function, frequency and/or survival, have been found in many autoimmune disorders both in mice [3,4,5,6,7] and humans [8,9]. In Tregs, IL-2 signaling is mainly transmitted by the signal transducer and activator of transcription (STAT) pathway, resulting in induced FOXP3 expression, peripheral expansion and inhibitory function of Tregs [28,29,30,31,32]. The consequence of Treg dysfunction associated with the lost tolerance is lower suppression of pathogenic Teffs including autoreactive T cells, allowing them to become hyperactivated during immune responses
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