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Abstract
Interleukin-4 (IL-4) has been considered as one of the tolerogenic cytokines in many autoimmune animal models and clinical settings. Despite its role in antagonizing pathogenic Th1 responses, little is known about whether IL-4 possesses functions that affect regulatory T cells (Tregs). Tregs are specialized cells responsible for the maintenance of peripheral tolerance through their immune modulatory capabilities. Interestingly, it has been suggested that IL-4 supplement at a high concentration protects responder T cells (Tresps) from Treg-mediated immune suppression. In addition, such supplement also impedes TGF-β-induced Treg differentiation in vitro. However, these phenomena may contradict the tolerogenic role of IL-4, and the effects of IL-4 on Tregs are therefore needed to be further elucidated. In this study, we utilized IL-4 knockout (KO) mice to validate the role of IL-4 on Treg-mediated immune suppression. Although IL-4 KO and control animals harbor similar frequencies of Tregs, Tregs from IL-4 KO mice weakly suppressed autologous Tresp activation. In addition, IL-4 deprivation impaired the ability of Tregs to modulate immune response, whereas IL-4 supplementation reinforced IL-4 KO Tregs in their function in suppressing Tresps. Finally, the presence of IL-4 was associated with increased cell survival and granzyme expression of Tregs. These results suggest the essential role of IL-4 in supporting Treg-mediated immune suppression, which may benefit the development of therapeutic strategies for autoimmune diseases.
Highlights
The effector and suppressor immune responses appear to be maintained in a well-tuned and active equilibrium, leading to immune system homeostasis
The pathological role of IL-4 and Th2 immune response in autoimmune development has been demonstrated in various autoimmune disorders, the role of IL-4 in autoimmunity remains controversial
Genetic polymorphisms of IL-4 and its signaling downstream element, STAT6, are related to systemic lupus erythematosus (SLE) in humans [42], and increased plasma IL-4 can be detected in patients with SLE or rheumatoid arthritis [43]
Summary
The effector and suppressor immune responses appear to be maintained in a well-tuned and active equilibrium, leading to immune system homeostasis. Studies performed in murine models have indicated that autoimmune-related inflammation can be controlled by IL-4 treatment through its pleiotropic effects on the immune system, which include inducing alternative activated macrophages [6, 7], equipping macrophages with regulatory functions [8], and combining with retinoic acid to endow dendritic cells with immune modulatory properties [9]. Suppression of the Th1 response through nasal administration of autoantigen-derived peptides has been proven to protect against disease development in spontaneous autoimmune disease model [10, 12, 13]. The lack of IL-4 impedes the generation of graft tolerance in a murine transplantation model [14] Together, these findings indicate that IL-4 is beneficial for the maintenance and establishment of peripheral tolerance
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