Interleukin-4 Supports the Suppressive Immune Responses Elicited by Regulatory T Cells

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.

The SNP rs2298383 Reduces ADORA2A Gene Transcription and Positively Associates with Cytokine Production by Peripheral Blood Mononuclear Cells in Patients with Multiple Chemical Sensitivity

“…Notably, MCS patients frequently report co-morbidities, such as hay fever, asthma and atopic dermatitis [3,10]. Moreover, IL-4 plays a role in antagonizing pathogenic Th1 responses [40]. The increased IL-4 serum levels observed in MCS patients recruited for this study and in other studies [9,10], and the here observed significant positive correlation with IFN-γ levels, suggest a compensative reaction to buffer the increase of IFN-γ production.…”

“…IL-4 is a cytokine associated with the activation of Th2 cells, and has long been considered as one of the tolerogenic cytokines in many autoimmune animal models and clinical settings; however, its overproduction has mainly been associated with the development of allergic reactions and atopy [40]. Notably, MCS patients frequently report co-morbidities, such as hay fever, asthma and atopic dermatitis [3,10].…”

Integration of immunome with disease-gene network reveals common cellular mechanisms between IMIDs and drug repurposing strategies

“…The key DAGs contributing to this cluster included B2M, IGHG3, IL7R, ETS1, RPS19, and TNFAIP3. The pathway enrichment for the SLE DIME network includes pathways that are heavily described in the literature for SLE, such as the neutrophil degranulation pathways or NETosis 37–41 , interleukin 4 and interleukin 13 signaling 42,43 , TLR signaling pathway 44 , translocation of ZAP70 to immunological synapsis 45 , and immune-regulatory interactions between lymphoid and non-lymphoid cells ( Supplementary Figure 4A ).…”

Lipid laden macrophages and electronic cigarettes in healthy adults

“…Among the e-cigs users, a significant association between LLM and lung inflammatory cytokines IL-4 and IL-10 was found, but not other cytokines associated with smoking [14] . Unlike the other cytokines that were tested, IL-4 and IL-10 play a role as an immune suppressor and are required to avoid inflammation and maintain tissue homeostasis [ 18 , 19 ]. IL-4 promotes macrophage activation into the M2 phenotype, and M2 macrophages produce IL-10 [20] .…”