Interleukin-4 Inhibits Regulatory T Cell Differentiation through Regulating CD103+ Dendritic Cells

Abstract

CD103+ dendritic cells (DCs) have been shown to play a crucial role in the pathogenesis of inflammatory bowel diseases (IBDs) through educating regulatory T (Treg) cells differentiation. However, the mechanism of CD103+ DCs subsets differentiation remains elusive. Interleukin (IL)-4 is a pleiotropic cytokine that is upregulated in certain types of inflammation, including IBDs and especially ulcerative colitis. However, the precise role of IL-4 in the differentiation of CD103+ DCs subpopulation remains unknown. In this study, we observed a repressive role of IL-4 on the CD103+ DCs differentiation in both mouse and human. High-dose IL-4 inhibited the CD103+ DC differentiation. In comparison to CD103− DCs, CD103+ DCs expressed high levels of the co-stimulatory molecules and indoleamine 2,3-dioxygenase (IDO). Interestingly, IL-4 diminished IDO expression on DCs in a dose-dependent manner. Besides, high-dose IL-4-induced bone marrow-derived DCs, and monocyte-derived DCs revealed mature DCs profiles, characterized by increased co-stimulatory molecules and decreased pinocytotic function. Furthermore, DCs generated under low concentrations of IL-4 favored Treg cells differentiation, which depend on IDO produced by CD103+ DCs. Consistently, IL-4 also reduced the frequency of CD103+ DC in vivo. Thus, we here demonstrated that the cytokine IL-4 involved in certain types of inflammatory diseases by orchestrating the functional phenotype of CD103+ DCs subsets.

Identification of molecules associated with response to abatacept in patients with rheumatoid arthritis

“…Since type I IFN is primarily produced by plasmacytoid dendritic cells (pDC), we selected dendritic cell-related genes or type I IFN-related genes with significant biological implications for quantification using RT-qPCR among the 218 genes as follows: BATF2, LAMP3, and CD83 are related to dendritic cell activation and maturation [17][18][19]; TNFSF10, BTLA, and IDO1 are expressed on dendritic cells (DCs) [20][21][22][23][24]. CLEC4A has a role in the production of type I IFN from pDC [25], and STAT1, STAT2, and IRF7 have roles in the signal of type I IFN production [26][27][28].…”

The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function

“…Interestingly, ILC2 in both mesenteric lymph nodes and the peritoneal lavage increase in H. polygyrus infections also expand and activate the host's T reg population, especially early in an infection when these cells appear to outpace the proliferation of effector T cells and modulate the immune response (Filbey, Grainger et al, 2014). An increased frequency of T reg -possibly as a result of low dose IL-4 exposure (Tu, Chen et al, 2017) was observed in the mesenteric lymph nodes of infected CCT8 T-/animals where these cells may further inhibit Th2 immunity (Grainger, Smith et al, 2010). However, the frequency of T reg was significantly reduced in the peritoneal lavage.…”

“…Upon re-infection with H. polygyrus, the ILC2 frequency was comparable for CCT8 T-/and CCT8 T+/+ mice but the absolute cellularity was lower in mutant mice (Figure 5h). This finding correlated with a lack of intestinal tuft cells, thus suggesting a feed-forward loop which increases numbers of these cells (Gerbe, Sidot et al, 2016, von Moltke et al, 2016 whereby ILC2 cells do not suffice and an adaptive T cell contribution is required. This is, however, absent in the CCT8 T+/+ mice, particularly during a secondary infection (Figure EV 4).…”

“…The type 2 cytokines IL-5 and IL-13 are also secreted early during a helminth infection by innate lymphocytes (ILC2) in response to the release of IL-33 and TSLP from mucosal epithelial sensor cells (Cortes, Munoz-Antoli et al, 2017, von Moltke, Ji et al, 2016. We therefore quantified these innate lymphocytes in mesenteric lymph nodes and in the peritoneal lavage of infected wild type and CCT8 -/mice.…”

Ketoprofen as an Add-on Treatment to Sertraline for Drug-Naïve Major Depressed Patients: Normalization of Plasma Levels of Indoleamine-2,3-Dioxygenase in Association with Pro-Inflammatory and Immune Regulatory Cytokines

“…Although increased IL-4 may initially constitute a protective response (by regulating M1 and Th1 activation), this Th2 cytokine also exhibits more detrimental effects. For example, in vitro studies show that IL-4 may diminish IDO expression in dendritic cells (Tu et al, 2017) (thereby decreasing the protective CIRS effects of the TRYCAT pathway), reduce dendritic cell expression of IL-10 thereby promoting a Th1 phenotype and inhibiting Treg cell differentiation (Yao et al, 2005;Tu et al, 2017). This may explain that IL-4 is involved in certain types of inflammatory diseases by orchestrating the functional phenotype of dendritic cells (Tu et al, 2017).…”