TGF‐β signaling via Smad4 drives IL‐10 production in effector Th1 cells and reduces T‐cell trafficking in EAE

Abstract

SUMMARY Effector Th1 cells perpetuate inflammatory damage in a number of autoimmune diseases, including MS and its animal model EAE. Recently, a self-regulatory mechanism was described where effector Th1 cells produce the immunomodulatory cytokine IL-10 to dampen the inflammatory response in both normal and autoimmune inflammation. While the presence of TGF-β has been suggested to enhance and stabilize an IFN-γ+IL-10+ phenotype, the molecular mechanism is poorly understood. Additionally, in the context of adoptive transfer EAE, it is unclear if IL-10 acts on the transferred Th1 cells or on cells within the host. In the present study, using myelinspecific TCR-Tg mice, repetitive Ag stimulation of effector Th1 cells in the presence of TGF-β increased the population of IFN-γ+IL-10+ cells, which correlated with a decrease in EAE severity. Additionally, TGF-β signaling caused binding of smad4 to the IL-10 promoter, providing molecular evidence for TGF-β-mediated IL-10 production from Th1 effector cells. Lastly, this study demonstrates that IL-10 reduced encephalitogenic markers such as IFN-γ and T-bet on Th1 effector cells expressing the IL-10R, but also prevented recruitment of both transferred and host-derived inflammatory T cells. These data establish a regulatory mechanism by which highly activated Th1 effector cells modulate their pathogenicity through induction of IL-10.

Analysis of TGF-β1 and TGF-β3 as regulators of encephalitogenic Th17 cells: Implications for multiple sclerosis

“…However, TGF-β clearly plays a critical role in the development of CD4 + regulatory cells, which would be consistent with the observation that administration of TGF-β results in amelioration of disease. It has also been shown that TGF-β has a regulatory effect on encephalitogenic Th1 cells (Huss et al, 2011; 2010), further supporting the dominant immunosuppressive role of TGF-β in autoimmune demyelinating disease.…”

Inflammation Markers in Multiple Sclerosis: CXCL16 Reflects and May Also Predict Disease Activity

“…High levels of MMP-9 have previously been reported to predict [28], and in agreement with our results reflect [29], MRI activity in MS. A similar trend, although not significant after Bonferroni correction, was recorded for TGFβ1. It is believed that the main role of TGFβ1 is to maintain immune tolerance and that it protects against inflammatory demyelination [30,31]. However, recent studies suggest that TGFβ1 could induce the generation of autoreactive Th17 cells [32], a subset believed to promote disease activity in MS.…”

Dimethyl Fumarate Inhibits Dendritic Cell Maturation via Nuclear Factor κB (NF-κB) and Extracellular Signal-regulated Kinase 1 and 2 (ERK1/2) and Mitogen Stress-activated Kinase 1 (MSK1) Signaling

“…Cells were stimulated with LPS (100 ng/ml) in the presence or absence of DMF (70 M) for 24 h. Supernatants were then removed, and DCs were washed twice in warm PBS. MOG Cytokine ELISA-Supernatants were collected for each culture condition and analyzed for IL-12p70, IL-6, IFN-␥, and IL-17 as described previously (15). ELISA was performed using purified anti-mouse capture antibodies and biotinylated rat anti-mouse detection antibodies (BD Biosciences).…”

“…Flow Cytometry and Intracellular Cytokine Staining-Flow cytometric analysis was performed to evaluate CD44 expression on T cells as described previously (15). In the co-culture, GolgiPlug (1 mg/ml; BD Biosciences) was used to block cytokine secretion for the last 4 h prior to staining.…”