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

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 in which 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-beta has been suggested to enhance and stabilize an IFN-gamma(+)IL-10(+) phenotype, the molecular mechanism is poorly understood. Additionally, in the context of adoptive transfer EAE, it is unclear whether IL-10 acts on the transferred Th1 cells or on endogenous host cells. In the present study, using myelin-specific TCR-Tg mice, we show that repetitive Ag stimulation of effector Th1 cells in the presence of TGF-beta increases the population of IFN-gamma(+)IL-10(+) cells, which correlates with a decrease in EAE severity. Additionally, TGF-beta signaling causes binding of Smad4 to the IL-10 promoter, providing molecular evidence for TGF-beta-mediated IL-10 production from Th1 effector cells. Finally, this study demonstrates that IL-10 not only reduces encephalitogenic markers such as IFN-gamma and T-bet on Th1 effector cells expressing the IL-10R but also prevents 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 the induction of IL-10.