The Tim-3/galectin-9 pathway involves in the homeostasis of hepatic Tregs in a mouse model of concanavalin A-induced hepatitis

Abstract T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is a negative regulator of interferon (IFN)-γ-secreting CD4 + Th1 cells and plays a key role in autoimmune diseases. Here, we report that galectin-9 expression was increased in hepatic CD4 + CD25 + T cells in a mouse model of concanavalin A (Con A)-induced hepatitis. Moreover, Tim-3 showed increased levels in CD4 + CD25 + Foxp3 + regulatory T cells (Tregs). Further analyses showed that blocking the Tim-3/galectin-9 pathway resulted in the suppression of Tregs in vitro, thereby significantly increasing interferon (IFN)-γ production from hepatic Teffs. Moreover, blockade of Tim-3 in vivo with an anti-Tim-3 antibody exacerbated the acute hepatitis, possibly by increased IFN-γ production. Furthermore, we found that in vitro activation of CD4 + CD25 − T cells with the T cell receptor (TCR) plus interleukin 2 (IL-2) up-regulated Tim-3 expression. And the induced Tim-3 interacted with galectin-9 to induce CD4 + T cell apoptosis which could be partly reversed by blocking Tim-3 signaling. Our results suggested that the Tim-3/galectin-9 pathway plays a critical role in the homeostasis of hepatic Tregs through the elimination induction in Teffs and the inhibition of IFN-γ release, which contributes to the pathogenesis of liver damage and constitutes at least part of the mechanism underlying the induction of hepatitis by Con A.