Regulatory T cells suppress TLR9-induced formation of intrahepatic myeloid-cell aggregates for T cell population expansion in liver.

Abstract

Toll-like receptor (TLR) 9 ligand has been reported to induce the formation of intrahepatic myeloid-cell aggregates for T cell population expansion (iMATEs), which enhances responses of cytotoxic T lymphocytes (CTLs). However, little is known about how the formation of iMATEs is regulated. Previously, various studies have demonstrated that regulatory T cells (Tregs) can suppress CTL responses through soluble cytokines or co-inhibitory molecules. It's unclear whether and how Tregs regulate the formation of iMATEs. In this study, we investigated whether Tregs are involved in regulating TLR9-induced iMATEs formation and the mechanisms behind it by using different gene knockout mice and blocking antibodies. We observed that intravenous injection of TLR9 ligand CpG induced significant iMATEs formation, accompanied by a marked increase in the number of Tregs infiltrating the liver as well as upregulation of IL-10 in both peripheral blood and liver. Importantly, depletion of Tregs either by anti-CD4, anti-CD25 blocking antibodies or diphtheria toxin (DT) in DEREG transgenic mice resulted in enhanced CpG-induced iMATEs formation. Conversely, knocking out IL-10 led to increased intrahepatic Treg infiltration and decreased CpG ODN-induced iMATEs formation. Consistently, depleting Kupffer cells (KCs), one of the main source of IL-10, also resulted in reduced formation of iMATEs. In conclusion, our results suggest that IL-10 suppresses Treg infiltration in the liver and thus promote CpG ODN-induced iMATEs formation. These results fill the gap in our understanding of the intrahepatic regulation mechanism of iMATEs formation.