Regulatory T cells ameliorate acetaminophen-induced immune-mediated liver injury

Abstract

The contribution of innate immune cells to acetaminophen (APAP)-induced liver injury has been extensively investigated. However, the roles of T cell populations among adaptive immune cells in APAP-induced liver injury remain to be elucidated. Herein, we found that distinct CD4(+) T cell subsets but not CD8(+) T cells modulated APAP-induced liver injury in mice. After APAP challenge, more CD62L(low)CD44(hi)CD4(+) T cells appeared in the liver, accompanied by increased IFN-γ. The removal of CD4(+) T cells by either antibody depletion or genetic deficiency markedly compromised pro-inflammatory cytokine levels and ameliorated liver injury. Meanwhile, we also found that the frequency and absolute number of Treg cells also increased. Treg cell depletion increased hepatic CD62L(low)CD44(hi)CD4(+) T cells, augmented pro-inflammatory cytokines, and exacerbated liver injury, while adoptive transfer of Treg cells ameliorated APAP-induced liver injury. Furthermore, the recruitment of Treg cells into the liver through specific expression of CXCL10 in the liver could ameliorate APAP-induced liver injury. Our investigation suggests that Th1 and Treg subsets are involved in regulating APAP-induced liver injury. Thus, modulating the Th1/Treg balance may be an effective strategy to prevent and/or treat APAP-induced liver injury.

Keywords: Acetaminophen; Adaptive immune cells; CXCL10; Liver injury; Regulatory T cells.