Abstract
Liver dendritic cells (DCs) display immunosuppressive activities and inhibit the CD4+ T cell response. The present study assessed whether and how liver DCs suppress CD8+ T cells. We found that bone marrow-derived mature DCs incubated with liver stromal cells were characterized by a longer life span, reduced CD11c, IA/IE, CD80, CD86, and CD40 expression, and increased CD11b expression. These unique liver stromal cell-educated mature DCs (LSed-DCs) stimulated CD8+ T cells to express CD25 and CD69, but inhibited their proliferation. CD8+ T cell suppression depended on soluble factors released by LSed-DCs, but not cell-cell contact. Compared with mature DCs, LSed-DCs produced more nitric oxide and IL-10. Addition of a nitric oxide synthase inhibitor, PBIT, but not an IL-10-blocking mAb, reversed LSed-DC inhibition of CD8+ T cell proliferation. We also found that LSed-DCs reduced CD8+ T cell-mediated liver damage in a mouse model of autoimmune hepatitis. These results demonstrate that the liver stroma induces mature DCs to differentiate into regulatory DCs that suppress CD8+ T cell proliferation, and thus contribute to liver tolerance.
Highlights
The liver is a lymphoid organ [1] that consists of two major lymphocyte groups: an innate component including abundant NK cells and NKT cells, and an adaptive component containing conventional CD4+ and CD8+ T cells
To investigate whether the liver microenvironment affected dendritic cells (DCs) differentiation, bone marrow (BM)derived mature DCs (mDCs) from C57BL/6 mice were seeded onto a monolayer of liver stromal cells (LSCs) from CD45.1+ B6.SJL mice in vitro
Our data showed that mDCs first adhered to the LSCs and subsequently divided into a clone of daughter cells that clustered on the liver stroma monolayer (Figure 1A)
Summary
The liver is a lymphoid organ [1] that consists of two major lymphocyte groups: an innate component including abundant NK cells and NKT cells, and an adaptive component containing conventional CD4+ and CD8+ T cells. As the hepatic immune system is constantly exposed to harmless dietary and commensal antigens, the liver is often regarded as a tolerogenic organ that favors peripheral tolerance induction [2, 3]. This tolerance is observed under certain conditions, such as administration of antigens via the portal vein, allogeneic liver transplantation and certain pathogen infections [4,5,6]. As a bridge connecting innate and adaptive immunity, DCs contribute to immune tolerance through both Treg induction and inhibition of T cell response [14, 15]. Understanding how liver DCregs regulate CD8+ T cells will enhance comprehension of liver immune tolerance
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