Hepatic stroma-educated regulatory DCs suppress CD8(+) T cell proliferation in mice

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.