Natural Killer T cells promote cholestatic liver disease independent of antigen presentation by cholangiocytes

BACKGROUND: Natural killer T (NKT) cells are an important lymphocyte subset in the liver that can be activated by CD1d-restricted lipid antigens presented on cholangiocytes, including lipids in bile from patients with chronic liver diseases. We hypothesized that during cholestasis, NKT cells play an essential role in the pathophysiology. METHODS: We explored this immune pathway by ligating the common bile duct (BDL) in CD1d knockout (Cd1d-/-) mice, Traj18-/- mice, wild-type (WT) mice, and created a novel model with conditional deletion of CD1d on cholangiocytes (Cd1dΔCC mice). RESULTS: Following BDL, we observed a clear and specific activation of hepatic NKT cells. Cd1d-/- mice, depleted of both invariant and noninvariant NKT cells, were protected from BDL-induced cholestatic liver damage. In contrast, Traj18-/- mice, lacking only invariant natural killer T cells, were not protected as compared with WT mice. Cd1dΔCC mice exhibited a deficiency in functional CD1d expression on cholangiocytes but had a comparable distribution and phenotype of NKT cells as WT mice. After BDL, Cd1dΔCC mice were not protected and developed similar liver disease as WT mice. CONCLUSIONS: A subset of hepatic NKT cells contributes to cholestatic liver disease, and their activation is independent of CD1d antigen presentation on cholangiocytes.