Rapid activation and hepatic recruitment of innate-like regulatory B cells after invariant NKT cell stimulation in mice

Background & Aims: Invariant natural killer T (iNKT) cells are present within the liver and have been implicated in the development of many liver diseases. Upon activation by glycolipid ligands (including alpha-galactosylceramide; alpha GalCer), hepatic iNKT cells produce numerous cytokines and recruit both pro-inflammatory and regulatory immune cells. However, the involvement of B cells in this process is poorly defined. Methods: Wild-type (male, C57BL/6), B cell deficient, or B cell depleted mice were injected with alpha GalCer or vehicle, hepatic B cell phenotype and liver injury was subsequently determined. Results: iNKT cell activation resulted in liver injury and the rapid activation and hepatic recruitment of B cells (mainly innate-like B1 and MZ-like B cells) from the spleen and peritoneal cavity. B cells recruited to the liver produce IL-10 and TGF beta, and express cell surface CD73 (ectoenzyme which generates adenosine). B cell deficient mice developed augmented alpha GalCer-induced hepatitis, enhanced neutrophil recruitment and striking alterations in the hepatic cytokine milieu. alpha GalCer-induced hepatitis was unaltered in IL-10(-/-) mice, or after TGFb neutralization, but was significantly worsened in mice treated with a CD73 inhibitor. Conclusions: iNKT cell stimulation recruits innate-like regulatory B cells to the liver which suppress hepatic inflammation through IL-10 and TGF beta 1 independent mechanisms, but involve CD73 activity. These findings highlight an important inflammation suppressing role for B cells at early time points during the development of an innate immune response within the liver, and represent a potential therapeutic target for the treatment of liver disease. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.