Abstract
Biliary obstruction and cholestasis can cause hepatocellular apoptosis and necrosis. Ligation of the common bile duct (BDL) in mice provides an excellent model in which to study the underlying mechanisms. NK1.1+ TCRαβint CD1d-restricted T (NKT) cells comprise approximately 30% of the hepatic lymphoid cells in mice, decidedly fewer reside in the spleen, thymus and peripheral blood. Purportedly, NKT cells play a key role in host defenses to infection. Indeed, it has been suggested that iNKT cells evolved primarily to respond to a diverse array of microbial pathogens. The increased replication of a limited number of parasites, bacteria and viruses in the organs of CD1d−/− or Jα18−/− [invariant (i)NKT cell-deficient] mice provides support for this suggestion. In many instances, however, NKT cells are not protective and their response to infection is largely detrimental. In agreement with the latter, we report here that iNKT cell-deficient mice express increased protective immunity to L. monocytogenes. Relative to wild-type animals, significantly fewer (≤1 log10) bacteria were recovered from the livers of Jα18−/− mice on day 3 post-infection i.v. with a sublethal dose of listeriae. In marked contrast to these findings, however, listerial replication, liver injury [plasma alanine aminotransferase activity (ALT)], and death from infection were increased sharply in iNKT cell-deficient mice subjected to BDL and cholestasis. Thus, iNKT cells play a critical role in host defenses to Listeria expressed in cholestatic, but not normal, livers.
