Targeting the diverse immunological functions expressed by hepatic NKT cells.

Introduction: NKT cells comprise approximately 30% of the hepatic lymphoid population in mice (∼ 50% in humans). Most mouse hepatic NKT cells [invariant (i)NKT cells] express T cell receptors, composed of invariant Vα14Jα18 chains. Unlike conventional T cells, iNKT cells recognize glycolipids presented in association with MHC class Ib (CD1d) molecules. Purportedly, iNKT cells serve key functions in several immunological events; the nature of these is often unclear. The consequences of hepatic iNKT cell activation can be beneficial or detrimental. α-Galactosylceramide stimulates the production of IFN-γ and IL-4. The reciprocal suppression exhibited by these cytokines limits the potential therapeutic value of α-galactosylceramide. Efforts are ongoing to develop α-galactosylceramide analogs that modulate iNKT cell activity and selectively promote IFN-γ or IL-4.

Areas Covered: An overview of hepatic iNKT cells and their purported role in liver disease. Efforts to develop therapeutic agents that promote their beneficial contributions.

Expert Opinion: While a growing body of literature documents the differential effects of α-GalCer analogs on IFN-γ and IL-4 production, the effects of these analogs on other iNKT cell activities remain to be determined. An exhaustive examination of the effects of these analogs on inflammation and liver injury in animal models remains prior to considering their utility in clinical trials.