NKT cell subsets as key participants in liver physiology and pathology

Abstract

Natural killer T (NKT) cells are innate-like lymphocytes that generally recognize lipid antigens and are enriched in microvascular compartments of the liver. NKT cells can be activated by self- or microbial-lipid antigens and by signaling through toll-like receptors. Following activation, NKT cells rapidly secrete pro-inflammatory or anti-inflammatory cytokines and chemokines, and thereby determine the milieu for subsequent immunity or tolerance. It is becoming clear that two different subsets of NKT cells-type I and type II-have different modes of antigen recognition and have opposing roles in inflammatory liver diseases. Here we focus mainly on the roles of both NKT cell subsets in the maintenance of immune tolerance and inflammatory diseases in liver. Furthermore, how the differential activation of type I and type II NKT cells influences other innate cells and adaptive immune cells to result in important consequences for tissue integrity is discussed. It is crucial that better reagents, including CD1d tetramers, be used in clinical studies to define the roles of NKT cells in liver diseases in patients.

Figure 1

A proposed model depicting the opposing roles of type I and type II NKT cells in inflammatory diseases in the liver. Type I NKT cells are rapidly activated following liver injuries induced by alcohol, high-fat diet, ischemia and/or gut-derived microbial products. Liver-resident antigen-presenting cells, such as KCs, and TLRs/cytokines mediate their activation, which results in the cytokine/chemokine-dependent recruitment of myeloid cells (CD11b+Gr-1+) and neutrophils, and the activation of HSC and NK cells. These cellular interactions lead to steatosis, fibrosis and hepatocyte necrosis. These events are also involved in the development of HCC. In contrast, type II NKT cells are activated following the presentation of self-lipids, such as sulfatide and LPC, which results in the induction of a cross-regulatory pathway that inhibits type I NKT cells, tolerizes cDCs and blocks the inflammatory cascade and liver disease. cDCs, conventional DCs; HCC, hepatocellular carcinoma; HSC, hepatic stellate cell; KC, Kupffer cell; LPC, lysophosphatidylcholine; NK, natural killer; NKT, natural killer T cells; OPN, osteopontin; TLR, toll-like receptor.