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.

Donor-unrestricted T cells in the human CD1 system

“…Diverse NKT cells appear to be more abundant in humans than invariant NKT cells, as shown with CD1d tetramer or dimer staining (Chang et al 2008; Nair et al 2015). In addition to sulfatide and glycosylceramide species, other self and exogenous lipids, including mammalian, bacterial, and pollen-derived phospholipids, have also been identified as antigens for diverse NKT cells as reviewed recently (Macho-Fernandez and Brigl 2015; Bandyopadhyay et al 2016). …”

“…This protective function of iNKT cells is induced by the stimulation of CD1d-presented host lysophospholipids (Zeissig et al 2012). In liver inflammation, invariant NKT cells were described as pathogenic for chronic injury but potential protective to acute injury (Gao et al 2009; Bandyopadhyay et al 2016). For example, the iNKT-deficient mice develop less alcohol-induced steatosis with reduced neutrophil infiltration (Cui et al 2015).…”

“…Similarly, autoimmune hepatitis is associated with IL-17 producing iNKT cells, which can also be antagonized by diverse NKT cells (Takeda et al 2000; Halder et al 2007). The opposing roles and interplay between invariant and diverse NKTs in liver inflammation suggests that the specificity of lipid antigens and sequences of TCR can be important for functional outcomes (Bandyopadhyay et al 2016). Therefore, future diagnostic or therapeutic applications based on NKT cells in liver diseases likely require further determination of CD1d-presented lipid antigens and better understanding of the apparently distinct functions of invariant or diverse NKT cells (Zeissig et al 2012; Maricic et al 2015).…”

Immunological aspect of the liver and metastatic uveal melanoma

“…It has been suggested that these lrNK cells have immune memory against specific antigens [39] . + T cell responses [40] .…”

Targeting inflammation for the treatment of alcoholic liver disease

“…NKT cells are another type of innate immune cells, which are enriched in the liver and play important roles in the pathogenesis of liver diseases (Bandyopadhyay, Marrero, & Kumar, 2016; Gao, Radaeva, & Park, 2009; Wang, Feng, Park, Yin, & Gao, 2013; Yin et al, 2014). NKT cells recognize lipid antigens presented by CD1d molecules.…”