Abstract
Invariant natural killer T (iNKT) cells play complex roles in bridging innate and adaptive immunity by engaging with glycolipid antigens presented by CD1d. Our earlier work suggested that iNKT cells were involved in the initiation of the original loss of tolerance in primary biliary cirrhosis (PBC). To address this issue in more detail and, in particular, to focus on whether iNKT cells activated by a Th2-biasing agonist (2s,3s,4r)-1-O-(α-D-galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol (OCH), can influence the development of PBC in a xenobiotic-induced PBC murine model. Groups of mice were treated with either OCH or, as a control, α-galactosylceramide (α-GalCer) and thence serially followed for cytokine production, markers of T cell activation, liver histopathology and anti-mitochondrial antibody responses. Further, additional groups of CD1d deleted mice were similarly studied. Our data indicate that administration of OCH has a dramatic influence with exacerbation of portal inflammation and hepatic fibrosis similar to mice treated with α-GalCer. Further, iNKT cell deficient CD1d knockout mice have decreased inflammatory portal cell infiltrates and reduced anti-mitochondrial antibody responses. We submit that activation of iNKT cells can occur via overlapping and/or promiscuous pathways and highlight the critical role of innate immunity in the natural history of autoimmune cholangitis. These data have implications for humans with PBC and emphasize that therapeutic strategies must focus not only on suppressing adaptive responses, but also innate immunity.
Highlights
Invariant natural killer T cells, expressing semi-invariant Vα14-Jα28 chain preferentially pair with Vβ2, Vβ7, or Vβ8.2 chain, hypersecrete Th1 and Th2 cytokines and chemokines upon stimulation with an appropriate ligand, such as α-galactosylceramide (α-GalCer) [1,2]
We report that mice administered with OCH have exacerbated portal inflammation and hepatic fibrosis similar to mice treated with α-GalCer. Invariant natural killer T (iNKT) cell deficient CD1d knockout mice immunized with 2-OA-BSA have reduced anti-mitochondrial antibody (AMA) production and cell infiltrates in the liver compared to that of immunized wild type mice
A predominant production of IL-4 was detected at 2 hours of OCH administration and it became undetectable at 18 hours (Fig. 1B)
Summary
Invariant natural killer T (iNKT) cells, expressing semi-invariant Vα14-Jα28 chain preferentially pair with Vβ2, Vβ7, or Vβ8.2 chain, hypersecrete Th1 and Th2 cytokines and chemokines upon stimulation with an appropriate ligand, such as α-galactosylceramide (α-GalCer) [1,2]. Innate Immunity in PBC both humans and mice. Upon ligation of their invariant T cell receptors with α-GalCer presented by CD1d of antigen presenting cells, iNKT cells rapidly produce large amount of cytokines, including IFN-γ and IL-4 [4,5,6]. (2s,3s,4r)-1-O(α-D-galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol (OCH), a synthetic analog of α-GalCer with a truncated sphingosine chain, stimulates iNKT cells to produce predominantly Th2 cytokines [8]. Studies using models of experimental autoimmune diseases, including arthritis, diabetes, and experimental autoimmune encephalomyelitis (EAE), have indicated that activation of iNKT cells by OCH ameliorates or prevents these Th1-mediated diseases, which was attributed to its induction of IL-4 and Th2 skewing [9,10,11,12]
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