Abstract
Natural killer T (NKT) cells are activated by lipid antigens presented by CD1d molecules and represent a major lymphocyte subset of the liver. NOD.c3c4 mice spontaneously develop biliary inflammation in extra‐ and intrahepatic bile ducts. We demonstrated by flow cytometry that invariant NKT (iNKT) cells were more abundant in the thymus, spleen, and liver of NOD.c3c4 mice compared to NOD mice. iNKT cells in NOD.c3c4 mice displayed an activated phenotype. Further, NOD and NOD.Cd1d ‐/‐ mice were irradiated and injected with NOD.c3c4 bone marrow, and injection of NOD.c3c4 bone marrow resulted in biliary infiltrates independently of CD1d expression in recipient mice. Activation or blocking of NKT cells with α‐galactosylceramide or anti‐CD1d antibody injections did not affect the biliary phenotype of NOD.c3c4 mice. NOD.c3c4.Cd1d ‐/‐ mice were generated by crossing NOD.Cd1d ‐/‐ mice onto a NOD.c3c4 background. NOD.c3c4.Cd1d ‐/‐ and NOD.c3c4 mice developed the same extent of biliary disease. This study demonstrates that iNKT cells are more abundant and activated in the NOD.c3c4 model. The portal inflammation of NOD.c3c4 mice can be transferred to irradiated recipients, which suggests an immune‐driven disease. Our findings imply that NKT cells can potentially participate in the biliary inflammation, but are not the primary drivers of disease in NOD.c3c4 mice.
Highlights
Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis) are severe human biliary diseases that can lead to end-stage liver disease and need for liver transplantation (Hirschfield et al 2010)
We further investigated the cellular phenotype of the invariant NKT (iNKT) cells in the nonobese diabetic (NOD).c3c4 mice compared to regular NOD mice
In the thymus and spleen, we saw a higher proportion of CD4-positive iNKT cells in NOD.c3c4 mice compared to NOD mice (Fig. 2), while the double negative (DN) iNKT cells were correspondingly lower in the NOD.c3c4 mice (Fig. 2)
Summary
Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis) are severe human biliary diseases that can lead to end-stage liver disease and need for liver transplantation (Hirschfield et al 2010). Natural killer T (NKT) cells are a subset of lymphocytes that respond to lipid antigens presented by the major histocompatibility complex class I-like molecule, CD1d (Chandra and Kronenberg 2015). These cells have functional qualities of both adaptive and innate immune cells and are able to rapidly secrete cytokines such as interleukin-4 and interferon-c upon activation (Salio et al 2014). NKT cells can play either a protective or detrimental role in autoimmune diseases such as inflammatory bowel diseases and diabetes (Berzins et al 2011; Brennan et al 2013; Sharif et al 2001), diseases associated with human biliary disease (Karlsen and Boberg 2013)
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