Liver Natural Killer T Cells Research Articles

Electric foot shock stress-induced exacerbation of alpha-galactosylceramide-triggered apoptosis in mouse liver.

Recently, liver natural killer T (NKT) cells, which are specifically stimulated by alpha-galactosylceramide (alpha-GalCer), were found to play a critical role in intrahepatic immunity to several infections and certain hepatic disorders. However, the role of psychophysical stress on NKT cell-dependent liver injury induced by alpha-GalCer still remains to be elucidated. In this study, we employed inescapable electric foot shock as the mode of psychophysical stress and evaluated its effect on alpha-GalCer-induced hepatitis. Pre-exposure of 12 hours of foot shock stress before alpha-GalCer administration significantly enhanced alpha-GalCer-triggered increase in serum alanine aminotransferase levels, followed by increases in both liver caspase-3 activity and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive hepatocytes, thus indicating that the liver NKT cell-dependent apoptotic response was exacerbated by stress. Foot shock stress also significantly increased both the number of liver NKT cells and Fas expression levels on hepatocytes. Pretreatment with RU-486, a glucocorticoid (GC) receptor antagonist, completely reversed such stress-induced enhancement of the alpha-GalCer-triggered serum alanine aminotransferase and hepatocyte Fas antigen responses. In contrast, such a reversal effect was not found in the mice pretreated with naloxone, a micro-opioid receptor antagonist, which thus suggests that an elevation of endogenous GCs, but not beta-endorphin, as responsible for such stress-induced aggravation in mouse hepatitis models. In conclusion, foot shock stress-induced elevation of endogenous GCs exacerbates alpha-GalCer-initiated hepatic apoptosis through the expansion of liver NKT cells and the up-regulation of hepatocyte Fas antigen.

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis.

It is not known why natural killer T (NKT) cells, which modulate liver injury by regulating local cytokine production, are reduced in leptin-deficient ob/ob mice. NKT cells express adrenoceptors. Thus, we hypothesize that the low norepinephrine (NE) activity of ob/ob mice promotes depletion of liver NKT cells, thereby sensitizing ob/ob livers to lipopolysaccharide (LPS) toxicity. To evaluate this hypothesis, hepatic NKT cells were quantified in wild-type mice before and after treatment with NE inhibitors, and in dopamine beta-hydroxylase knockout mice (which cannot synthesize NE) and ob/ob mice before and after 4 weeks of NE supplementation. Decreasing NE activity consistently reduces liver NKT cells, while increasing NE has the opposite effect. Analysis of hepatic and thymic NKT cells in mice of different ages demonstrate an age-related accumulation of hepatic NKT cells in normal mice, while liver NKT cells become depleted after birth in ob/ob mice, which have increased apoptosis of hepatic NKT cells. NE treatment inhibits apoptosis and restores hepatic NKT cells. In ob/ob mice with reduced hepatic NKT cells, hepatic T and NKT cells produce excessive T helper (Th)-1 proinflammatory cytokines and the liver is sensitized to LPS toxicity. NE treatment decreases Th-1 cytokines, increases production of Th-2 cytokines, and reduces hepatotoxicity. Studies of CD1d-deficient mice, which lack the receptor required for NKT cell development, demonstrate that they are also unusually sensitive to LPS hepatotoxicity. In conclusion, low NE activity increases hepatic NKT cell apoptosis and depletes liver NKT cells, promoting proinflammatory polarization of hepatic cytokine production that sensitizes the liver to LPS toxicity.

Liver NKT cells: an account of heterogeneity

The liver is a rich provenance of an unconventional group of T cells called natural killer T (NKT) cells that coexpress NKR-P1, a type II membrane glycoprotein of the C-type lectin superfamily (NK1.1). Accumulating evidence suggests that NKT cells comprise a far more heterogeneous population than originally thought. In addition to ‘classical’ NKT cells, which are restricted by CD1d, ‘nonclassical’ NKT cells exist that express a diverse T-cell receptor and develop independently of CD1d. Classical and nonclassical NKT cells are most abundant in the liver, and unique molecular and cellular mechanisms control their migration and/or retention in this organ. Although evidence is accumulating that NKT cells contribute to various forms of pathology and to immune surveillance in the liver, these responses appear to involve different cell populations, including NK cells and NKT cells.

Total Enantioselective Synthesis and in vivo Biological Evaluation of a Novel Fluorescent BODIPY α‐Galactosylceramide.

ChemInformVolume 34, Issue 14 Natural Products Total Enantioselective Synthesis and in vivo Biological Evaluation of a Novel Fluorescent BODIPY α-Galactosylceramide. Yen Vo-Hoang, Yen Vo-Hoang Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorLaurent Micouin, Laurent Micouin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorCatherine Ronet, Catherine Ronet Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorGabriel Gachelin, Gabriel Gachelin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorMartine Bonin, Martine Bonin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this author Yen Vo-Hoang, Yen Vo-Hoang Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorLaurent Micouin, Laurent Micouin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorCatherine Ronet, Catherine Ronet Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorGabriel Gachelin, Gabriel Gachelin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this authorMartine Bonin, Martine Bonin Lab. Chim. Ther., CNRS, Fac. Sci. Pharm. Biol., Univ. R. Descartes, F-75270 Paris, Fr.Search for more papers by this author First published: 20 March 2003 https://doi.org/10.1002/chin.200314228Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume34, Issue14April 8, 2003 RelatedInformation

Total enantioselective synthesis and in vivo biological evaluation of a novel fluorescent BODIPY alpha-galactosylceramide.

Natural killer T (NKT) cells are a distinct subset of mature lymphocytes endowed with features of activated and regulatory T cells. alpha-Galactosylceramides (alpha-GalCers), the synthetic prototype of which is KRN7000, are the only natural reagents recognised by the T-cell receptor of NKT cells. The alpha-GalCer-activated NKT cells promptly release IFN gamma and IL-4 (IFN=interferon; IL=interleukin) and undergo apoptotic death within hours. In mice, activated NKT cells are responsible for antitumour activity and protection against autoimmune diseases. KRN7000 can thus be considered as the root of a family of novel immunoregulatory drugs. To get insights into the in vivo behaviour of alpha-galactosylceramides, an original fluorescent derivative has been prepared by following a convergent synthetic scheme. This strategy allows the introduction of different acyl chains, carbohydrate residues and various labels in the final steps of the synthesis. The fluorescent BODIPY probe derived from a versatile glycolipid precursor is as active as KRN7000 for inducing apoptosis of liver NKT cells. Fluorescence was detected in peritoneal macrophages and splenic antigen-presenting cells, in Kupffer-like cells in the liver, but not in lymphocytes.

Critical contribution of liver natural killer T cells to a murine model of hepatitis.

Natural killer T (NKT) cells constitute a distinct subpopulation of T cells with a unique antigen specificity, prompt effector functions, and an unusual tissue distribution. NKT cells are especially abundant in the liver, but their physiological function in this organ remains unclear. In the present study, we examined the possible contribution of NKT cells to a murine model of hepatitis induced by i.v. injection of Con A. CD1-deficient mice lacking NKT cells were highly resistant to Con A-induced hepatitis. Adoptive transfer of hepatic NKT cells isolated from wild-type mice, but not from FasL-deficient gld mice, sensitized CD1-deficient mice to Con A-induced hepatitis. Furthermore, adoptive transfer of hepatic mononuclear cells from wild-type mice, but not from CD1-deficient mice, sensitized gld mice to Con A-induced hepatitis. Upon Con A administration, hepatic NKT cells rapidly up-regulated cell surface FasL expression and FasL-mediated cytotoxicity. At the same time, NKT cells underwent apoptosis leading to their rapid disappearance in the liver. These results implicated FasL expression on liver NKT cells in the pathogenesis of Con A-induced hepatitis, suggesting a similar pathogenic role in human liver diseases such as autoimmune hepatitis.