Adoptive transfer of regulatory NKT lymphocytes ameliorates non-alcoholic steatohepatitis and glucose intolerance in ob/ob mice and is associated with intrahepatic CD8 trapping

Abstract

The aim of this study was to determine the effect of adoptive transfer of regulatory natural killer T (NKT) lymphocytes on the metabolic disorder in leptin-deficient ob/ob mice, which feature depletion and defective function of NKT and CD4 lymphocytes. Leptin-deficient ob/ob mice were subjected to transplantation of 1 x 10(6) of either ob/ob or wild-type-derived NKT lymphocytes, or to transplantation of either ob/ob or wild-type-derived splenocytes. The effect on hepatic fat content was measured by magnetic resonance imaging (signal intensity index) and histology, using the steatohepatitis grading scale. The degree of glucose intolerance was measured by an oral glucose tolerance test (GTT). Adoptive transfer of wild-type or ob/ob-derived regulatory NKT cells led to a 12% decrease in hepatic fat content. A significant histological shift from macrosteatosis to microsteatosis was observed. Marked improvement in the GTT was noted in wild-type or ob/ob-derived NKT recipients. Metabolic effects were associated with a significant decrease in peripheral and intrahepatic CD4/CD8 lymphocyte ratios. Intrahepatic CD8 trapping was observed in all responders. Serum interleukin 10 levels decreased significantly. In conclusion, adoptive transfer of a relatively small number of regulatory NKT lymphocytes into ob/ob mice results in a significant reduction in hepatic fat content, a shift from macro to microsteatosis, and significant improvement in glucose intolerance. These effects were associated with decreased peripheral and intrahepatic CD4/CD8 ratios and decreased interleukin 10 levels. The results further support a role for regulatory NKT lymphocytes in the pathogenesis of non-alcoholic steatohepatitis in the leptin-deficient murine model.

Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function

“…For example, iNKT cells have been shown to drive hyperlipidemia and atherosclerosis but protect from hepatic steatosis (32,(59)(60)(61)(62). Although the effects of MTP deficiency on lipoprotein metabolism are sufficient to explain both lack of atherosclerosis and frequent hepatic steatosis in ABL (1), it is possible that CD1 and NKT dysfunction may contribute to these phenomena.…”

Lymphocytes in obesity-related adipose tissue inflammation

“…However, it has recently been demonstrated that the aforementioned effects of NKT cell deletion on metabolism can only occur in the absence of CD8 + T cells [66]. Moreover, previous studies have reported that adoptive transfer or agonist activation of NKT cells ameliorate the metabolic dysregulation of the ob/ob mice [55,67], suggesting that the role of NKT cells in obesity-related inflammation may be complex.…”

Inflammation hépatique liée à l’obésité (NASH)

“…Les resultats sont spectaculaires puisque seulement 12 jours apres le transfert on constate une diminution de la steatose, une amelioration des transaminases hepatiques, reflet de l'atteinte hepatique, ainsi qu'une amelioration de la tolerance au glucose. La restauration du nombre de lymphocytes NKT permet donc de moderer la steatose et la sensibilite au glucose dans des etudes a court terme (Elinav et al, 2006). Il est egalement possible de restaurer un nombre de cellules NKT hepatique par des traitements chez la souris.…”