Objective: In this study, we investigated whether dyslipidemia-associated perturbed invariant natural killer T (iNKT) cell function is due to intrinsic changes in iNKT cells or defects in the ability of antigen-presenting cells to activate iNKT cells. Methods and Results: We compared iNKT cell expansion and cytokine production in C57BL/6J (B6) and apolipoprotein E-deficient (apoE -/-) mice. In response to in vivo stimulation with α-galactosylceramide, a prototypic iNKT cell glycolipid antigen, apoE -/- mice showed significantly decreased splenic iNKT cell expansion at 3 days after injection, a profile associated with iNKT cell anergy due to chronic stimulation. This decrease in expansion and cytokine production was accompanied by a 2-fold increase in percentage of iNKT cells expressing the inhibitory marker programmed death-1 in apoE-/- mice compared with controls. However, in vivo and in vitro blockade of programmed death-1 using monoclonal antibody was not able to restore functions of iNKT cells from apoE-/- mice to B6 levels. iNKT cells from apoE-/- mice also had increased intracellular T cell receptor and Ly49 expression, a phenotype associated with previous activation. Changes in iNKT cell functions were cell autonomous, because dendritic cells from apoE-/- mice were able to activate B6 iNKT cells, but iNKT cells from apoE-/- mice were not able to respond to B6 dendritic cells. Conclusion: These data suggest that chronic dyslipidemia induces an iNKT cell phenotype that is unresponsive to further simulation by exogenous glycolipid and that sustained unresponsiveness is iNKT cell intrinsic.
|Number of pages
|Arteriosclerosis, thrombosis, and vascular biology
|Published - Sep 2010
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine