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Title page for ETD etd-03252011-131927


Type of Document Dissertation
Author Braun, Nicole Ann
URN etd-03252011-131927
Title Effects of Dyslipidemia on Invariant Natural Killer T Cell Activation
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Jay Jerome Committee Chair
Anne Kenworthy Committee Member
Gregory Sephel Committee Member
Larry Swift Committee Member
Luc van Kaer Committee Member
Keywords
  • lipids
  • NKT cells
  • apolipoprotein E
  • atherosclerosis
  • immunity
Date of Defense 2011-02-24
Availability unrestricted
Abstract
Invariant natural killer T (iNKT) cells are a specialized subset of immune regulatory cells that recognize glycolipid antigens and are thought to be pro-atherogenic under hyperlipidemic conditions. We previously reported that hyperlipidemic apolipoprotein E-deficient (apoE-/-) mice have decreased iNKT cell-mediated cytokine production in vitro and in vivo in response to alpha-galactosylceramide (a-GalCer), a prototypic iNKT cell glycolipid antigen. These data suggested changes in endogenous circulating lipids can affect normal iNKT cell functions. In the current study, we investigated whether dyslipidemia-associated perturbed iNKT cell function is due to intrinsic changes in iNKT cells or defects in the ability of antigen presenting cells to activate iNKT cells. Our data reveal that iNKT cells from dyslipidemic apoE-/- mice exhibit a phenotype similar to those rendered anergic due to chronic stimulation. We also tested the ability of B6 and apoE-/- splenic dendritic cells (DCs) to present a-GalCer to purified iNKT cells. Although DCs from apoE-/- mice were able to activate B6 iNKT cells, iNKT cells from apoE-/- mice were not able to respond to B6 DCs. These data suggest that chronic hyperlipidemia induces an iNKT cell phenotype that is unresponsive to further simulation by exogenous glycolipid, and that sustained unresponsiveness appears to be iNKT cell intrinsic. Additionally, our results indicate that increased circulating lipids exert direct effects upon iNKT cells which lead to decreased responsiveness.
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