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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03252011-131927 |
| Date | 03 May 2011 |
| Creators | Braun, Nicole Ann |
| Contributors | Luc van Kaer, Anne Kenworthy, Gregory Sephel, Larry Swift, Jay Jerome |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03252011-131927/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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