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Development of spontaneous anergy in invariant natural killer T cells in a mouse model of dyslipidemia.

Braun NA, Mendez-Fernandez YV, Covarrubias R, Porcelli SA, Savage PB, Yagita H, Van Kaer L, Major AS
Arterioscler Thromb Vasc Biol. 2010 30 (9): 1758-65

PMID: 20539017 · PMCID: PMC2963029 · DOI:10.1161/ATVBAHA.110.206045

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 alpha-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.

CONCLUSIONS - 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.

MeSH Terms (28)

Animals Antigen-Presenting Cells Antigens, Surface Apolipoproteins E Apoptosis Regulatory Proteins Cell Proliferation Cells, Cultured Chronic Disease Clonal Anergy Cytokines Dendritic Cells Disease Models, Animal Galactosylceramides Hyperlipidemias Injections, Intraperitoneal Interleukin-2 Lymphocyte Activation Lymphocyte Count Male Mice Mice, Inbred C57BL Mice, Knockout Natural Killer T-Cells NK Cell Lectin-Like Receptor Subfamily A Phenotype Programmed Cell Death 1 Receptor Receptors, Antigen, T-Cell Time Factors

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