The Journal of Experimental Medicine
Fluorescence In Vivo Endomicroscopy
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Published online 26 January 2004 doi:10.1084/jem.20030997
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 3, 417-422
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Brief Definitive Report

 CD1d-dependent Activation of NKT Cells Aggravates Atherosclerosis

Emmanuel Tupin1,2, Antonino Nicoletti2, Rima Elhage1,3, Mats Rudling4, Hans-Gustaf Ljunggren5, Göran K. Hansson1, and Gabrielle Paulsson Berne1

1 Center for Molecular Medicine, Department of Medicine, Karolinska Institute, 17176 Stockholm, Sweden
2 INSERM U430, Immunopathologie Humaine, Institut des Cordeliers, 75006 Paris, France
3 INSERM U589, Institut Louis Bugnard, Toulouse, France
4 Center for Metabolism and Endocrinology, Karolinska Institute, Huddinge University Hospital, 141 86 Stockholm, Sweden
5 Center for Infectious Medicine, Karolinska Institute, Huddinge University Hospital, 141 86 Stockholm, Sweden

Address correspondence to Gabrielle Paulsson Berne, Center for Molecular Medicine, CMM L8: 03 Karolinska Hospital, S-17176 Stockholm, Sweden. Phone: 46-8-51776223; Fax: 46-8-313147; email: gabrielle.berne{at}cmm.ki.se

Adaptive and innate immunity have been implicated in the pathogenesis of atherosclerosis. Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response. Natural killer T (NKT) cells can recognize lipid antigens presented by CD1 molecules. We have explored the role of CD1d-restricted NKT cells in atherosclerosis by using apolipoprotein E–deficient (apoE-/-) mice, a hypercholesterolemic mouse model that develops atherosclerosis. ApoE-/- mice crossed with CD1d-/- (CD1d-/-apoE-/-) mice exhibited a 25% decrease in lesion size compared with apoE-/- mice. Administration of {alpha}-galactosylceramide, a synthetic glycolipid that activates NKT cells via CD1d, induced a 50% increase in lesion size in apoE-/- mice, whereas it did not affect lesion size in apoE-/-CD1d-/- mice. Treatment was accompanied by an early burst of cytokines (IFN{gamma}, MCP-1, TNF{alpha}, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFN{gamma} and IL-4 transcripts in the spleen and aorta. Early activation of both T and B cells was followed by recruitment of T and NKT cells to the aorta and activation of inflammatory genes. These results show that activation of CD1d-restricted NKT cells exacerbates atherosclerosis.

Key Words: {alpha}-galactosylceramide • cytokines • inflammation • apolipoprotein E • mice

The online version of this article contains supplemental material.


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