CD1d-dependent Activation of NKT Cells Aggravates Atherosclerosis

Abstract

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 α-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 (IFNγ, MCP-1, TNFα, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNγ 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.

Natural Killer T Cells Are Involved in Adipose Tissues Inflammation and Glucose Intolerance in Diet-Induced Obese Mice

“…8 These lymphocytes are mainly CD4-positive lymphocytes that express proinflammatory T H 1 cytokines, such as IFN-␥, and orchestrate the inflammatory response in the vascular wall by activating other cells. Previous studies, 9,10 including our own studies, demonstrated that NKT cells were present in atherosclerotic lesions and are critically important in atherogenesis. These findings suggest that NKT cells can also be involved in inflammation within adipose tissue.…”

FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration

“…However, several studies have shown that NKT cells also promote the development or progression of immune diseases, such as asthma, 14 rheumatoid arthritis, 4 and atherosclerosis. 15 Therefore, there is a need for therapeutic strategies to inhibit these immune diseases by inhibiting NKT cell function. Our study clearly shows that FTY720 inhibits cytokine production but not joint tissue migration of NKT cells in an antibody-induced arthritis model, suggesting that FTY720 may be a useful therapeutic agent for the suppression of NKT cell cytokine production.…”

“…Similar to antibody-induced arthritis, NKT cells promote asthma and atherosclerosis by producing various cytokines. 4,14,15 On the basis of these findings, the suppression of cytokine production by NKT cells may be a useful therapeutic strategy for preventing asthma and atherosclerosis, as shown for antibody-induced joint inflammation. 14,15 Moreover, FTY720 attenuates asthma, arthritis, and atherosclerosis in animal models.…”

“…4,14,15 On the basis of these findings, the suppression of cytokine production by NKT cells may be a useful therapeutic strategy for preventing asthma and atherosclerosis, as shown for antibody-induced joint inflammation. 14,15 Moreover, FTY720 attenuates asthma, arthritis, and atherosclerosis in animal models. [53][54][55] Therefore, we hypothesize that the suppressive effects of FTY720 on asthma and atherosclerosis may partly be attributed to the inhibition of cytokine production by NKT cells.…”

“…However, NKT cells also promote, rather than suppress, immune diseases. 4,14,15 Therefore, it has been suggested that the suppressive reagents for NKT cell function might be useful in regulating some of the immune diseases promoted by NKT cells.…”