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CD1d-dependent activation of NKT cells aggravates atherosclerosis.

Tupin E, Nicoletti A, Elhage R, Rudling M, Ljunggren HG, Hansson GK, Berne GP - J. Exp. Med. (2004)

Bottom Line: Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response.Treatment was accompanied by an early burst of cytokines (IFNgamma, MCP-1, TNFalpha, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNgamma 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.

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 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 (IFNgamma, MCP-1, TNFalpha, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNgamma 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.

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Effect of αGalCer injection on cytokine and TCR transcripts in spleen and aorta of apoE−/− mice. (a) Proportion of spleen cells double positive for TCRβ and NK1.1 in mice injected once and killed at 12 h and in mice injected 20 times, starting at 5 wk of age, and killed 48 h after the last injection. FACS® data expressed as the percentage of forward/side scatter-gated lymphocytes. (b) CD1d-dimer+ NKT cells in spleen and liver of 5-wk-old mice injected once i.v. with PBS (Ctrl) (n = 6) or αGalCer and killed 12 h (n = 5) or 72 h (n = 6) later. FACS® data expressed as the percentage of forward /side scatter-gated lymphocytes. (c and d) Levels of total TCRβ and Vα14Jα281- specific TCR mRNA (c) and of IFNγ and IL-4 mRNA (d) in the aorta of mice treated with PBS or αGalCer as described for panel b. Real-time RT-PCR data are expressed as relative mRNA units normalized to β-actin mRNA. Mean ± SEM (*P < 0.05; **P < 0.01 versus PBS-injected mice; §P < 0.05; §§P < 0.01 versus αGalCer-injected mice, killed at 12 h).
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fig4: Effect of αGalCer injection on cytokine and TCR transcripts in spleen and aorta of apoE−/− mice. (a) Proportion of spleen cells double positive for TCRβ and NK1.1 in mice injected once and killed at 12 h and in mice injected 20 times, starting at 5 wk of age, and killed 48 h after the last injection. FACS® data expressed as the percentage of forward/side scatter-gated lymphocytes. (b) CD1d-dimer+ NKT cells in spleen and liver of 5-wk-old mice injected once i.v. with PBS (Ctrl) (n = 6) or αGalCer and killed 12 h (n = 5) or 72 h (n = 6) later. FACS® data expressed as the percentage of forward /side scatter-gated lymphocytes. (c and d) Levels of total TCRβ and Vα14Jα281- specific TCR mRNA (c) and of IFNγ and IL-4 mRNA (d) in the aorta of mice treated with PBS or αGalCer as described for panel b. Real-time RT-PCR data are expressed as relative mRNA units normalized to β-actin mRNA. Mean ± SEM (*P < 0.05; **P < 0.01 versus PBS-injected mice; §P < 0.05; §§P < 0.01 versus αGalCer-injected mice, killed at 12 h).

Mentions: αGalCer injections led to dramatic systemic changes in the NKT cell population. When comparing apoE−/− mice injected once or repeatedly with αGalCer, a transient decrease followed by recovery was observed for TCR+ NK1.1+ cells in the spleen (Fig. 4 a) and liver (not depicted). This could either be due to activation-induced apoptosis or down-regulation of the NK1.1 receptor. To address this issue, NKT cells were also detected using CD1d-dimer staining in mice injected once i.v. with αGalCer and killed 12 or 72 h later. In the spleen, activation through αGalCer injection led to an initial reduction of NKT cells, but after 72 h the spleen had five times more NKT cells than spleens from PBS-injected controls (Fig. 4 b). In the liver, the NKT cell population decreased 12 h after the injection but returned to normal levels after 72 h (Fig. 4 b).


CD1d-dependent activation of NKT cells aggravates atherosclerosis.

Tupin E, Nicoletti A, Elhage R, Rudling M, Ljunggren HG, Hansson GK, Berne GP - J. Exp. Med. (2004)

Effect of αGalCer injection on cytokine and TCR transcripts in spleen and aorta of apoE−/− mice. (a) Proportion of spleen cells double positive for TCRβ and NK1.1 in mice injected once and killed at 12 h and in mice injected 20 times, starting at 5 wk of age, and killed 48 h after the last injection. FACS® data expressed as the percentage of forward/side scatter-gated lymphocytes. (b) CD1d-dimer+ NKT cells in spleen and liver of 5-wk-old mice injected once i.v. with PBS (Ctrl) (n = 6) or αGalCer and killed 12 h (n = 5) or 72 h (n = 6) later. FACS® data expressed as the percentage of forward /side scatter-gated lymphocytes. (c and d) Levels of total TCRβ and Vα14Jα281- specific TCR mRNA (c) and of IFNγ and IL-4 mRNA (d) in the aorta of mice treated with PBS or αGalCer as described for panel b. Real-time RT-PCR data are expressed as relative mRNA units normalized to β-actin mRNA. Mean ± SEM (*P < 0.05; **P < 0.01 versus PBS-injected mice; §P < 0.05; §§P < 0.01 versus αGalCer-injected mice, killed at 12 h).
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fig4: Effect of αGalCer injection on cytokine and TCR transcripts in spleen and aorta of apoE−/− mice. (a) Proportion of spleen cells double positive for TCRβ and NK1.1 in mice injected once and killed at 12 h and in mice injected 20 times, starting at 5 wk of age, and killed 48 h after the last injection. FACS® data expressed as the percentage of forward/side scatter-gated lymphocytes. (b) CD1d-dimer+ NKT cells in spleen and liver of 5-wk-old mice injected once i.v. with PBS (Ctrl) (n = 6) or αGalCer and killed 12 h (n = 5) or 72 h (n = 6) later. FACS® data expressed as the percentage of forward /side scatter-gated lymphocytes. (c and d) Levels of total TCRβ and Vα14Jα281- specific TCR mRNA (c) and of IFNγ and IL-4 mRNA (d) in the aorta of mice treated with PBS or αGalCer as described for panel b. Real-time RT-PCR data are expressed as relative mRNA units normalized to β-actin mRNA. Mean ± SEM (*P < 0.05; **P < 0.01 versus PBS-injected mice; §P < 0.05; §§P < 0.01 versus αGalCer-injected mice, killed at 12 h).
Mentions: αGalCer injections led to dramatic systemic changes in the NKT cell population. When comparing apoE−/− mice injected once or repeatedly with αGalCer, a transient decrease followed by recovery was observed for TCR+ NK1.1+ cells in the spleen (Fig. 4 a) and liver (not depicted). This could either be due to activation-induced apoptosis or down-regulation of the NK1.1 receptor. To address this issue, NKT cells were also detected using CD1d-dimer staining in mice injected once i.v. with αGalCer and killed 12 or 72 h later. In the spleen, activation through αGalCer injection led to an initial reduction of NKT cells, but after 72 h the spleen had five times more NKT cells than spleens from PBS-injected controls (Fig. 4 b). In the liver, the NKT cell population decreased 12 h after the injection but returned to normal levels after 72 h (Fig. 4 b).

Bottom Line: Given their abundance in the lesion, lipids might be targets of the atherosclerosis-associated immune response.Treatment was accompanied by an early burst of cytokines (IFNgamma, MCP-1, TNFalpha, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNgamma 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.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.

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 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 (IFNgamma, MCP-1, TNFalpha, IL-2, IL-4, IL-5, and IL-6) followed by sustained increases in IFNgamma 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.

Show MeSH
Related in: MedlinePlus