T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia

Sally Ann Huber, P. Sakkinen, C. David, M. K. Newell, R. P. Tracy

Research output: Contribution to journalArticle

158 Citations (Scopus)

Abstract

Background - T cells are implicated in atherosclerosis, but little is known about the genetic control or molecular pathways, especially under conditions of mild hypercholesterolemia. Methods and Results - BALB/c mice, making a CD4+ Th2 (IL-4+) cell response, express both MHC class II antigens (IAd, IEd) and are atherosclerosis-resistant. C57B1/6 mice produce a CD4+ Th1 (interferon [IFN]γ+) response, express IAb but no IE, and are atherosclerosis-prone. To evaluate T helper-cell phenotype in fatty streak formation, wild-type C57B1/6 mice (IAb+IE-) and transgenic mice, either ABo, IAb-IE-; ABEα, IA-IEk+; or B1.Tg.Eα, IAb+IEk+, were fed a high-cholesterol diet for 16 weeks and evaluated histomorphometrically for aortic lesions. Lesion size in ABo, ABEα, and B1.Tg.Eα strains was decreased by 54%, 79%, and 82%, respectively, compared with wild-type, correlating with decreased Th1 and increased Th2 expression and suggesting that T helper-cell phenotype is important in fatty lesion development. Decreasing Th1 cells by antibodies (α-CD4) or cytokines (IL-4) also caused ≥80% reductions in lesion size. Immunohistology revealed IFN-γ but not IL-4, colocalized with activated macrophages. Confirming these findings in a different mouse strain, BALB/c Stat 6 knockout mice (Th2 cell-deficient) developed aortic lesions comparable to C57B1/6 mice on the same diet. Conclusions - In mildly hypercholesterolemic C57B1/6 mice, presence of IAb and absence of IE regulated CD4+ T helper-cell phenotype; fatty lesions were proportional to IFNγ+ Th1 cells in both C57B1/6 and BALB/c strains. IFN-γ may participate through macrophage activation, whereas IL-4 may act to limit Th1-cell response.

Original languageEnglish (US)
Pages (from-to)2610-2616
Number of pages7
JournalCirculation
Volume103
Issue number21
StatePublished - May 29 2001

Fingerprint

Helper-Inducer T-Lymphocytes
Hypercholesterolemia
Atherosclerosis
Phenotype
Interleukin-4
Interferons
Th1 Cells
Diet
Th2 Cells
Macrophage Activation
Histocompatibility Antigens Class II
Knockout Mice
Transgenic Mice
Macrophages
Cholesterol
Cytokines
T-Lymphocytes
Antibodies

Keywords

  • Arteriosclerosis
  • Immunology
  • Lipids

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Huber, S. A., Sakkinen, P., David, C., Newell, M. K., & Tracy, R. P. (2001). T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation, 103(21), 2610-2616.

T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. / Huber, Sally Ann; Sakkinen, P.; David, C.; Newell, M. K.; Tracy, R. P.

In: Circulation, Vol. 103, No. 21, 29.05.2001, p. 2610-2616.

Research output: Contribution to journalArticle

Huber, SA, Sakkinen, P, David, C, Newell, MK & Tracy, RP 2001, 'T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia', Circulation, vol. 103, no. 21, pp. 2610-2616.
Huber SA, Sakkinen P, David C, Newell MK, Tracy RP. T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation. 2001 May 29;103(21):2610-2616.
Huber, Sally Ann ; Sakkinen, P. ; David, C. ; Newell, M. K. ; Tracy, R. P. / T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. In: Circulation. 2001 ; Vol. 103, No. 21. pp. 2610-2616.
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T1 - T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia

AU - Huber, Sally Ann

AU - Sakkinen, P.

AU - David, C.

AU - Newell, M. K.

AU - Tracy, R. P.

PY - 2001/5/29

Y1 - 2001/5/29

N2 - Background - T cells are implicated in atherosclerosis, but little is known about the genetic control or molecular pathways, especially under conditions of mild hypercholesterolemia. Methods and Results - BALB/c mice, making a CD4+ Th2 (IL-4+) cell response, express both MHC class II antigens (IAd, IEd) and are atherosclerosis-resistant. C57B1/6 mice produce a CD4+ Th1 (interferon [IFN]γ+) response, express IAb but no IE, and are atherosclerosis-prone. To evaluate T helper-cell phenotype in fatty streak formation, wild-type C57B1/6 mice (IAb+IE-) and transgenic mice, either ABo, IAb-IE-; ABEα, IA-IEk+; or B1.Tg.Eα, IAb+IEk+, were fed a high-cholesterol diet for 16 weeks and evaluated histomorphometrically for aortic lesions. Lesion size in ABo, ABEα, and B1.Tg.Eα strains was decreased by 54%, 79%, and 82%, respectively, compared with wild-type, correlating with decreased Th1 and increased Th2 expression and suggesting that T helper-cell phenotype is important in fatty lesion development. Decreasing Th1 cells by antibodies (α-CD4) or cytokines (IL-4) also caused ≥80% reductions in lesion size. Immunohistology revealed IFN-γ but not IL-4, colocalized with activated macrophages. Confirming these findings in a different mouse strain, BALB/c Stat 6 knockout mice (Th2 cell-deficient) developed aortic lesions comparable to C57B1/6 mice on the same diet. Conclusions - In mildly hypercholesterolemic C57B1/6 mice, presence of IAb and absence of IE regulated CD4+ T helper-cell phenotype; fatty lesions were proportional to IFNγ+ Th1 cells in both C57B1/6 and BALB/c strains. IFN-γ may participate through macrophage activation, whereas IL-4 may act to limit Th1-cell response.

AB - Background - T cells are implicated in atherosclerosis, but little is known about the genetic control or molecular pathways, especially under conditions of mild hypercholesterolemia. Methods and Results - BALB/c mice, making a CD4+ Th2 (IL-4+) cell response, express both MHC class II antigens (IAd, IEd) and are atherosclerosis-resistant. C57B1/6 mice produce a CD4+ Th1 (interferon [IFN]γ+) response, express IAb but no IE, and are atherosclerosis-prone. To evaluate T helper-cell phenotype in fatty streak formation, wild-type C57B1/6 mice (IAb+IE-) and transgenic mice, either ABo, IAb-IE-; ABEα, IA-IEk+; or B1.Tg.Eα, IAb+IEk+, were fed a high-cholesterol diet for 16 weeks and evaluated histomorphometrically for aortic lesions. Lesion size in ABo, ABEα, and B1.Tg.Eα strains was decreased by 54%, 79%, and 82%, respectively, compared with wild-type, correlating with decreased Th1 and increased Th2 expression and suggesting that T helper-cell phenotype is important in fatty lesion development. Decreasing Th1 cells by antibodies (α-CD4) or cytokines (IL-4) also caused ≥80% reductions in lesion size. Immunohistology revealed IFN-γ but not IL-4, colocalized with activated macrophages. Confirming these findings in a different mouse strain, BALB/c Stat 6 knockout mice (Th2 cell-deficient) developed aortic lesions comparable to C57B1/6 mice on the same diet. Conclusions - In mildly hypercholesterolemic C57B1/6 mice, presence of IAb and absence of IE regulated CD4+ T helper-cell phenotype; fatty lesions were proportional to IFNγ+ Th1 cells in both C57B1/6 and BALB/c strains. IFN-γ may participate through macrophage activation, whereas IL-4 may act to limit Th1-cell response.

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