(Circulation. 2001;103:2610.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
T Helper–Cell Phenotype Regulates Atherosclerosis in Mice Under Conditions of Mild Hypercholesterolemia
From the Departments of Pathology (S.A.H., P.S., R.P.T.), Biochemistry (R.P.T.), and Medicine (M.K.N.), University of Vermont, Burlington, and the Department of Immunology, Mayo Clinic, Rochester, Minn (C.D.).
Correspondence to Sally Ann Huber, PhD, Department of Pathology, University of Vermont, 208 S Park Dr, Suite 2, Colchester, VT 05446. E-mail shuber{at}salus.uvm.edu
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. C57Bl/6 mice
produce a CD4+ Th1 (interferon [IFN]
+) response, express
IAb but no IE, and are
atherosclerosis-prone. To evaluate T helper–cell
phenotype in fatty streak formation, wild-type C57Bl/6 mice
(IAb+IE-) and transgenic mice, either
ABo, IAb-IE-;
ABE
, IA-IEk+; or Bl.Tg.E,
IAb+IEk+, were
fed a high-cholesterol diet for 16 weeks and evaluated
histomorphometrically for aortic lesions. Lesion size in
ABo, ABE, and Bl.Tg.E 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 (-CD4)
or cytokines (IL-4) also caused 
80% reductions in lesion
size. Immunohistology revealed IFN-, 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 C57Bl/6 mice on
the same diet.
Conclusions—In mildly
hypercholesterolemic C57Bl/6 mice, presence of
IAb and absence of IE regulated CD4+ T
helper–cell phenotype; fatty lesions were proportional to
IFN+ Th1 cells in both C57Bl/6 and BALB/c strains. IFN- may
participate through macrophage activation, whereas IL-4 may act
to limit Th1-cell
response.
Key Words: arteriosclerosis • immunology • lipids
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