© 2000 American Heart Association, Inc.
Vascular Biology |
Oligoclonal T Cell Expansions in Atherosclerotic Lesions of Apolipoprotein E–Deficient Mice
From the Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
Correspondence to Göran K. Hansson, Center for Molecular Medicine L8:03, Karolinska Hospital, S-17176 Stockholm, Sweden. E-mail Goran.Hansson{at}cmm.ki.se
Abstract—T cells are present
in atherosclerotic lesions at all stages of development. They exhibit
activation markers and are particularly prominent at sites of plaque
rupture. This suggests that T-cell–mediated immune responses are
involved in the pathogenesis of atherosclerosis.
Antigen-specific T cells reactive with oxidized lipoproteins and heat
shock proteins have been isolated from plaques, indicating that local
activation and clonal expansion might occur. To analyze
different stages of atherosclerosis, we have used a
murine model. Targeted deletion of the apolipoprotein E gene results in
severe hypercholesterolemia and spontaneous
atherosclerosis, with lesions containing large numbers
of T cells and macrophages. We have analyzed mRNA for
T-cell antigen receptors (TCRs) from aortic fatty streaks, early
fibrofatty plaques, and advanced fibrofatty plaques of such mice.
Polymerase chain reaction amplification of complementarity-determining
region 3 (CDR3 region) of TCRs was followed by spectratyping of
fragment lengths. This analysis detected all types of
variable (V) segments with a gaussian distribution of CDR3 in lymph
nodes. In contrast, a restricted heterogeneity was
found in atherosclerotic lesions, with expansion of a limited set of
Vß and V
segments and a monotypic or oligotypic CDR3
spectrum in each lesion. Vß6 was expressed in all lesions; Vß5.2,
Vß16, V34s, and V9, in the majority of lesions; and Vß6,
Vß5.2, and V34S, in lesions at all 3 stages of development. The
strongly skewed pattern of the CDR3 region in the TCR is indicative of
oligoclonal expansions of T cells and suggests the occurrence of
antigen-driven T-cell proliferation in atherosclerosis.
Key Words: atherosclerosis • antigen receptors • rearrangement • T-cell antigen receptors • hypercholesterolemia
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