doi: 10.1161/hq0701.092162
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Interleukin-15 Expression in Atherosclerotic Plaques
An Alternative Pathway for T-Cell Activation in Atherosclerosis?
From the Departments of Cardiovascular Pathology (M.A.H., A.C.W., O.J.B., C.M.L., A.E.B.) and Anatomy and Embryology (P.A.J.B., A.F.M.M.), Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
Correspondence to Anton E. Becker, MD, Department of Cardiovascular Pathology, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail m.i.schenker{at}amc.uva.nl
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Abstract |
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Abstract—T-cell activation in atherosclerotic plaques is thought to be initiated by plaque-derived antigens, such as oxidized LDL (oxLDL). An alternative pathway of T-cell activation independent of antigen stimulation, mediated by the cytokine interleukin (IL)-15, was recently described. We investigated IL-15 expression in atherosclerotic plaques in relation to plaque morphology, inflammatory cells, T-cell activation, and oxidation-specific epitopes by use of immunohistochemistry. In situ hybridization was used to evaluate IL-15 mRNA expression. We also studied the proliferative response of plaque-derived T-cell lines to IL-15 in vitro using [3H]thymidine incorporation. Fresh-frozen specimens were classified as fibrous (n=9), fibrolipid (n=8), and lipid-rich (n=14) plaques; normal vessels (n=4) served as reference. Expression of IL-15 mRNA and protein was found almost solely in fibrolipid and lipid-rich plaques, associated with oxLDL-positive macrophages. Sequential immunostains revealed colocalization between IL-15– and CD40L-positive T cells. Moreover, plaque-derived T-cell lines were highly responsive to IL-15. Hence, IL-15 could provide a pathway for antigen-independent T-cell activation.
Key Words: cell-mediated immunity • interleukin-15 • macrophages • T-cell activation
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Introduction |
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It is currently appreciated that chronic inflammatory cell–mediated immune responses are involved in the pathogenesis of atherosclerosis.1 2 3 Activated macrophages and T lymphocytes are present in human atherosclerotic lesions at all stages of development from precursor lesions (fatty streaks) to advanced lipid-rich atherosclerotic plaques.1 4 In the latter situation, inflammatory cells are often found preferentially at sites that are vulnerable to rupture.5 In the atherosclerotic plaque, T cells reside in a microenvironment suitable for antigen-specific stimulation, exemplified by the presence of HLA-DR–positive macrophages5 expressing costimulatory molecules (B7-1/B7-2).6 Indeed, it is currently widely acknowledged that antigen-dependent T-cell activation in atherosclerotic plaques occurs, a notion supported by observations that in humans, plaque-derived T cells respond to oxLDL,7 Chlamydia pneumoniae antigens, and heat-shock protein 60.8 9 10
An alternative pathway of T-cell activation independent
of antigen presentation was recently described, mediated by
the cytokine interleukin
(IL)-15.11 IL-15 is a
cytokine that shares many similarities in biological function
with IL-2, but without sharing sequence
homology.12 It interacts
with a heterotrimeric receptor that consists of the ß- and
-subunits of the IL-2 receptor and its own unique 
-chain
(designated
IL-15R-).13 14
Important effector functions of IL-15 are the ability to
induce proliferation of mature T cells, generation of cytotoxic T
cells, and stimulation of cytokine
production.15 At
optimal concentrations, IL-15 induces expression of the activation
molecules CD69 and CD40L on T
cells.16 17 18
Furthermore, IL-15 acts as a chemoattractant for T
cells,19 inhibits
apoptosis of T
cells,20 and induces
monocytes to secrete proinflammatory and chemotactic
cytokines.21 22 23
The functional importance of IL-15 in chronic inflammatory disorders is
endorsed by recent studies, which showed that administration of soluble
IL-15R- chain antagonist or IL-15 mutant/Fc2a protein
abrogated collagen-induced arthritis and delayed-type hypersensitivity
in mice.24 25 In
the context of chronic inflammatory disorders, macrophages may
act as a major source of IL-15
protein.26 This implies that
IL-15 could also be expressed in advanced atherosclerotic plaques,
because macrophages are often abundantly present in these
lesions. We investigated the expression of IL-15 in relation to the
atherosclerotic process. Because IL-15 expression is controlled at the
levels of transcription, translation, and intracellular
trafficking,27 we studied
both IL-15 mRNA and its protein expression in atherosclerotic plaques
in relation to plaque morphology, cellular composition, T-cell
activation, and oxidation-specific epitopes by use of
immunohistochemical techniques and in situ hybridization. In addition,
we studied the in vitro proliferative response to recombinant IL-15 of
isolated T-cell lines derived from atherosclerotic
plaques.
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Methods |
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Human Tissue Samples
Arterial wall specimens containing atherosclerotic plaques were obtained from 28 patients (5 women, 23 men; age±SD 67±10 years, range 45 to 85 years) and harvested from the coronary arteries (8 plaques from 5 different patients), carotid arteries (n=9; 9 patients), and aorta (n=14; 14 patients). Normal vessels (1 aorta, 3 coronary arteries; 4 patients) without atherosclerotic disease were used as reference material. The aortic and carotid arteries were obtained at surgery, whereas coronary arteries were collected at autopsy (postmortem interval <12 hours).
Biopsies of inflamed rheumatoid synovium served as positive control for the detection of IL-15 with both immunohistochemistry and in situ hybridization.11 28 Informed consent from the patients was obtained before surgery, and the study was approved by the local ethical committee of the Academic Medical Center.
Full-thickness biopsies of the vessels were rapidly frozen in liquid nitrogen. Morphological classification of atherosclerotic plaques was performed with the use of 6-µm sections stained with hematoxylin-eosin or elastic van Gieson. Each section was screened for its ratio of fibrous cap thickness versus lipid core. The plaques were classified as either lipid-rich, fibrolipid, or fibrous. Accordingly, lipid-rich plaques contain a large atheroma and a thin or virtually absent fibrous cap. In fibrous plaques, fibrocellular or fibrosclerotic tissue is the predominant component. In fibrolipid plaques, the cap/lipid core ratio is between 25% and 75%.29 Adjacent sections were mounted for immunohistochemistry and in situ hybridization.
Immunohistochemistry
Immunohistochemical single staining was performed
with a standard streptavidin-biotin complex method. Serial sections of
frozen tissue biopsies were cut at 6 µm, fixed in acetone, and
blocked for endogenous peroxidase activity by 0.3%
H2O2/0.1% sodium azide.
Sections were incubated with mouse monoclonal antibodies directed
against IL-15 (clone M112, Genzyme), T cells
(CD3, clone Leu-4, Becton-Dickinson), macrophages (CD68, clone
EBM-11, DAKO), -smooth muscle actin (clone
1A4, DAKO), malondialdehyde-modified LDL (clone 12E7, Biodesign
International), and CD40L (clone Trap-1, a kind gift of Prof Dr R.
Kroczek,30 Robert
Koch-Institute, Berlin, Germany). Rabbit polyclonal antibodies against
vWF (DAKO) were used to detect endothelial cells. The
primary antibody was applied to the sections in appropriate optimal
predetermined dilution followed by incubation with biotin-conjugated
goat anti-mouse (GAM-BIO) or goat anti-rabbit (GAR-BIO) immunoglobulins
and streptavidin-biotin–horseradish peroxidase complex (all from
DAKO). In the case of the T-cell activation marker CD40L, tyramide
signal amplification was used (NEN, Life Science
Products) according to the instructions of the manufacturer. In
this instance, endogenous peroxidase was blocked with
glucose oxidase (Sigma). Peroxidase activity was
visualized by 3-amino-9-ethyl carbazole (AEC). Sections were
counterstained with hematoxylin. Control sections were incubated
according to the same technique, but with the substitution of the
primary antibody by irrelevant monoclonal reagents of similar isotype
and immunoglobulin concentration.
In a number of cases, the following immunoenzyme double stainings were performed: IL-15/CD68, IL-15/CD3, IL-15/1A4, and IL-15/vWF. The combination of 1 unlabeled monoclonal antibody with 1 fluorescein isothiocyanate (FITC)– or digoxigenin (DIG)-conjugated monoclonal antibody was used in the case of IL-15/CD68 (DIG) and IL-15/CD3 (FITC), whereas the immunoenzyme double-staining protocol based on differences of the host or isotype of the primary antibody immunoglobulins was used in the case of IL-15 (mouse)/vWF (rabbit) and IL-15 (IgG1)/1A4 (IgG2a), respectively.31 Peroxidase activity was detected with AEC, whereas alkaline phosphatase activity was detected with either fast blue BB or nitro blue tetrazolium/5-bromo-4-chloro-3-indolyl phosphate (NBT/BCIP, DAKO).
In serial sections, anti-CD40L and anti-CD3–positive cells in the intimal plaque were enumerated by light microscopy. The percentage of activated T cells (CD40L+/CD3+ cells) was calculated for each specimen.
RNA In Situ Hybridization
In situ hybridization was performed as described by
Woodroofe and Cuzner,32 with
some minor modifications on all normal vessels (n=4) and a number of
atherosclerotic plaques, including lipid-rich (n=6), fibrolipid (n=5),
and fibrous plaques (n=3). Frozen specimens of vessels were serially
sectioned at 10 µm, fixed at 50°C for 10 minutes, defatted with
chloroform for 5 minutes, and finally fixed in freshly made 4%
paraformaldehyde in PBS (4% PFA/PBS) for 20 minutes.
Before hybridization, sections were incubated for 10 minutes with 2x
SSC at 70°C, subsequently treated with 0.001% pepsin (Sigma P7000)
for 20 minutes at 37°C, dipped in 0.1% glycerin/PBS, and postfixed
with 4% PFA/PBS.
After this pretreatment, the sections were air-dried and
hybridized with FITC-labeled oligonucleotides, encoding
for IL-15 and including 5'-CTGCACTGAAACAGCCCAAAATGAAGACAT-3',
5'-GCAACTGGGGTGAACATCACTTTCCGTATA-3', and
5'-CTCCAGTTCCTCACATTCTTTGCATCCAGA-3' (Amersham
Pharmacia), used as an equimolar probe mix. As
negative control probe, a FITC-labeled synthetic
oligonucleotide
(5'-GGCGA-CGCGCCGTATTTATAATTCATTATG-3') was used (Amersham
Pharmacia), as described
previously.33 A FITC-labeled
oligo-dT probe was used as positive control to determine the presence
and spatial distribution of (total) mRNA in the lesions. Hybridization
was carried out overnight at 37°C with 4 ng/µL of IL-15 probe mix,
4 ng/µL of control probe, and 1 ng/µL of oligo-dT probe in
hybridization buffer containing 25% deionized formamide, 2x
Denhardt’s solution, 2x SSC, 10% dextran sulfate, 0.1 mg/mL
single-strand herring sperm DNA, and 0.1 mg/mL tRNA. After
hybridization, the slides were washed twice for 15 minutes in 1x SSC
at 37°C. Subsequently, the slides were incubated with alkaline
phosphatase–conjugated sheep anti-FITC antibody (Sh--FITC-AP;
Boehringer Mannheim) for 2 hours in 1% BSA at room temperature
and washed twice for 5 minutes with TBS. Alkaline phosphatase activity
was visualized with NBT/BCIP substrate system (DAKO). The sections were
counterstained with methyl green and aqueously mounted. Negative
controls included treatment of sections with RNase (0.1 mg/mL) for 30
minutes at 37°C after the pepsin treatment or omission of
oligonucleotides in the hybridization
mix.
T-Cell Proliferation Assay
T-cell lines were generated from
endarterectomy tissue of 2 patients, as described
previously.8 T-cell lines
were cultured for 3 days in Iscove’s modification of Dulbecco’s
medium (Life Technologies) supplemented with
10% heat-inactivated pooled human serum and antibiotics
(penicillin/streptomycin, Life Technologies) with or without
recombinant (r) IL-15 (1, 5, and 10 ng/mL; Strathmann Biotech GmbH) in
96-well round-bottom culture plates (Costar) at
a concentration of 1.105 cells/well.
Phytohemagglutinin (10 µg/mL) was used as positive control.
Anti–IL-15 blocking antibody (0.05 and 0.2 ng/mL; mAb 247, R&D) was
added to investigate the specificity of the response.
All combinations were analyzed as triplicates. During the last 16 hours of culture, 0.3 µCi [3H]thymidine was present per well. Cultures were harvested with an automatic harvester, and incorporated radioactivity was measured by liquid scintillation counting and expressed as mean counts per minute. Differences between experimental conditions of the T-cell lines were analyzed by ANOVA with Bonferroni correction. A value of P<0.05 was considered statistically significant.
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Results |
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Vessels selected as normal showed diffuse intimal thickening, as anticipated, but no atherosclerotic disease (Figure 1
). On the basis of hematoxylin-eosin– and elastic
van Gieson–stained sections, a total of 31 atherosclerotic plaques
were categorized as either lipid-rich (n=14;
Figure 3A), fibrolipid (n=8), or fibrous (n=9;
Figure 2A).
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The presence of plaque inflammation was investigated by use of anti-CD68 and anti-CD3 antibodies. In all lipid-rich plaques, the fibrous cap was heavily infiltrated with both types of inflammatory cells. In all fibrolipid plaques, inflammatory infiltrates were also present, either as diffuse infiltrates throughout the cap or as multifocal infiltrates in otherwise fibrous tissue. In fibrous lesions, macrophages and T cells were either scarce or present in a small cluster associated with a small, more deeply located atheroma.
Immunohistochemical Analysis of IL-15
in Atherosclerotic Vessels
In normal vessels (n=4) and fibrous plaques (n=9),
immunoreactive IL-15 was virtually absent
(Figures 1B
and 2B). In lipid-rich (n=14) and fibrolipid (n=8)
plaques, strong immunoreactive IL-15 was detected, colocalizing with
the majority of CD68-positive macrophages
(Figure 3B and 3C). This was confirmed with immunoenzyme
double staining, showing that IL-15 expression on macrophages
was membrane-associated
(Figure 3F), whereas no IL-15 expression was observed on
smooth muscle cells, endothelial cells
(Figure 3G and 3H), or T cells
(Figure 4A). IL-15–positive macrophages had an
elongated morphology in the superficial parts of the cap or were
present as lipid-laden cells in the deeper parts of the fibrous
cap. Macrophages around the lipid core, often loaded with
ceroid pigment, and all large foam cells, however, were IL-15–negative
(Figure 3B). Comparison of IL-15 and CD68 staining on serial
sections of each plaque revealed that the vast majority of the
macrophages showed distinct anti–IL-15 staining.
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OxLDL immunostaining was found in all
fibrolipid and lipid-rich plaques and always colocalized with
IL-15–positive cells
(Figures 3B and 3E). CD3-positive T cells were frequently
encountered in substantial numbers in both lipid-rich and fibrolipid
plaques, in particular in those regions containing clusters of
IL-15–positive macrophages
(Figure 4A). In normal vessels and fibrous plaques,
conversely, both oxLDL- and CD3-positive T cells were only scarce or
absent, similar to the scarcity of IL-15–positive macrophages
in these lesions (see above). The percentage of
CD40L-positive/CD3-positive cells in IL-15–positive regions of all
examined lesions was 26.1±11.0%. Only T cells were found to be
CD40L-positive
(Figure 4A and 4B).
IL-15 mRNA Expression in Atherosclerotic
Lesions
In situ hybridization with FITC-labeled IL-15 probe
mix, comprising 3x30-bp oligonucleotides, revealed a
positive cytoplasmic staining signal in all lipid-rich (n=6) and
fibrolipid (n=5) plaques
(Figure 5B and 5C). Similar staining patterns were obtained
with each individual oligonucleotide of the IL-15 probe
mix (data not shown). The positive mRNA signal colocalized with
inflammatory cells, apart from the population of foam cells in
continuity with the lipid core. Staining of adjacent sections with CD68
showed colocalization between the IL-15 mRNA signal and CD68-positive
macrophages
(Figure 5A and 5B).
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In fibrous plaques (n=3) and normal vessels (n=4), in
contrast, IL-15 mRNA expression was almost completely absent (data not
shown), a finding similar to that observed with
immunostaining. Positive controls (oligo-dT-FITC) were
always positive, indicating mRNA expression in all vessels. Negative
controls (FITC-labeled control probe, RNAse pretreatment) were always
negative
(Figure 5D).
Proliferative Response of Plaque-Derived T-Cell
Lines to IL-15
Addition of rIL-15 to atherosclerotic plaque–derived
T-cell lines resulted in a significant dose-dependent increase of
proliferation. This proliferative response was inhibited in a
dose-dependent manner by anti–IL-15 antibody, demonstrating the
specificity of the response. The results of a
representative experiment are illustrated in
Figure 6.
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Discussion |
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This study reveals that high levels of IL-15 mRNA and its protein are expressed by the majority of macrophages in both lipid-rich and fibrolipid plaques but that there is hardly any IL-15 expression in fibrous plaques and normal vessels. Immunoenzyme double staining showed that IL-15 expression is present on the cell membrane of macrophages, whereas T cells, arterial and microvascular endothelial cells, and smooth muscle cells were IL-15–negative. In both fibrolipid and lipid-rich plaques, activated (CD40L+) T cells were found in close association with IL-15–positive macrophages. Immunoreactive oxLDL was found exclusively in these plaques and always colocalizing with IL-15 expression. In addition, it was shown in vitro that T-cell lines derived from atherosclerotic plaques were responsive to IL-15. The strong expression of IL-15 protein by macrophages in atherosclerotic lesions is of particular interest, given the functional potentials of IL-15. In vitro studies have shown that IL-15 is capable of activating T cells by inducing proliferation,11 synthesis of cytokines (interferon [IFN]-
),15 and
expression of adhesion molecules (CD69,
CD40L).16 17
Furthermore, IL-15 inhibits apoptosis of T
cells.20
Currently, T cells in atherosclerotic plaques are considered
to play a role as an effector cell on direct cell contact with
macrophages and concomitant presentation of
antigens.3 On such
interaction, T cells are activated and produce mediators, such
as IFN-, resulting in the activation of macrophages and
possible destabilization of unstable plaques by decreasing the
synthesis of collagen
fibrils.34 In addition,
activated T cells induce the production of
macrophage-derived mediators with plaque-destabilizing
properties, such as tumor necrosis factor- and matrix
metalloproteinases,35 via
ligation with the surface molecules CD40L and
CD69.36 37
The present study reveals that IL-15 could be highly
instrumental in this context, because it is capable of activating
memory T cells, prolonging their
survival,38 and inducing
IFN- synthesis.15 It is
of particular interest that activation of T cells by IL-15 is dependent
on direct cell-cell contact but independent of specific antigenic
stimulation.37 Because the
majority of plaque T cells are of the memory
phenotype,5 39
known to be responsive to IL-15, one could speculate that IL-15
expression in atherosclerotic plaques contributes to local T-cell
activation and survival. The present study supports this hypothesis
by the observations that T cells are abundant near or adjacent to
IL-15–positive macrophages and show significant expression of
the IL-15–inducible T-cell activation marker
CD40L.16 18
Luminal and microvascular endothelium in
atherosclerotic plaques appeared to be negative for IL-15 with both
immunohistochemistry and in situ hybridization. This contrasts with a
previous study that showed that in vitro, endothelium
expressed both IL-15 mRNA and intracellularly, IL-15 protein, as was
determined with reverse transcription–polymerase chain reaction and
fluorescence-activated cell sorter analysis. On
activation, endothelial cells also expressed IL-15
protein on the cell
membrane.40 41
These in vitro data were confirmed in vivo with immunohistochemistry,
showing that microvessels in rheumatoid synovia were
IL-15–positive.40
Because luminal endothelium and microvascular endothelium in atherosclerotic plaques are considered to be activated, exemplified by the expression of adhesion molecules,42 43 one could speculate that endothelial cells in atherosclerotic plaques are IL-15–positive. Staining for IL-15 was never observed, however, with immunohistochemistry. The observed discrepancy in IL-15 staining between microvessels in rheumatoid synovium and atherosclerotic plaques might be due to differences that exist between the anti–IL-15 antibodies used as well as differences in the activation state of endothelium in the respective tissues.
It is of additional interest that IL-15–positive macrophages and oxLDL show distinct colocalization. It is known that modified lipoproteins may induce the synthesis of several (pro)inflammatory cytokines, including IL-8, monocyte chemotactic protein-1, and IL-12,44 45 46 and therefore, one could hypothesize that oxLDL is involved in the upregulation of IL-15 in atherosclerotic lesions. If so, the high levels of IL-15 expression and its sustained effects on T-cell activation and survival could provide an additional explanation why the effects of inflammation are most prominent in lipid-rich plaques.
Our observations suggest that antigen-independent T-cell activation in atherosclerotic plaques can occur, which may expand horizons as to the mechanisms involved in the genesis of plaque complications.
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Acknowledgments |
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The authors thank Prof Dr R. Kroczek, Department of Molecular Immunology, Robert Koch-Institute, Berlin, Germany, for providing the anti-CD40L (Trap-1) antibody and help with the tyramide-amplification method. The authors also thank T. Smeets, BSc, and Prof Dr P.P. Tak, Department of Rheumatology, Academic Medical Center, Amsterdam, Netherlands, for providing the rheumatoid synovial biopsies.
Received December 1, 2000; accepted April 3, 2001.
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