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Regular Articles |
From the Division of Rheumatology, Immunology and
Allergy*
and the Division of
Cardiology,
Department of Medicine, Brigham
and Women's Hospital, Boston, Massachusetts; and the Cardiovascular
and Pulmonary Research Institute,
Allegheny
University of the Health Sciences, Pittsburgh, Pennsylvania
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several lines of clinical and experimental evidence suggest a role for
the cellular immune system in the development of atherosclerosis. In
humans, the development of accelerated coronary arteriosclerosis in
heart transplant patients supports the involvement of the immune system
in arterial disease.8-12
In mice a similar process has
been shown to be associated with mismatching at major and minor
histocompatibility loci,13
implying that activation of T
cells may initiate or accelerate lesion formation. Studies of
atherosclerosis in apolipoprotein E (ApoE)-deficient mice also indicate
a role for lymphocytes, since crossing these animals with recombinase
activating gene-1 (RAG-1)-deficient animals, which lack T and B
lymphocytes, results in a 40% reduction in lesion formation in animals
maintained on a standard laboratory mouse diet.14
Although
this partial attenuation of atherogenesis by the immunodeficiency state
can be overcome by feeding a high fat diet, these findings nonetheless
point to a potentially important role for the cellular immune response
in accelerating arterial lesion formation. The inhibition of
atherosclerosis in low-density lipoprotein (LDL)
receptor-deficient and C57BL/6 hyperlipidemic mice seen upon treatment
with monoclonal antibodies against lymphocyte surface molecules such as
CD4 and CD40 further support this concept.15,16
Likewise,
apoE-deficient mice also lacking the interferon 
receptor have a
substantial reduction in atherosclerotic lesion size, lipid content,
and cellularity. Thus, this important T-cell-derived cytokine is
implicated in the progression of this disease.17
Atherosclerotic lesions are characterized by the abundant expression of major histocompatibility complex (MHC) class I and II molecules on macrophages, endothelia, and smooth muscle cells.4,15-19 These molecules may present foreign or autologous peptide antigens to T cells present within atherosclerotic plaques.20-23 In this regard, it is extremely provocative that several investigators have demonstrated the presence of chlamydia species and cytomegalovirus within human atherosclerotic lesions, suggesting potential foreign microbial targets that may drive the activation of infiltrating T cells.24-26 Alternatively, T cells within atherosclerotic plaques could also react with self-antigens and thus generate an autoimmune response with inflammatory changes characteristic of these lesions. The possibility that T cell recognition of altered self-antigens could contribute to atherosclerosis has been suggested by Stemme et al, who demonstrated that T cell clones derived from atherosclerotic plaques recognize oxidized LDL in a MHC class II-dependent manner.23
Recent work has identified a novel mechanism for antigen presentation in which T cells recognize specific lipids and glycolipids in the context of non-MHC-encoded CD1 molecules.27-29 Both foreign microbial or synthetic lipids and glycolipids are presented to CD1-restricted T cells.30-32 In addition, a substantial number of CD1-reactive T cells have been isolated that recognize CD1 molecules in the absence of deliberately added exogenous lipid antigens.33-36 Endogenous glycolipids have been demonstrated to enhance CD1 restricted T cell responses37 and autologous cellular lipids have been eluted from CD1 molecules.38 These data suggest that CD1-restricted T cells not only respond to exogenous lipids, but may also recognize endogenous self-lipids. These findings raise the possibility that CD1 molecules could present native or altered lipid epitopes derived from the abundant lipid deposits in atherosclerotic plaques and, thus, drive a T-cell-dependent inflammatory reaction in this disease.
As a step toward evaluating the possible role of antigen presentation by CD1 molecules in the pathogenesis of atherosclerosis, we have examined the expression of CD1 proteins in atherosclerotic plaques in human pathological specimens. We observed the expression of all four previously characterized human CD1 proteins (CD1a, -b, -c, and -d) within atherosclerotic lesions. These proteins were expressed strongly and specifically by lipid-laden macrophages (foam cells) and not by other cells in the lesions. CD1+ monocyte-derived foam cells generated in vitro were able to present lipid antigens to CD1-restricted T cells, suggesting that this mechanism for T cell activation may be active for the phenotypically similar cells observed within atherosclerotic plaques in vivo. Given the abundance of potential lipid antigens within atherosclerotic lesions, our results suggest that lipid antigen presentation by CD1 proteins could contribute to the activation of T cells within plaques, and thus play a role in the cascade of inflammatory processes that influence the progression of this disease.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissues from atherosclerotic lesions were obtained from material removed and discarded during carotid endarterectomy procedures. Surgical specimens of human carotid atheroma and aorta were obtained by protocols approved by the Human Investigations Internal Review Board at the Brigham and Women's Hospital. Monoclonal antibodies (mAbs) were either generated as mouse ascites fluids or purified from culture supernatants by protein G affinity column chromatography (Pharmacia, Uppsala, Sweden), or obtained commercially as purified immunoglobulins. Previously unpublished mAbs F10/21A3 and BCD1b2.1 were produced from mice immunized with GM-CSF- and interleukin (IL)-4-activated monocytes as previously described.39 Monoclonal antibodies CD1d51.1.3, CD1d27.1, and CD1d68.3 were produced by fusion of spleen cells from mice immunized with CD1d-mouse IgG2a fusion proteins.40 The specificities of anti-CD1 antibodies were confirmed by FACS analysis of CD1a, -b, -c, and -d transfected C1R cells.36,40 Antibodies tested included: OKT6 (IgG1, anti-CD1a),36 10D12 (IgG1, anti-CD1a),41 BCD1b2.1 (IgG1, anti-CD1b; SM Behar and SA Porcelli, unpublished), 4A7.6.5 (IgG2a, anti-CD1b),41 10C3 (IgG1, anti-CD1c>>CD1b),42 F10/21A3 (IgG1, anti-CD1c; SM Behar and SA Porcelli, unpublished), CD1d51.1.3 (IgG2b, anti-CD1d > -b >>-c),40 CD1d27.1 (IgG1, anti-CD1d; SA Porcelli, unpublished), CD1d68.3 (IgG1, anti-CD1d; SA Porcelli, unpublished), MT310 (IgG1, anti-CD4; Dako, Carpinteria, CA), DK25 (IgG1, anti-CD8; Dako), KP1 (anti-CD68, Dako), W6/32 (IgG2a, anti-HLA-A, -B, -C),43 L243 (IgG2a, anti-HLA-DR),44 3C10 (IgG2b, anti-CD14),45 IC3/1 (IgG1, anti-ICAM-3),46 LM2/1 (IgG1, anti-Mac-1),47 and YZI (IgG1, anti-complement receptor 1).48 Non-binding isotype-matched controls were ascites fluids or purified immunoglobulins generated from mouse myeloma cell lines P3X63Ag8 (P3; IgG1), MPC11 (IgG2b), and RPC5.4 (IgG2a), all obtained from the American Type Culture Collection (ATCC, Manassas, VA).
Immunohistochemistry and Flow Cytometry
Serial cryostat sections (5 µm thickness) were air-dried onto glass microscope slides and fixed in acetone at -20°C for 5 minutes. Sections preincubated with phosphate buffered saline (PBS) containing 0.3% hydrogen peroxide were incubated with primary or control antibody diluted in PBS with 5% horse serum. This was followed by incubation with biotinylated secondary antibody for 45 minutes, and then by avidin-biotin-peroxidase complex (Vectastain ABC kit, Vector Laboratories, Burlingame, CA). Antibody binding was visualized with 3-amino-9-ethyl carbazole, with counterstaining using Gill's hematoxylin (Sigma Chemical, St. Louis, MO). For double immunostaining, sections were first stained with anti-CD1a mAb followed by biotinylated anti-mouse IgG, avidin-biotin-peroxidase complex, and 3-amino-9-ethyl carbazole, as above. After development of the first immunostain (red color), sections were subjected to treatment with an avidin/biotin blocking kit (Vector Laboratories) according to the manufacturer's recommendations, and further blocked with 5% normal horse serum for 20 minutes. Tissue sections were then processed for detection of the second antigen using anti-human CD68 mAb (clone KP1, DAKO), followed by biotinylated horse anti-murine secondary antibody and streptavidin coupled to alkaline phosphatase followed 30 minutes later by Fast Blue substrate.
Flow cytometry was performed as described,49 with gating on viable cells according to forward and side scatter and exclusion of propidium iodide-stained cells.
T Cell Proliferation Assays
T cell lines DN1 (CD4-CD8-; M. tuberculosis mycolic acid-specific and CD1b-restricted) and CD8.1 (CD4-CD8+, M. tuberculosis phospholipid-specific and CD1c-restricted) have been described.30,50-52 Maintenance of T cell lines and T cell proliferation assays were performed as previously described.51 To induce antigen-specific proliferation, DN1 T cells were stimulated with either a sonicate of M. tuberculosis (strain H37Ra; DIFCO, Detroit, MI) or with purified mycolic acids (Sigma). A total lipid extract of M. tuberculosis (strain H37Ra) was used to stimulate CD8.1 T cells as previously described.52 Serial dilutions of the antigens were performed as described in Results and in figure legends. All cultures contained 50,000 T cells and 50,000 irradiated monocyte-derived antigen-presenting cells per well.
Preparation of Cytokine-Activated Monocytes and Foam Cells
Monocytes were isolated from leukocyte concentrates of normal donors by plastic adherence53 and incubated in medium alone or in medium containing either 100 µg/ml oxidized LDL or 100 µg/ml acetylated LDL (both from Biotechnologies Inc., Stoughton, MA) for 7 days at 37°C in a 5% CO2 incubator. Cells were collected by centrifugation and recultured in fresh medium on day 5. Medium for incubations was RPMI-1640 (Gibco BRL, Gaithersburg, MD) with 10% fetal calf serum (FCS, Hyclone, Logan, UT) with or without a combination of 300 U/ml of GM-CSF (Immunex, Seattle, WA) and 200 U/ml IL-4 (Schering Corp., Kenilworth, NJ). Foam cells were analyzed on day 7 by Nile Red staining according to the method of Greenspan et al.54 Quantitative fluorescence analysis was performed with a FACSort flow cytometer (Becton-Dickinson, Mountain View, CA) using 488-nm excitation wavelength and 515–545 nm detectors. Qualitative analysis was carried out by fluorescence microscopy of Nile Red-stained cells in PBS on glass slides and cover slips using a Nikon Optiphot 2 fluorescent microscope with 470- to 490-nm excitation filters and a 505-nm dichroic mirror and 520- to 560-nm visualization filters.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Monoclonal antibodies specific for each of the four currently
defined human CD1 proteins were tested for staining of frozen sections
from a total of 14 atherosclerotic plaques and 6 non-atherosclerotic
arteries used as normal controls (Figure 1)
. The latter included normal human
aorta and carotid arteries. Lesions studied were predominantly advanced
carotid plaques with characteristic fibrous caps, lipid-laden
macrophages, intimal hyperplasia, and lymphocytes distributed
throughout the lesions. Reactivity of CD1-specific mAbs was noted
exclusively in the intima where gross changes associated with the
atherosclerotic process were visible, but not in adjacent areas of the
media, which generally had grossly normal architecture and cellularity.
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, whereas these
proteins were not detected in similarly processed specimens of normal
arterial tissue (Figure 1, g and h)
. No reactivity was seen using
non-binding isotype matched control mAbs (Figures 1b and 2d)
, demonstrating that reactivity with
anti-CD1 mAbs was specific and was not due to binding to Fc receptors
present on cells within the lesions. Expression of CD1a, -b, -c, and -d
occurred, for the most part, in the same regions of the atherosclerotic
plaques. However, subtle differences did exist, with the expression of
CD1c generally appearing more diffuse within the lesions. CD1 molecules
were expressed predominantly in areas that also had a relatively high
density of CD3+ lymphocytes (Figure 2, a and b)
, indicating close
contact and possible interactions between T cells and cells expressing
CD1 molecules.
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Staining of adjacent serial sections of the same plaque with
anti-CD68, a marker for macrophages, revealed that CD1 expression
occurred predominantly in macrophage-rich areas of the lesion (Figures 1, a–f, and 2, e and f
). High-power views of atherosclerotic lesions
demonstrated that CD1 expression was restricted to the peripheral
regions of large irregular cells containing abundant lipid inclusions
(Figure 2, c and e)
. The appearance of these cells was characteristic
of the macrophage-derived lipid-laden foam cells commonly found in
mature atherosclerotic plaques. To verify that CD1 expression was
restricted to macrophage-derived foam cells, we performed double
staining of individual sections with mAbs specific for CD68 and either
CD1a or CD1b. High-power views of these sections revealed that all CD1+
cells were also co-stained for CD68, and that all of these
double-labeled cells had vacuolated cytoplasmic inclusions (Figure 2g)
.
These findings demonstrated the macrophage origin of the CD1+ foam
cells in atherosclerotic lesions.
Generation of CD1+ Monocyte-Derived Foam Cells in Vitro
The expression of CD1 molecules by lipid-laden foam cells
suggested that these cells might present lipid antigens to T cells
present in atherosclerotic plaques. Because the relatively small number
of such cells in the available tissue specimens precluded their direct
isolation for in vitro functional analyses, we produced
monocyte-derived foam cells in vitro to assess their ability
to act as antigen-presenting cells for CD1-restricted T cell responses.
Peripheral blood monocytes were cultured in media containing GM-CSF and
IL-4 to augment the expression of CD1 molecules (CD1a, -b, and -c). To
induce foam cell formation, some cultures were incubated with medium
containing either acetylated LDL or oxidized LDL. In contrast to
untreated control cells, staining of these LDL-loaded cells with the
lipid stain Nile Red demonstrated lipid accumulation characteristic of
foam cells (Figure 3, a and b)
.
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. Acetylated LDL-treated cells were
brighter, with distinct lipid droplets present diffusely throughout the
cytoplasm, consistent with a foam cell phenotype. Oxidized LDL-treated
cells were less bright, with hazy Nile Red staining in a perinuclear
distribution in addition to the cytoplasmic droplet appearance,
suggesting lipid accumulation in additional compartments in these
cells. In contrast, when compared to these cells, GM-CSF and
IL-4-treated monocytes (G/4) cultured in the absence of modified LDL
treatment gave only weak fluorescence (Figure 3b)
.
CD1a, -b, and -c proteins were expressed on monocyte-derived foam cells
from cultures treated with either oxidized or acetylated LDL in the
presence of GM-CSF and IL-4, as determined by flow cytometry (Figure 4)
. These cells also expressed a variety
of cell surface proteins typically found on macrophages, including MHC
class I and class II molecules, CD11b (Mac1), complement receptor 1
(CR-1), CD14, and ICAM 3 (Figure 4
, Table 1
, and additional data not shown).
Overall, this cell-surface phenotype showed strong similarities to that
described previously for foam cells in atherosclerotic lesions in
vivo,4,15-19,55-58
as summarized in Table 1
.
Interestingly, incubation with oxidized LDL consistently reduced the
expression of most of the cell surface molecules studied when compared
to acetylated LDL-treated monocytes or cytokine-activated controls
(Figure 4
, Table 1
, and additional data not shown). These in
vitro findings suggested that lipid accumulation resulting from
uptake of certain types of lipoprotein particles (eg, oxidized LDL)
could be responsible for further differentiation and phenotypic
modulation of CD1+ foam cells within atherosclerotic lesions in
vivo.
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CD1-expressing monocyte-derived foam cells were tested in T cell
proliferation assays for their ability to present known bacterial lipid
antigens to established CD1b- and CD1c-restricted T cell lines. Foam
cells generated in vitro by loading with either oxidized or
acetylated LDL were capable of inducing antigen-dependent proliferation
of the mycolic acid-specific CD1b-restricted T cell line DN1 (Figure 5a)
. Similarly, the CD1c-restricted T cell line CD8.1 was also induced
to proliferate by presentation of mycobacterial phospholipid antigens
by both types of in vitro-derived foam cells (Figure 5b)
. As
expected, neither T cell line showed responses to the specific lipid
antigens in the presence of cultured macrophages, which lack expression
of the relevant CD1b and -c antigen-presenting proteins (Figure 5, a and b)
.
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, and we
observed similar reductions in antigen-presenting function when GM-CSF
plus IL-4-treated monocytes were exposed to crude lipids extracted
directly from atherosclerotic plaques (data not shown). This reduction
of antigen-presenting capacity was particularly pronounced at low
concentrations of the exogenously added bacterial lipid antigen (Figure 5c)
. This observation provided additional evidence that accumulation of
certain forms of lipid may induce further differentiation of foam
cells, resulting in effects on their antigen-presenting function.
Nevertheless, CD1+ foam cells generated by either method activated
lipid antigen-specific CD1-restricted T cells, indicating that they
retained the capacity to present lipid antigens to T cells through the
CD1 pathway. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The expression of CD1 proteins on foam cells in atheroma agrees with the known distribution of these molecules on cells derived from the myelomonocytic lineage.27 However, whereas previous studies have frequently shown the pronounced expression of CD1a, -b, and -c on dendritic cells in various tissues, these molecules have generally not been detected on resident tissue macrophages.27 Information on the expression of the fourth CD1 protein, CD1d, is currently limited. Studies on the homologue of this protein in the mouse have indicated its expression on a variety of hematopoietic cell types,59,60 but have not established its expression by resident tissue macrophage populations. Thus, the finding of strong expression of all four known human CD1 proteins on the macrophage-derived foam cells of atheromatous plaques was an unexpected, novel result of this study. Besides the thymus,61 the atherosclerotic plaque is to our knowledge the only tissue thus far demonstrated to express all four of these human CD1 molecules in vivo.
The mechanisms that induce the expression of CD1 proteins in
atherosclerotic lesions are unknown. CD1 proteins, with the exception
of low levels of CD1d, have not generally been detected on circulating
myelomonocytic cells in vivo.27
Thus, the
expression of CD1 proteins that we have observed on foam cells suggests
that the local environment of the atherosclerotic plaque may contain
factors that increase transcription or translation of these proteins.
Leading possibilities for such inducing factors are the cytokines
produced within these lesions, which include interferon- (IFN),
GM-CSF, tumor necrosis factor-
(TNF), tumor necrosis factor-ß
(TNFß), and interleukin-2 (IL-2).3,7,21
Among these,
GM-CSF is the only cytokine currently known to induce CD1 proteins on
monocyte-derived cells.27,51
The possibility of other
inducing factors within these lesions remains to be investigated. These
could potentially include other secreted proteins as well as signals
mediated through receptors interacting with either cell-bound or
matrix-associated factors present within the plaques.
Studies on the antigen-presenting function of CD1 proteins suggest that CD1 restricted T cells can respond to foreign as well as potential endogenous lipid antigens. It is now well established that these molecules can present a variety of foreign lipid and glycolipid antigens found in the cell walls of pathogenic mycobacteria to human T cells. Several of the lipid antigens presented by the human CD1b protein have been isolated and structurally characterized.30-32 These studies reveal the existence of a potentially broad range of CD1-presented lipid antigens, including molecules as disparate in structure as the mycolic acids and phosphatidylinositol-containing lipoglycans.30-32 In addition, CD1d proteins can present glycosylated ceramide-like and glycosylphosphatidylinositol (GPI)-containing lipids to T cells.37,62 The mechanism of this lipid antigen presenting function of CD1 proteins has been illuminated by the solution of the crystal structure of a mouse CD1 protein, which reveals a large hydrophobic antigen-binding cavity that is well suited to function as a lipid binding site.63
Several observations suggest that CD1 proteins may also be capable of binding and presenting normal endogenous cellular lipids to T cells. For example, the mouse CD1d protein produced in Drosophila cells that was studied by X-ray crystallography contained additional electron dense material within its putative lipid-binding cavity.63 Based on the linear and unbranched appearance of this density, it was suggested to most likely represent a bound cellular lipid, presumably inserted during synthesis and assembly of the protein. Consistent with this possibility, mouse CD1 proteins expressed in mammalian cells and purified on affinity columns were shown to contain detectable amounts of bound cellular GPI,38 and another study has shown that a synthetic form of a mammalian GPI can be recognized by CD1-restricted murine T cells.37 More recently, evidence has been obtained that suggests that gangliosides found in mammalian brain tissue may be presented to human CD1b-restricted T cells.64 These findings indicate that normal or structurally altered endogenous lipids could serve as targets for CD1-restricted T cells, particularly in inflammatory lesions where CD1 molecules are up-regulated.
Although our data do not yet establish a functional role for CD1
proteins expressed on foam cells in atheroscerotic plaques, several
features of these lesions support this possibility. T cells within
atheroma appear to be chronically activated19,21,65,66
and
frequently express markers of activation including HLA-DR, CD26, and
VLA-1.65
Immunohistochemical and PCR analyses demonstrate
that T cells within these lesions actively transcribe and secrete
cytokines, including IFN and IL-2.3,7,21
Other studies
suggest that T cells within atherosclerotic plaques proliferate, as
might be expected after antigen recognition.67
Plaque T
cells are predominately CD45RA low and CD45RO high, which is
characteristic of the memory phenotype typically displayed by
antigen-selected T cells.65
Although none of these findings
directly demonstrates that ongoing antigen presentation occurs within
lesions, together they form a strong circumstantial argument in favor
of this hypothesis.
Potential targets that may contribute to the activation of plaque-infiltrating T cells include infectious organisms that have been identified in these lesions, such as cytomegalovirus or chlamydia, and also normal or chemically modified self-antigens. Presentation of such antigens may occur through the MHC class I or II pathways, as these molecules are expressed by cells within the lesions. In fact, studies directly examining the specificity of plaque-infiltrating T cells have demonstrated that a fraction of these may recognize oxidized LDLs presented by MHC class II proteins, whereas others appear to respond to heat shock proteins.21,23,68 However, previous studies have not considered the possibility that antigen presentation by CD1 might account for some component of T cell activation in atheroma. Clearly, as CD1 is now recognized to function in the presentation of lipid antigens and because atheroma contain an abundance of chemically altered lipids, it now appears reasonable to consider and carefully assess this possibility.
Using foam cells generated in vitro, we demonstrated the capability of such cells to present defined exogenous foreign lipid antigens to CD1-restricted T cells. These in vitro cultured foam cells, similar to their in vivo counterparts,4,15-19,55-58 developed typical lipid inclusions and expressed MHC class I and II, Mac-1, CR-1, CD14, and CD1 proteins. Our results demonstrated that these cells are capable of presenting lipid antigens by either the CD1b or CD1c antigen presentation pathways. Although our experiments have not yet directly demonstrated lipid antigen presentation within atherosclerotic plaques, the large accumulations of normal and altered lipids within the same cells that express the CD1 proteins in these lesions clearly suggests this possibility. Future studies should help determine if direct recognition of foreign or endogenous lipids is a common feature of plaque-infiltrating T cells. And our initial studies on in vitro cultured foam cells suggest they may be suitable for use to test for CD1-restricted antigen recognition by these cells.
In summary, the present data suggest a potential role for CD1-restricted antigen presentation in atherosclerosis. Atheroma are inflammatory lesions, and the progression of these lesions is likely to be driven and regulated by the cells within the lesions. The activation of T cells within atherosclerotic plaques likely contributes to the development and evolution of these lesions, and macrophage-derived foam cells probably play a central role in this process. Our finding that these cells express the CD1 system of lipid antigen-presenting molecules, coupled with the abundance of abnormal lipids within atherosclerotic lesions, points to a novel potential mechanism for sustained T cell activation. Further development of the in vitro system described here may allow direct analysis of this component of atherosclerosis and may lead to new strategies for prevention and therapeutic intervention in this disease.
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Acknowledgements |
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Footnotes |
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Supported by grants from the National Institutes of Health K11AIO13858 (NIH/NIAID) to A. M., AI40135 (NIH/NIAID) to S. P., and R37-HL34636 to P. L. Additional support was provided by the American Heart Association/Bugher Foundation fellowships to A. M. and by a grant from the American Cancer Society to S. P.
Accepted for publication June 30, 1999.
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References |
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24+ CD4-CD8- T cells. J Exp Med 1997, 186:109-120 2/V 
2 subset in human mycobacteria-responsive T cells suggests germline gene encoded recognition. J Immunol 1991, 147:3360-3369[Abstract]
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