(Circulation. 2000;102:2919.)
© 2000 American Heart Association, Inc.
Brief Rapid Communications |
Transfer of CD4+ T Cells Aggravates Atherosclerosis in Immunodeficient Apolipoprotein E Knockout Mice
From the Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (X.Z., R.E., G.K.H.), and INSERM U430, Hôpital Broussais, Paris, France (A.N.).
Correspondence to Dr Göran K. Hansson, Center for Molecular Medicine L8:03, Karolinska Hospital, SE-17176 Stockholm, Sweden. E-mail Goran.Hansson{at}cmm.ki.se
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Atherosclerosis is associated with immune responses to oxidized lipoproteins and certain microorganisms, but the role of specific immunity has remained unclear.
Methods and Results—To
study the role of immunity in atherosclerosis, we
crossed atherosclerosis-prone
apoE—/– mice with immunodeficient
scid/scid mice. The offspring
showed a 73% reduction in aortic fatty streak lesions when compared
with immunocompetent apoE–/– mice.
Transfer of CD4+ T cells from
apoE–/– to immunodeficient
apoE–/–/scid/scid
mice increased lesions by 164%. This was associated with the
infiltration of transferred T cells into lesions, increased circulating
interferon-
levels, and increased I-A expression in
lesions.
Conclusions—CD4+ T cells carry disease-promoting immunity in atherosclerosis.
Key Words: atherosclerosis • lymphocytes • immune system • mice, knockout
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Atherosclerosis is characterized by focal arterial lesions containing cholesterol, fibrosis, and inflammatory infiltrates.1 The latter consist mainly of macrophages and T lymphocytes, many of which are immunoreactive against oxidized LDL.2 3 Patients with atherosclerosis exhibit systemic immune responses against oxidized LDL,4 5 heat shock proteins,6 Chlamydia pneumoniae,7 and other antigens, but the role of adaptive immunity in the disease process has remained unclear. New knockout models such as the apoE–/– mouse, which develops spontaneous hypercholesterolemia and atherosclerosis, have permitted detailed studies of atherogenesis.8 9
The extent of disease is reduced when selective or generalized immune defects are induced in such mice by crossbreeding with other knockout strains10 11 12 or by treatment with blocking antibodies.13 14 All these data point to a proatherogenic role for adaptive immunity, but the finding that immunization with oxidized LDL reduces lesions15 suggests that protective immunity may also occur. The role of immunocompetent cells in the disease process has, therefore, remained unclear.
To study the role of adaptive immunity in atherosclerosis, we generated immunodeficient, atherosclerosis-prone mice by crossing apoE–/– mice with the scid strain, which lacks T and B cells. Our data indicate that CD4+ T cells play an important role in atherosclerosis.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Animal Breeding and Immunological Analyses
ApoE–/– mice (M&B, Bomholtgaard, Denmark) and scid/scid mice (Jackson Laboratory, Maine), both backcrossed for 10 generations to C57BL/6 background, were mated to generate apoE+/–/scid/+ offspring. The homozygous apoE–/–/scid/scid offspring were bred by brother-sister mating in a specific pathogen-free environment. Genetic screening was performed by polymerase chain reaction using apoE primers (Jackson Laboratory) and the scid gene primers 5'-GTCAGTCTCATGTTGCCAATG-3' and 5'-AGTTATAACAGCTGGGTTGGC-3'.16 To minimize background differences, immunocompetent apoE–/– mice were from the same founders as the apoE–/–/scid/scid mice. All experiments were approved by the local ethics committee. Female mice (n=4 to 6 per group) were fed standard mouse chow and killed at 18 weeks of age. Splenocytes were stained with FITC-conjugated anti-CD3, phyroerythrin anti-CD8, and CyChrome anti-CD4 and analyzed by flow cytometry. Interferon-
,
interleukin-4, interleukin-10, IgM, and IgG were analyzed in
sera by sandwich ELISA (PharMingen), and serum cholesterol
was analyzed by a cholesterol oxidase method
(Boehringer Mannheim).
Cell Transfer
Splenocytes from 5-month-old female
apoE–/– mice were incubated in dishes for
90 minutes. Nonadherent cells were incubated with
biotin-rat-anti–mouse-CD19 followed by the addition of
streptavidin-coated microbeads and elimination on MiniMACS columns.
Harvested cells were depleted of CD8 cells by a similar protocol. The
purified cells were >95% viable and contained >99%
CD3+CD4+ T cells
and <1% CD22+ B cells, as judged by flow
cytometry. A total of 18 to 20x106
cells/mouse were injected into the tail veins of 6-week-old female
apoE–/–/scid/scid
mice.
Analysis of
Atherosclerosis
Frozen sections were collected every 100 µm over a
500-µm interval from the aortic root, stained with oil red
O–hematoxylin, and analyzed for lesion
size.14 Immunohistochemical
staining was performed using monoclonal anti-CD4 and
anti–I-Ab followed by
biotin-avidin-horseradish
peroxidase.17 Data were
analyzed by ANOVA, the Mann-Whitney test, and Spearman’s rank
correlation.
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Results |
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The apoE–/–/scid/scid mice lacked T and B cells in lymphoid organs, and no immunoglobulins could be detected in sera. No significant differences were observed in body weight (data not shown) or serum cholesterol levels (12.1±1.9 mmol/L in apoE–/–/scid/scid mice and 10.2±0.9 mmol/L in apoE–/– mice).
Fatty streak lesions were significantly reduced in
apoE–/–/scid/scid
mice compared with apoE–/– animals
(Figures 1
and 2). There was a 73% reduction in lesion size,
with fewer macrophages, very few
I-Ab–expressing cells, and a complete
absence of CD4+ cells in
apoE–/–/scid/scid
mice when compared with apoE–/– mice
(Figures 1D, 1E, 1G, and 1H).
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To explore the role of CD4+ T
cells, such cells were isolated from the spleens of 5-month-old female
apoE–/– mice, which have significant
atherosclerosis,18
and injected into 6-week-old female
apoE–/–/scid/scid
recipients. Cell transfer did not affect body weight or serum
cholesterol (data not shown). Serum levels of the Th1
cytokine interferon- were very low in
apoE–/–/scid/scid
mice, but they increased substantially (
8x) after cell transfer, to
a level not significantly different from that in immunocompetent
apoE–/– mice
(Figure 2B
). The correlation between interferon-
concentration and lesion size was rs=0.75 in the
apoE–/–/scid/scid
mice with and without CD4+ cell transfer and
rs=0.56 in the entire material
(P<0.05). The Th2
cytokines interleukin-4 and interleukin-10 were not detected in
sera from any of the groups. CD4+ but not
CD8+ T cells were increased in the spleens
of
apoE–/–/scid/scid
mice after cell transfer. Of the total spleen cells,
CD4+ cells were 1.2±0.5% of the total in
apoE–/–/scid/scid
mice, 7.7±1.5% in
apoE–/–/scid/scid
mice transferred with CD4+ cells, and
13.3±1.6% in apoE–/–mice;
CD8+ cells were 0.2±0.1%, 0.7±0.3%, and
3.7±0.8%, respectively.
Fatty streak lesions in the aorta were 164% larger in
apoE–/–/scid/scid
mice that received CD4+ T cells compared
with untreated
apoE–/–/scid/scid
mice and not significantly smaller than those in fully immunocompetent
apoE–/– mice
(Figures 1 and 2). Substantial numbers of
CD4+ cells infiltrated the lesions
(Figure 1F), and abundant I-Ab
expression was also observed
(Figure 1I).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study shows that (1) mice lacking adaptive immunity exhibit reduced development of fatty streak lesions, (2) transfer of CD4+ T cells from atherosclerotic donors into immunodeficient recipients aggravates the atherosclerotic process, (3) CD4+ T cells home to lesions, and (4) T-cell transfer is accompanied by elevated systemic interferon-
levels and expression of the interferon-
induced I-Ab gene in the lesions. These
findings are compatible with a proatherogenic role for
CD4+ T cells and suggest that it is exerted,
at least in part, by local action of the (interferon-–producing)
Th1 subset in the artery wall. The finding that mice lacking T and B cells have reduced atherosclerosis is in line with previous studies of mice lacking the recombinase-activating gene.10 That adaptive immunity plays an important accelerating role in atherogenesis is also supported by recent findings that immune-activating CD40-CD40L interactions promote atherosclerosis.12 13
The CD4+ subset of T cells dominates in the lesions of patients and apoE–/– mice, and the pattern of local cytokine secretion suggests a Th1 dominance among effector cells.19 20 The present adoptive transfer experiments provide evidence for a proatherogenic role of these T cells. Injecting CD4+ T cells into apoE–/–/scid/scid recipients accelerated atherosclerosis to a level almost as high as that in immunocompetent apoE–/– mice. Because the transferred CD4+ T cells were obtained from atherosclerotic apoE–/– mice, it is likely that specific immunity to disease-related antigens was instrumental in producing this effect. It is noteworthy that the spleen T cells of apoE–/– mice exhibit strong reactivity toward oxidized LDL.21 Further experiments will be needed to test whether responses to this antigen account for the proatherogenic effect. The fact that transferred CD4+ T cells homed to atherosclerotic lesions suggests the presence of powerful recruitment mechanisms. It is also possible that some of the transferred cells may proliferate locally after encountering specific antigens in the lesions.
Interferon- levels were elevated in
CD4+ T cell–recipient
apoE–/–/scid/scid
mice but low in untouched
apoE–/–/scid/scid
animals. Although the low interferon- levels in the latter mice were
probably caused by natural killer cell secretion, the high
levels after the transfer of CD4+ T cells
suggest that the Th1 activity of transferred cells generated large
amounts of interferon-. Interestingly, interferon-
receptor–deficient apoE–/– mice exhibit a
substantial reduction in atherosclerosis and a changed
lipid
metabolism.11 22
Furthermore, interferon- accelerates transplant vascular lesions in
arteries xenografted into
scid/scid
mice.23 Because the
I-Ab gene is induced by interferon-,
increased expression of I-Ab in mice
receiving CD4+ T cells suggests that
transferred T cells induce gene expression in lesions through
cytokine secretion. The present findings suggest that
interferon- has an important aggravating effect on
lesions.
In summary, our results demonstrate an important role for adaptive immunity in early atherosclerosis. It will now be important to identify antigens and effector molecules that activate proatherogenic immunity.
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Acknowledgments |
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This work was supported by the Swedish Medical Research Council (project 6816) and the Heart-Lung and Söderberg Foundations. We thank Kristina Edwarsson for maintaining the mouse colony and Ingrid Törnberg for technical assistance.
Received July 26, 2000; revision received October 13, 2000; accepted October 16, 2000.
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R. Elhage, P. Gourdy, J. Jawien, L. Brouchet, C. Castano, C. Fievet, G. K. Hansson, J.-F. Arnal, and F. Bayard The Atheroprotective Effect of 17{beta}-Estradiol Depends on Complex Interactions in Adaptive Immunity Am. J. Pathol., July 1, 2005; 167(1): 267 - 274. [Abstract] [Full Text] [PDF]
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H. Methe, S. Brunner, D. Wiegand, M. Nabauer, J. Koglin, and E. R. Edelman Enhanced T-Helper-1 Lymphocyte Activation Patterns in Acute Coronary Syndromes J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1939 - 1945. [Abstract] [Full Text] [PDF]
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I. Goncalves, M.-L. M. Gronholdt, I. Soderberg, M. P.S. Ares, B. G. Nordestgaard, J. F. Bentzon, G. N. Fredrikson, and J. Nilsson Humoral Immune Response Against Defined Oxidized Low-Density Lipoprotein Antigens Reflects Structure and Disease Activity of Carotid Plaques Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1250 - 1255. [Abstract] [Full Text] [PDF]
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H. Methe, J.-O. Kim, S. Kofler, M. Weis, M. Nabauer, and J. Koglin Expansion of Circulating Toll-Like Receptor 4-Positive Monocytes in Patients With Acute Coronary Syndrome Circulation, May 24, 2005; 111(20): 2654 - 2661. [Abstract] [Full Text] [PDF]
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G. Caligiuri, S. Kaveri, and A. Nicoletti When Interleukin-18 Conducts, the Preludio Sounds the Same no Matter Who Plays Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 655 - 657. [Full Text] [PDF]
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C. Tenger, A. Sundborger, J. Jawien, and X. Zhou IL-18 Accelerates Atherosclerosis Accompanied by Elevation of IFN-{gamma} and CXCL16 Expression Independently of T Cells Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 791 - 796. [Abstract] [Full Text] [PDF]
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X. Zhou, A.-K. L. Robertson, M. Rudling, P. Parini, and G. K. Hansson Lesion Development and Response to Immunization Reveal a Complex Role for CD4 in Atherosclerosis Circ. Res., March 4, 2005; 96(4): 427 - 434. [Abstract] [Full Text] [PDF]
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G. S. Getz Thematic review series: The Immune System and Atherogenesis. Immune function in atherogenesis J. Lipid Res., January 1, 2005; 46(1): 1 - 10. [Abstract] [Full Text] [PDF]
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J. Nilsson, G. K. Hansson, and P. K. Shah Immunomodulation of Atherosclerosis: Implications for Vaccine Development Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 18 - 28. [Abstract] [Full Text] [PDF]
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R. Elhage, P. Gourdy, L. Brouchet, J. Jawien, M.-J. Fouque, C. Fievet, X. Huc, Y. Barreira, J. C. Couloumiers, J.-F. Arnal, et al. Deleting TCR{alpha}{beta}+ or CD4+ T Lymphocytes Leads to Opposite Effects on Site-Specific Atherosclerosis in Female Apolipoprotein E-Deficient Mice Am. J. Pathol., December 1, 2004; 165(6): 2013 - 2018. [Abstract] [Full Text] [PDF]
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J. W. Homeister, A. Daugherty, and J. B. Lowe {alpha}(1,3)Fucosyltransferases FucT-IV and FucT-VII Control Susceptibility to Atherosclerosis in Apolipoprotein E-/- Mice Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1897 - 1903. [Abstract] [Full Text] [PDF]
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 Y. Nakai, K. Iwabuchi, S. Fujii, N. Ishimori, N. Dashtsoodol, K. Watano, T. Mishima, C. Iwabuchi, S. Tanaka, J. S. Bezbradica, et al. Natural killer T cells accelerate atherogenesis in mice Blood, October 1, 2004; 104(7): 2051 - 2059. [Abstract] [Full Text] [PDF]
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B. Ludewig, P. Krebs, and E. Scandella Immunopathogenesis of atherosclerosis J. Leukoc. Biol., August 1, 2004; 76(2): 300 - 306. [Abstract] [Full Text] [PDF]
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J. Yang, K. Sato, T. Aprahamian, N. J. Brown, J. Hutcheson, A. Bialik, H. Perlman, and K. Walsh Endothelial Overexpression of Fas Ligand Decreases Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1466 - 1473. [Abstract] [Full Text] [PDF]
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 L. R. Portugal, L. R. Fernandes, G. C. Cesar, H. C. Santiago, D. R. Oliveira, N. M. Silva, A. A. Silva, J. Lannes-Vieira, R. M. E. Arantes, R. T. Gazzinelli, et al. Infection with Toxoplasma gondii Increases Atherosclerotic Lesion in ApoE-Deficient Mice Infect. Immun., June 1, 2004; 72(6): 3571 - 3576. [Abstract] [Full Text] [PDF]
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P. Y. Hsue, J. C. Lo, A. Franklin, A. F. Bolger, J. N. Martin, S. G. Deeks, and D. D. Waters Progression of Atherosclerosis as Assessed by Carotid Intima-Media Thickness in Patients With HIV Infection Circulation, April 6, 2004; 109(13): 1603 - 1608. [Abstract] [Full Text] [PDF]
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D. de Kleijn and G. Pasterkamp Toll-like receptors in cardiovascular diseases Cardiovasc Res, October 15, 2003; 60(1): 58 - 67. [Abstract] [Full Text] [PDF]
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O. J de Boer, A. E Becker, and A. C van der Wal T lymphocytes in atherogenesis--functional aspects and antigenic repertoire Cardiovasc Res, October 15, 2003; 60(1): 78 - 86. [Full Text] [PDF]
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Z. Mallat, A. Gojova, V. Brun, B. Esposito, N. Fournier, F. Cottrez, A. Tedgui, and H. Groux Induction of a Regulatory T Cell Type 1 Response Reduces the Development of Atherosclerosis in Apolipoprotein E-Knockout Mice Circulation, September 9, 2003; 108(10): 1232 - 1237. [Abstract] [Full Text] [PDF]
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P. Davenport and P. G. Tipping The Role of Interleukin-4 and Interleukin-12 in the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Am. J. Pathol., September 1, 2003; 163(3): 1117 - 1125. [Abstract] [Full Text] [PDF]
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 Z. Yuan, C. Kishimoto, H. Sano, K. Shioji, Y. Xu, and M. Yokode Immunoglobulin treatment suppresses atherosclerosis in apolipoprotein E-deficient mice via the Fc portion Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H899 - H906. [Abstract] [Full Text] [PDF]
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R. Elhage, J. Jawien, M. Rudling, H.-G. Ljunggren, K. Takeda, S. Akira, F. Bayard, and G. K Hansson Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice Cardiovasc Res, July 1, 2003; 59(1): 234 - 240. [Abstract] [Full Text] [PDF]
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A. S. Major, S. Fazio, and M. F. Linton B-Lymphocyte Deficiency Increases Atherosclerosis in LDL Receptor-Null Mice Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1892 - 1898. [Abstract] [Full Text] [PDF]
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R Ezzahiri, H.J.M.G Nelissen-Vrancken, H.A.J.M Kurvers, F.R.M Stassen, I Vliegen, G.E.L.M Grauls, M.M.L van Pul, P.J.E.H.M Kitslaar, and C.A Bruggeman Chlamydophila pneumoniae (Chlamydia pneumoniae) accelerates the formation of complex atherosclerotic lesions in Apo E3-Leiden mice Cardiovasc Res, November 1, 2002; 56(2): 269 - 276. [Abstract] [Full Text] [PDF]
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D. Harats, N. Yacov, B. Gilburd, Y. Shoenfeld, and J. George Oral tolerance with heat shock protein 65 attenuates mycobacterium tuberculosis-inducedand high-fat-diet-driven atherosclerotic lesions J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1333 - 1338. [Abstract] [Full Text] [PDF]
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G. K. Hansson Vaccination Against Atherosclerosis: Science or Fiction? Circulation, September 24, 2002; 106(13): 1599 - 1601. [Full Text] [PDF]
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G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF]
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N. Marx, B. Kehrle, K. Kohlhammer, M. Grub, W. Koenig, V. Hombach, P. Libby, and J. Plutzky PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis Circ. Res., April 5, 2002; 90(6): 703 - 710. [Abstract] [Full Text] [PDF]
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G. K. Hansson The B Cell: A Good Guy in Vascular Disease? Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 523 - 524. [Full Text] [PDF]
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P. Dimayuga, B. Cercek, S. Oguchi, G. N. Fredrikson, J. Yano, P. K. Shah, S. Jovinge, and J. Nilsson Inhibitory Effect on Arterial Injury-Induced Neointimal Formation by Adoptive B-Cell Transfer in Rag-1 Knockout Mice Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 644 - 649. [Abstract] [Full Text] [PDF]
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B. Zhu, C. A. Reardon, G. S. Getz, and D. Y. Hui Both Apolipoprotein E and Immune Deficiency Exacerbate Neointimal Hyperplasia After Vascular Injury in Mice Arterioscler Thromb Vasc Biol, March 1, 2002; 22(3): 450 - 455. [Abstract] [Full Text] [PDF]
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Q. Zhang, X. Zeng, J. Guo, and X. Wang Oxidant stress mechanism of homocysteine potentiating Con A-induced proliferation in murine splenic T lymphocytes Cardiovasc Res, March 1, 2002; 53(4): 1035 - 1042. [Abstract] [Full Text] [PDF]
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A. G. Pockley Heat Shock Proteins, Inflammation, and Cardiovascular Disease Circulation, February 26, 2002; 105(8): 1012 - 1017. [Full Text] [PDF]
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B. Garner, D. A. Priestman, R. Stocker, D. J. Harvey, T. D. Butters, and F. M. Platt Increased glycosphingolipid levels in serum and aortae of apolipoprotein E gene knockout mice J. Lipid Res., February 1, 2002; 43(2): 205 - 214. [Abstract] [Full Text] [PDF]
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G. K. Hansson Immune Mechanisms in Atherosclerosis Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1876 - 1890. [Abstract] [Full Text] [PDF]
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B. J.M. van Vlijmen, G. Gerritsen, A. L. Franken, L. S.M. Boesten, M. M. Kockx, M. J. Gijbels, M. P. Vierboom, M. van Eck, B. van de Water, T. J.C. van Berkel, et al. Macrophage p53 Deficiency Leads to Enhanced Atherosclerosis in APOE*3-Leiden Transgenic Mice Circ. Res., April 27, 2001; 88(8): 780 - 786. [Abstract] [Full Text] [PDF]
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P. Dimayuga, B. Cercek, S. Oguchi, G. N. Fredrikson, J. Yano, P. K. Shah, S. Jovinge, and J. Nilsson Inhibitory Effect on Arterial Injury-Induced Neointimal Formation by Adoptive B-Cell Transfer in Rag-1 Knockout Mice Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 644 - 649. [Abstract] [Full Text] [PDF]
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N. Marx, B. Kehrle, K. Kohlhammer, M. Grub, W. Koenig, V. Hombach, P. Libby, and J. Plutzky PPAR Activators as Antiinflammatory Mediators in Human T Lymphocytes: Implications for Atherosclerosis and Transplantation-Associated Arteriosclerosis Circ. Res., April 5, 2002; 90(6): 703 - 710. [Abstract] [Full Text] [PDF]
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