Abstract
Although infiltration of CD8+ T cells in human atherosclerotic lesions has been described 30 years ago, the role of these cells in lesion development has long remained enigmatic. While experimental models hinted at their pro-atherogenic role based on circumstantial evidence, genetic mouse models of cytotoxic CD8+ T cell-specific immune deficiency suggested no crucial role of these cells in lesion development. However, in recent years, more refined models of adoptive cell transfer, disruption of specific immune regulatory pathways or monoclonal antibody-mediated cell depletion have proposed both atheroprotective and pro-atherogenic functions for CD8+ T cells in atherosclerosis. In particular, MHC class I-restricted CD8+ T cell responses may protect from atherosclerosis, and Qa-1 restricted regulatory CD8+ T cells have been defined. In addition, regulatory CD8+CD25+ T cells possess atheroprotective properties. However, CD8+ T cells can also promote monopoiesis in hyperlipidemia, and exert prototypical cytotoxic functions to promote vascular inflammation and macrophage accumulation leading to atherosclerotic lesion development. Here, we review these findings, mostly from experimental studies that reveal a previously unrecognized complexity and important role of CD8+ T cells in atherosclerosis.
Similar content being viewed by others
References
Ait-Oufella H, Sage AP, Mallat Z, Tedgui A (2014) Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis. Circ Res 114:1640–1660. doi:10.1161/CIRCRESAHA.114.302761
Akiba H, Takeda K, Kojima Y, Usui Y, Harada N, Yamazaki T, Ma J, Tezuka K, Yagita H, Okumura K (2005) The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J Immunol 175:2340–2348
Barry M, Bleackley RC (2002) Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2:401–409. doi:10.1038/nri819
Bevan MJ (2004) Helping the CD8(+) T-cell response. Nat Rev Immunol 4:595–602. doi:10.1038/nri1413
Bisikirska B, Colgan J, Luban J, Bluestone JA, Herold KC (2005) TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+ CD25+ Tregs. J Clin Invest 115:2904–2913. doi:10.1172/JCI23961
Campbell LA, Rosenfeld ME (2015) Infection and atherosclerosis development. Arch Med Res 46:339–350. doi:10.1016/j.arcmed.2015.05.006
Chess L, Jiang H (2004) Resurrecting CD8+ suppressor T cells. Nat Immunol 5:469–471. doi:10.1038/ni0504-469
Churlaud G, Pitoiset F, Jebbawi F, Lorenzon R, Bellier B, Rosenzwajg M, Klatzmann D (2015) Human and mouse CD8(+)CD25(+)FOXP3(+) regulatory T cells at steady state and during interleukin-2 therapy. Front Immunol 6:171. doi:10.3389/fimmu.2015.00171
Chyu KY, Zhao X, Dimayuga PC, Zhou J, Li X, Yano J, Lio WM, Chan LF, Kirzner J, Trinidad P, Cercek B, Shah PK (2012) CD8+ T cells mediate the athero-protective effect of immunization with an ApoB-100 peptide. PLoS One 7:e30780. doi:10.1371/journal.pone.0030780
Clement M, Guedj K, Andreata F, Morvan M, Bey L, Khallou-Laschet J, Gaston AT, Delbosc S, Alsac JM, Bruneval P, Deschildre C, Le Borgne M, Castier Y, Kim HJ, Cantor H, Michel JB, Caligiuri G, Nicoletti A (2015) Control of the T follicular helper-germinal center B-cell axis by CD8(+) regulatory T cells limits atherosclerosis and tertiary lymphoid organ development. Circulation 131:560–570. doi:10.1161/CIRCULATIONAHA.114.010988
Cochain C, Chaudhari SM, Koch M, Wiendl H, Eckstein HH, Zernecke A (2014) Programmed cell death-1 deficiency exacerbates T cell activation and atherogenesis despite expansion of regulatory T cells in atherosclerosis-prone mice. PLoS One 9:e93280. doi:10.1371/journal.pone.0093280
Cochain C, Koch M, Chaudhari SM, Busch M, Pelisek J, Boon L, Zernecke A (2015) CD8+ T cells regulate monopoiesis and circulating Ly6C-high monocyte levels in atherosclerosis in mice. Circ Res 117:244–253. doi:10.1161/CIRCRESAHA.117.304611
Cochain C, Zernecke A (2015) Macrophages and immune cells in atherosclerosis: recent advances and novel concepts. Basic Res Cardiol 110:34. doi:10.1007/s00395-015-0491-8
Combadiere C, Potteaux S, Rodero M, Simon T, Pezard A, Esposito B, Merval R, Proudfoot A, Tedgui A, Mallat Z (2008) Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 117:1649–1657. doi:10.1161/CIRCULATIONAHA.107.745091
Elhage R, Gourdy P, Brouchet L, Jawien J, Fouque MJ, Fievet C, Huc X, Barreira Y, Couloumiers JC, Arnal JF, Bayard F (2004) 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 165:2013–2018
Ensan S, Li A, Besla R, Degousee N, Cosme J, Roufaiel M, Shikatani EA, El-Maklizi M, Williams JW, Robins L, Li C, Lewis B, Yun TJ, Lee JS, Wieghofer P, Khattar R, Farrokhi K, Byrne J, Ouzounian M, Zavitz CC, Levy GA, Bauer CM, Libby P, Husain M, Swirski FK, Cheong C, Prinz M, Hilgendorf I, Randolph GJ, Epelman S, Gramolini AO, Cybulsky MI, Rubin BB, Robbins CS (2016) Self-renewing resident arterial macrophages arise from embryonic CX3CR1(+) precursors and circulating monocytes immediately after birth. Nat Immunol 17:159–168. doi:10.1038/ni.3343
Filardo S, Di Pietro M, Farcomeni A, Schiavoni G, Sessa R (2015) Chlamydia pneumoniae-mediated inflammation in atherosclerosis: a meta-analysis. Mediators Inflamm 2015:378658. doi:10.1155/2015/378658
Fyfe AI, Qiao JH, Lusis AJ (1994) Immune-deficient mice develop typical atherosclerotic fatty streaks when fed an atherogenic diet. J Clin Invest 94:2516–2520. doi:10.1172/JCI117622
Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82
Getz GS, Reardon CA (2012) Animal models of atherosclerosis. Arterioscler Thromb Vasc Biol 32:1104–1115. doi:10.1161/ATVBAHA.111.237693
Gewaltig J, Kummer M, Koella C, Cathomas G, Biedermann BC (2008) Requirements for CD8 T-cell migration into the human arterial wall. Hum Pathol 39:1756–1762. doi:10.1016/j.humpath.2008.04.018
Grivel JC, Ivanova O, Pinegina N, Blank PS, Shpektor A, Margolis LB, Vasilieva E (2011) Activation of T lymphocytes in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 31:2929–2937. doi:10.1161/ATVBAHA.111.237081
Honjo T, Chyu KY, Dimayuga PC, Yano J, Lio WM, Trinidad P, Zhao X, Zhou J, Chen S, Cercek B, Arditi M, Shah PK (2015) ApoB-100-related peptide vaccine protects against angiotensin II-induced aortic aneurysm formation and rupture. J Am Coll Cardiol 65:546–556. doi:10.1016/j.jacc.2014.11.054
Hopkins PN (2013) Molecular biology of atherosclerosis. Physiol Rev 93:1317–1542. doi:10.1152/physrev.00004.2012
Hu D, Ikizawa K, Lu L, Sanchirico ME, Shinohara ML, Cantor H (2004) Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat Immunol 5:516–523. doi:10.1038/ni1063
Hu D, Mohanta SK, Yin C, Peng L, Ma Z, Srikakulapu P, Grassia G, MacRitchie N, Dever G, Gordon P, Burton FL, Ialenti A, Sabir SR, McInnes IB, Brewer JM, Garside P, Weber C, Lehmann T, Teupser D, Habenicht L, Beer M, Grabner R, Maffia P, Weih F, Habenicht AJ (2015) Artery tertiary lymphoid organs control aorta immunity and protect against atherosclerosis via vascular smooth muscle cell lymphotoxin beta receptors. Immunity 42:1100–1115. doi:10.1016/j.immuni.2015.05.015
Hwang Y, Yu HT, Kim DH, Jang J, Kim HY, Kang I, Kim HC, Park S, Lee WW (2016) Expansion of CD8(+) T cells lacking the IL-6 receptor alpha chain in patients with coronary artery diseases (CAD). Atherosclerosis 249:44–51. doi:10.1016/j.atherosclerosis.2016.03.038
Jansen MF, Hollander MR, van Royen N, Horrevoets AJ, Lutgens E (2016) CD40 in coronary artery disease: a matter of macrophages? Basic Res Cardiol 111:38. doi:10.1007/s00395-016-0554-5
Jiang H, Canfield SM, Gallagher MP, Jiang HH, Jiang Y, Zheng Z, Chess L (2010) HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes. J Clin Invest 120:3641–3650. doi:10.1172/JCI43522
Joffre OP, Segura E, Savina A, Amigorena S (2012) Cross-presentation by dendritic cells. Nat Rev Immunol 12:557–569. doi:10.1038/nri3254
Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK (1986) Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 6:131–138
Keul P, Lucke S, von Wnuck Lipinski K, Bode C, Graler M, Heusch G, Levkau B (2011) Sphingosine-1-phosphate receptor 3 promotes recruitment of monocyte/macrophages in inflammation and atherosclerosis. Circ Res 108:314–323. doi:10.1161/CIRCRESAHA.110.235028
Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H (2010) Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature 467:328–332. doi:10.1038/nature09370
Kimura T, Tse K, Sette A, Ley K (2015) Vaccination to modulate atherosclerosis. Autoimmunity 48:152–160. doi:10.3109/08916934.2014.1003641
Klingenberg R, Lebens M, Hermansson A, Fredrikson GN, Strodthoff D, Rudling M, Ketelhuth DF, Gerdes N, Holmgren J, Nilsson J, Hansson GK (2010) Intranasal immunization with an apolipoprotein B-100 fusion protein induces antigen-specific regulatory T cells and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 30:946–952. doi:10.1161/ATVBAHA.109.202671
Koch AE, Haines GK, Rizzo RJ, Radosevich JA, Pope RM, Robinson PG, Pearce WH (1990) Human abdominal aortic aneurysms. Immunophenotypic analysis suggesting an immune-mediated response. Am J Pathol 137:1199–1213
Kolbus D, Ljungcrantz I, Andersson L, Hedblad B, Fredrikson GN, Bjorkbacka H, Nilsson J (2013) Association between CD8+ T-cell subsets and cardiovascular disease. J Intern Med 274:41–51. doi:10.1111/joim.12038
Kolbus D, Ramos OH, Berg KE, Persson J, Wigren M, Bjorkbacka H, Fredrikson GN, Nilsson J (2010) CD8+ T cell activation predominate early immune responses to hypercholesterolemia in Apoe(−)(/)(−) mice. BMC Immunol 11:58. doi:10.1186/1471-2172-11-58
Kyaw T, Winship A, Tay C, Kanellakis P, Hosseini H, Cao A, Li P, Tipping P, Bobik A, Toh BH (2013) Cytotoxic and proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in apoE-deficient mice. Circulation 127:1028–1039. doi:10.1161/CIRCULATIONAHA.112.001347
Legein B, Janssen EM, Theelen TL, Gijbels MJ, Walraven J, Klarquist JS, Hennies CM, Wouters K, Seijkens TT, Wijnands E, Sluimer JC, Lutgens E, Zenke M, Hildner K, Biessen EA, Temmerman L (2015) Ablation of CD8alpha(+) dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice. Sci Rep 5:15414. doi:10.1038/srep15414
Lievens D, Habets KL, Robertson AK, Laouar Y, Winkels H, Rademakers T, Beckers L, Wijnands E, Boon L, Mosaheb M, Ait-Oufella H, Mallat Z, Flavell RA, Rudling M, Binder CJ, Gerdes N, Biessen EA, Weber C, Daemen MJ, Kuiper J, Lutgens E (2013) Abrogated transforming growth factor beta receptor II (TGFbetaRII) signalling in dendritic cells promotes immune reactivity of T cells resulting in enhanced atherosclerosis. Eur Heart J 34:3717–3727. doi:10.1093/eurheartj/ehs106
Lindau A, Hardtner C, Hergeth SP, Blanz KD, Dufner B, Hoppe N, Anto-Michel N, Kornemann J, Zou J, Gerhardt LM, Heidt T, Willecke F, Geis S, Stachon P, Wolf D, Libby P, Swirski FK, Robbins CS, McPheat W, Hawley S, Braddock M, Gilsbach R, Hein L, von zur Muhlen C, Bode C, Zirlik A, Hilgendorf I (2016) Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression. Basic Res Cardiol 111:20. doi:10.1007/s00395-016-0535-8
Lochner M, Berod L, Sparwasser T (2015) Fatty acid metabolism in the regulation of T cell function. Trends Immunol 36:81–91. doi:10.1016/j.it.2014.12.005
Ludewig B, Freigang S, Jaggi M, Kurrer MO, Pei YC, Vlk L, Odermatt B, Zinkernagel RM, Hengartner H (2000) Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model. Proc Natl Acad Sci USA 97:12752–12757. doi:10.1073/pnas.220427097
Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738
Mohanta SK, Yin C, Peng L, Srikakulapu P, Bontha V, Hu D, Weih F, Weber C, Gerdes N, Habenicht AJ (2014) Artery tertiary lymphoid organs contribute to innate and adaptive immune responses in advanced mouse atherosclerosis. Circ Res 114:1772–1787. doi:10.1161/CIRCRESAHA.114.301137
Nadareishvili ZG, Koziol DE, Szekely B, Ruetzler C, LaBiche R, McCarron R, DeGraba TJ (2001) Increased CD8(+) T cells associated with Chlamydia pneumoniae in symptomatic carotid plaque. Stroke 32:1966–1972
Olofsson PS, Soderstrom LA, Wagsater D, Sheikine Y, Ocaya P, Lang F, Rabu C, Chen L, Rudling M, Aukrust P, Hedin U, Paulsson-Berne G, Sirsjo A, Hansson GK (2008) CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation 117:1292–1301. doi:10.1161/CIRCULATIONAHA.107.699173
Qiu MK, Wang SC, Dai YX, Wang SQ, Ou JM, Quan ZW (2015) PD-1 and Tim-3 Pathways Regulate CD8+ T Cells Function in Atherosclerosis. PLoS One 10:e0128523. doi:10.1371/journal.pone.0128523
Santos M, Schilham MW, Rademakers LH, Marx JJ, de Sousa M, Clevers H (1996) Defective iron homeostasis in beta 2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man. J Exp Med 184:1975–1985
Schurch CM, Riether C, Ochsenbein AF (2014) Cytotoxic CD8+ T cells stimulate hematopoietic progenitors by promoting cytokine release from bone marrow mesenchymal stromal cells. Cell Stem Cell 14:460–472. doi:10.1016/j.stem.2014.01.002
Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R, Pittet MJ (2007) Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 117:195–205. doi:10.1172/JCI29950
Tabas I, Bornfeldt KE (2016) Macrophage phenotype and function in different stages of atherosclerosis. Circ Res 118:653–667. doi:10.1161/CIRCRESAHA.115.306256
Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ (2007) Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 117:185–194. doi:10.1172/JCI28549
Xu QB, Oberhuber G, Gruschwitz M, Wick G (1990) Immunology of atherosclerosis: cellular composition and major histocompatibility complex class II antigen expression in aortic intima, fatty streaks, and atherosclerotic plaques in young and aged human specimens. Clin Immunol Immunopathol 56:344–359
Xu S, Liu X, Bao Y, Zhu X, Han C, Zhang P, Zhang X, Li W, Cao X (2012) Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps-SHP-2 pathway. Nat Immunol 13:551–559. doi:10.1038/ni.2283
Zafiratos MT, Manam S, Henderson KK, Ramsey KH, Murthy AK (2015) CD8+ T cells mediate Chlamydia pneumoniae-induced atherosclerosis in mice. Pathog Dis. doi:10.1093/femspd/ftv052
Zhou J, Dimayuga PC, Zhao X, Yano J, Lio WM, Trinidad P, Honjo T, Cercek B, Shah PK, Chyu KY (2014) CD8(+)CD25(+) T cells reduce atherosclerosis in apoE(−/−) mice. Biochem Biophys Res Commun 443:864–870. doi:10.1016/j.bbrc.2013.12.057
Zhou X, Stemme S, Hansson GK (1996) Evidence for a local immune response in atherosclerosis. CD4+ T cells infiltrate lesions of apolipoprotein-E-deficient mice. Am J Pathol 149:359–366
Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (SFB688 TPA22).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
Rights and permissions
About this article
Cite this article
Cochain, C., Zernecke, A. Protective and pathogenic roles of CD8+ T cells in atherosclerosis. Basic Res Cardiol 111, 71 (2016). https://doi.org/10.1007/s00395-016-0589-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00395-016-0589-7