1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Hansson, G.K.; Hermansson, A. The immune system in atherosclerosis. Nat. Immunol. 2011, 12, 204–212. [CrossRef]
Tabas, I.; Lichtman, A.H. Monocyte-macrophages and T cells in atherosclerosis. Immunity 2017, 47, 621–634. [CrossRef]
Lutgens, E.; Atzler, D.; Doring, Y.; Duchene, J.; Steffens, S.; Weber, C. Immunotherapy for cardiovascular disease. Eur. Heart J.
2019, 40, 3937–3946. [CrossRef] [PubMed]
Ridker, P.M.; Everett, B.M.; Thuren, T.; MacFadyen, J.G.; Chang, W.H.; Ballantyne, C.; Fonseca, F.; Nicolau, J.; Koenig, W.;
Anker, S.D.; et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 2017, 377, 1119–1131.
[CrossRef] [PubMed]
Tardif, J.C.; Kouz, S.; Waters, D.D.; Bertrand, O.F.; Diaz, R.; Maggioni, A.P.; Pinto, F.J.; Ibrahim, R.; Gamra, H.; Kiwan, G.S.; et al.
Efficacy and safety of low-dose colchicine after myocardial infarction. N. Engl. J. Med. 2019, 381, 2497–2505. [CrossRef]
Nidorf, S.M.; Fiolet, A.T.L.; Mosterd, A.; Eikelboom, J.W.; Schut, A.; Opstal, T.S.J.; The, S.H.K.; Xu, X.F.; Ireland, M.A.;
Lenderink, T.; et al. Colchicine in patients with chronic coronary disease. N. Engl. J. Med. 2020, 383, 1838–1847. [CrossRef]
[PubMed]
Saigusa, R.; Winkels, H.; Ley, K. T cell subsets and functions in atherosclerosis. Nat. Rev. Cardiol. 2020, 17, 387–401.
Sakaguchi, S.; Mikami, N.; Wing, J.B.; Tanaka, A.; Ichiyama, K.; Ohkura, N. Regulatory T cells and human disease. Annu. Rev.
Immunol. 2020, 38, 541–566. [CrossRef]
Sasaki, N.; Yamashita, T.; Kasahara, K.; Takeda, M.; Hirata, K. Regulatory T cells and tolerogenic dendritic cells as critical immune
modulators in atherogenesis. Curr. Pharm. Des. 2015, 21, 1107–1117. [CrossRef] [PubMed]
Ait-Oufella, H.; Lavillegrand, J.R.; Tedgui, A. Regulatory T cell-enhancing therapies to treat atherosclerosis. Cells 2021, 10, 723.
Ross, R. Atherosclerosis—An inflammatory disease. N. Engl. J. Med. 1999, 340, 115–126. [CrossRef] [PubMed]
Zhang, S.H.; Reddick, R.L.; Piedrahita, J.A.; Maeda, N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking
apolipoprotein E. Science 1992, 258, 468–471. [CrossRef]
Ishibashi, S.; Brown, M.S.; Goldstein, J.L.; Gerard, R.D.; Hammer, R.E.; Herz, J. Hypercholesterolemia in low density lipoprotein
receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J. Clin. Investig. 1993, 92, 883–893. [CrossRef]
Ait-Oufella, H.; Sage, A.P.; Mallat, Z.; Tedgui, A. Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis.
Circ. Res. 2014, 114, 1640–1660. [CrossRef]
Paulsson, G.; Zhou, X.; Tornquist, E.; Hansson, G.K. Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein
E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 2000, 20, 10–17. [CrossRef]
Nilsson, J.; Hansson, G.K. Vaccination strategies and immune modulation of atherosclerosis. Circ. Res. 2020, 126, 1281–1296.
Sage, A.P.; Tsiantoulas, D.; Binder, C.J.; Mallat, Z. The role of B cells in atherosclerosis. Nat. Rev. Cardiol. 2019, 16, 180–196.
[CrossRef] [PubMed]
Winkels, H.; Ehinger, E.; Vassallo, M.; Buscher, K.; Dinh, H.Q.; Kobiyama, K.; Hamers, A.A.J.; Cochain, C.; Vafadarnejad, E.;
Saliba, A.E.; et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass
cytometry. Circ. Res. 2018, 122, 1675–1688. [CrossRef] [PubMed]
J. Clin. Med. 2021, 10, 5907
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
16 of 20
Fernandez, D.M.; Rahman, A.H.; Fernandez, N.F.; Chudnovskiy, A.; Amir, E.D.; Amadori, L.; Khan, N.S.; Wong, C.K.; Shamailova,
R.; Hill, C.A.; et al. Single-cell immune landscape of human atherosclerotic plaques. Nat. Med. 2019, 25, 1576–1588. [CrossRef]
[PubMed]
Gupta, S.; Pablo, A.M.; Jiang, X.; Wang, N.; Tall, A.R.; Schindler, C. IFN-gamma potentiates atherosclerosis in ApoE knock-out
mice. J. Clin. Investig. 1997, 99, 2752–2761. [CrossRef]
Whitman, S.C.; Ravisankar, P.; Elam, H.; Daugherty, A. Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein
E−/− mice. Am. J. Pathol. 2000, 157, 1819–1824. [CrossRef]
Buono, C.; Binder, C.J.; Stavrakis, G.; Witztum, J.L.; Glimcher, L.H.; Lichtman, A.H. T-bet deficiency reduces atherosclerosis and
alters plaque antigen-specific immune responses. Proc. Natl. Acad. Sci. USA 2005, 102, 1596–1601. [CrossRef] [PubMed]
Frostegard, J.; Ulfgren, A.K.; Nyberg, P.; Hedin, U.; Swedenborg, J.; Andersson, U.; Hansson, G.K. Cytokine expression
in advanced human atherosclerotic plaques: Dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines.
Atherosclerosis 1999, 145, 33–43. [CrossRef]
King, V.L.; Szilvassy, S.J.; Daugherty, A. Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific
manner in female LDL receptor−/− mice. Arterioscler. Thromb. Vasc. Biol. 2002, 22, 456–461. [CrossRef]
King, V.L.; Cassis, L.A.; Daugherty, A. Interleukin-4 does not influence development of hypercholesterolemia or angiotensin
II-induced atherosclerotic lesions in mice. Am. J. Pathol. 2007, 171, 2040–2047. [CrossRef] [PubMed]
Littman, D.R.; Rudensky, A.Y. Th17 and regulatory T cells in mediating and restraining inflammation. Cell 2010, 140, 845–858.
[CrossRef]
Erbel, C.; Chen, L.; Bea, F.; Wangler, S.; Celik, S.; Lasitschka, F.; Wang, Y.; Bockler, D.; Katus, H.A.; Dengler, T.J. Inhibition of
IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J. Immunol. 2009, 183, 8167–8175. [CrossRef]
Smith, E.; Prasad, K.M.; Butcher, M.; Dobrian, A.; Kolls, J.K.; Ley, K.; Galkina, E. Blockade of interleukin-17A results in reduced
atherosclerosis in apolipoprotein E-deficient mice. Circulation 2010, 121, 1746–1755. [CrossRef] [PubMed]
Danzaki, K.; Matsui, Y.; Ikesue, M.; Ohta, D.; Ito, K.; Kanayama, M.; Kurotaki, D.; Morimoto, J.; Iwakura, Y.; Yagita, H.; et al.
Interleukin-17A deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein E-deficient mice. Arterioscler.
Thromb. Vasc. Biol. 2012, 32, 273–280. [CrossRef]
Kyaw, T.; Winship, A.; Tay, C.; Kanellakis, P.; Hosseini, H.; Cao, A.; Li, P.; Tipping, P.; Bobik, A.; Toh, B.H. Cytotoxic and
proinflammatory CD8+ T lymphocytes promote development of vulnerable atherosclerotic plaques in ApoE-deficient mice.
Circulation 2013, 127, 1028–1039. [CrossRef]
van Duijn, J.; Kritikou, E.; Benne, N.; van der Heijden, T.; van Puijvelde, G.H.; Kroner, M.J.; Schaftenaar, F.H.; Foks, A.C.; Wezel,
A.; Smeets, H.; et al. CD8+ T-cells contribute to lesion stabilization in advanced atherosclerosis by limiting macrophage content
and CD4+ T-cell responses. Cardiovasc. Res. 2019, 115, 729–738. [CrossRef]
Ley, K.; Gerdes, N.; Winkels, H. ATVB distinguished scientist award: How costimulatory and coinhibitory pathways shape
atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2017, 37, 764–777. [CrossRef] [PubMed]
Wing, K.; Yamaguchi, T.; Sakaguchi, S. Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends
Immunol. 2011, 32, 428–433. [CrossRef]
Matsumoto, T.; Sasaki, N.; Yamashita, T.; Emoto, T.; Kasahara, K.; Mizoguchi, T.; Hayashi, T.; Yodoi, K.; Kitano, N.; Saito, T.; et al.
Overexpression of cytotoxic T-lymphocyte-associated antigen-4 prevents atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol.
2016, 36, 1141–1151. [CrossRef]
Amin, H.Z.; Sasaki, N.; Yamashita, T.; Mizoguchi, T.; Hayashi, T.; Emoto, T.; Matsumoto, T.; Yoshida, N.; Tabata, T.; Horibe, S.; et al.
CTLA-4 protects against angiotensin II-induced abdominal aortic aneurysm formation in mice. Sci. Rep. 2019, 9, 8065. [CrossRef]
[PubMed]
Amin, H.Z.; Sasaki, N.; Hirata, K.I.; Rikitake, Y. Cytotoxic T lymphocyte-associated antigen-4 protects against angiotensin
II-induced kidney injury in mice. Circ. Rep. 2020, 2, 339–342. [CrossRef] [PubMed]
Linsley, P.S.; Nadler, S.G. The clinical utility of inhibiting CD28-mediated costimulation. Immunol. Rev. 2009, 229, 307–321.
[CrossRef]
Ma, K.; Lv, S.; Liu, B.; Liu, Z.; Luo, Y.; Kong, W.; Xu, Q.; Feng, J.; Wang, X. CTLA4-IgG ameliorates homocysteine-accelerated
atherosclerosis by inhibiting T-cell overactivation in apoE−/− mice. Cardiovasc. Res. 2013, 97, 349–359. [CrossRef]
Gotsman, I.; Grabie, N.; Dacosta, R.; Sukhova, G.; Sharpe, A.; Lichtman, A.H. Proatherogenic immune responses are regulated by
the PD-1/PD-L pathway in mice. J. Clin. Investig. 2007, 117, 2974–2982. [CrossRef]
Bu, D.X.; Tarrio, M.; Maganto-Garcia, E.; Stavrakis, G.; Tajima, G.; Lederer, J.; Jarolim, P.; Freeman, G.J.; Sharpe, A.H.;
Lichtman, A.H. Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler. Thromb. Vasc. Biol. 2011, 31, 1100–1107.
Ribas, A.; Wolchok, J.D. Cancer immunotherapy using checkpoInt blockade. Science 2018, 359, 1350–1355. [CrossRef] [PubMed]
Drobni, Z.D.; Alvi, R.M.; Taron, J.; Zafar, A.; Murphy, S.P.; Rambarat, P.K.; Mosarla, R.C.; Lee, C.; Zlotoff, D.A.; Raghu, V.K.; et al.
Association between immune checkpoInt. inhibitors with cardiovascular events and atherosclerotic plaque. Circulation 2020, 142,
2299–2311. [CrossRef] [PubMed]
Sakaguchi, S.; Sakaguchi, N.; Asano, M.; Itoh, M.; Toda, M. Immunologic self-tolerance maintained by activated T cells expressing
IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J.
Immunol. 1995, 155, 1151–1164. [PubMed]
J. Clin. Med. 2021, 10, 5907
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
17 of 20
Hori, S.; Nomura, T.; Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299,
1057–1061. [CrossRef]
Fontenot, J.D.; Gavin, M.A.; Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells.
Nat. Immunol. 2003, 4, 330–336. [CrossRef]
Brunkow, M.E.; Jeffery, E.W.; Hjerrild, K.A.; Paeper, B.; Clark, L.B.; Yasayko, S.A.; Wilkinson, J.E.; Galas, D.; Ziegler, S.F.;
Ramsdell, F. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the
scurfy mouse. Nat. Genet. 2001, 27, 68–73. [CrossRef]
Bennett, C.L.; Christie, J.; Ramsdell, F.; Brunkow, M.E.; Ferguson, P.J.; Whitesell, L.; Kelly, T.E.; Saulsbury, F.T.; Chance, P.F.;
Ochs, H.D. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of
FOXP3. Nat. Genet. 2001, 27, 20–21. [CrossRef]
Sakaguchi, S.; Yamaguchi, T.; Nomura, T.; Ono, M. Regulatory T cells and immune tolerance. Cell 2008, 133, 775–787. [CrossRef]
Shevach, E.M.; Thornton, A.M. tTregs, pTregs, and iTregs: Similarities and differences. Immunol. Rev. 2014, 259, 88–102. [CrossRef]
Greenwald, R.J.; Freeman, G.J.; Sharpe, A.H. The B7 family revisited. Annu. Rev. Immunol. 2005, 23, 515–548. [CrossRef] [PubMed]
Ait-Oufella, H.; Salomon, B.L.; Potteaux, S.; Robertson, A.K.; Gourdy, P.; Zoll, J.; Merval, R.; Esposito, B.; Cohen, J.L.;
Fisson, S.; et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat. Med. 2006, 12, 178–180.
[CrossRef] [PubMed]
Mor, A.; Planer, D.; Luboshits, G.; Afek, A.; Metzger, S.; Chajek-Shaul, T.; Keren, G.; George, J. Role of naturally occurring CD4+
CD25+ regulatory T cells in experimental atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 893–900. [CrossRef] [PubMed]
Winkels, H.; Meiler, S.; Lievens, D.; Engel, D.; Spitz, C.; Burger, C.; Beckers, L.; Dandl, A.; Reim, S.; Ahmadsei, M.; et al. CD27
co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice. Eur. Heart J.
2017, 38, 3590–3599. [CrossRef] [PubMed]
Lahl, K.; Loddenkemper, C.; Drouin, C.; Freyer, J.; Arnason, J.; Eberl, G.; Hamann, A.; Wagner, H.; Huehn, J.; Sparwasser, T.
Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 2007, 204, 57–63. [CrossRef] [PubMed]
Klingenberg, R.; Gerdes, N.; Badeau, R.M.; Gistera, A.; Strodthoff, D.; Ketelhuth, D.F.; Lundberg, A.M.; Rudling, M.; Nilsson, S.K.;
Olivecrona, G.; et al. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J. Clin. Investig.
2013, 123, 1323–1334. [CrossRef]
De Boer, O.J.; van der Meer, J.J.; Teeling, P.; van der Loos, C.M.; van der Wal, A.C. Low numbers of FOXP3 positive regulatory T
cells are present in all developmental stages of human atherosclerotic lesions. PLoS ONE 2007, 2, e779. [CrossRef] [PubMed]
Depuydt, M.A.C.; Prange, K.H.M.; Slenders, L.; Ord, T.; Elbersen, D.; Boltjes, A.; de Jager, S.C.A.; Asselbergs, F.W.; de Borst, G.J.;
Aavik, E.; et al. Microanatomy of the human atherosclerotic plaque by single-cell transcriptomics. Circ. Res. 2020, 127, 1437–1455.
[CrossRef]
Mor, A.; Luboshits, G.; Planer, D.; Keren, G.; George, J. Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute
coronary syndromes. Eur. Heart J. 2006, 27, 2530–2537. [CrossRef] [PubMed]
Ammirati, E.; Cianflone, D.; Banfi, M.; Vecchio, V.; Palini, A.; De Metrio, M.; Marenzi, G.; Panciroli, C.; Tumminello, G.;
Anzuini, A.; et al. Circulating CD4+CD25hiCD127lo regulatory T-Cell levels do not reflect the extent or severity of carotid and
coronary atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 1832–1841. [CrossRef]
George, J.; Schwartzenberg, S.; Medvedovsky, D.; Jonas, M.; Charach, G.; Afek, A.; Shamiss, A. Regulatory T cells and IL-10 levels
are reduced in patients with vulnerable coronary plaques. Atherosclerosis 2012, 222, 519–523. [CrossRef]
Zhang, W.C.; Wang, J.; Shu, Y.W.; Tang, T.T.; Zhu, Z.F.; Xia, N.; Nie, S.F.; Liu, J.; Zhou, S.F.; Li, J.J.; et al. Impaired thymic export
and increased apoptosis account for regulatory T cell defects in patients with non-ST segment elevation acute coronary syndrome.
J. Biol. Chem. 2012, 287, 34157–34166. [CrossRef] [PubMed]
Potekhina, A.V.; Pylaeva, E.; Provatorov, S.; Ruleva, N.; Masenko, V.; Noeva, E.; Krasnikova, T.; Arefieva, T. Treg/Th17 balance in
stable CAD patients with different stages of coronary atherosclerosis. Atherosclerosis 2015, 238, 17–21. [CrossRef] [PubMed]
Wigren, M.; Bjorkbacka, H.; Andersson, L.; Ljungcrantz, I.; Fredrikson, G.N.; Persson, M.; Bryngelsson, C.; Hedblad, B.; Nilsson, J.
Low levels of circulating CD4+FoxP3+ T cells are associated with an increased risk for development of myocardial infarction but
not for stroke. Arterioscler. Thromb. Vasc. Biol. 2012, 32, 2000–2004. [CrossRef] [PubMed]
Klingenberg, R.; Brokopp, C.E.; Grives, A.; Courtier, A.; Jaguszewski, M.; Pasqual, N.; Vlaskou Badra, E.; Lewandowski, A.;
Gaemperli, O.; Hoerstrup, S.P.; et al. Clonal restriction and predominance of regulatory T cells in coronary thrombi of patients
with acute coronary syndromes. Eur. Heart J. 2015, 36, 1041–1048. [CrossRef] [PubMed]
Miyara, M.; Yoshioka, Y.; Kitoh, A.; Shima, T.; Wing, K.; Niwa, A.; Parizot, C.; Taflin, C.; Heike, T.; Valeyre, D.; et al. Functional
delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009, 30,
899–911. [CrossRef]
Emoto, T.; Sasaki, N.; Yamashita, T.; Kasahara, K.; Yodoi, K.; Sasaki, Y.; Matsumoto, T.; Mizoguchi, T.; Hirata, K. Regulatory/effector T-cell ratio is reduced in coronary artery disease. Circ. J. 2014, 78, 2935–2941. [CrossRef]
Joly, A.L.; Seitz, C.; Liu, S.; Kuznetsov, N.V.; Gertow, K.; Westerberg, L.S.; Paulsson-Berne, G.; Hansson, G.K.; Andersson, J.
Alternative splicing of FOXP3 controls regulatory T cell effector functions and is associated with human atherosclerotic plaque
stability. Circ. Res. 2018, 122, 1385–1394. [CrossRef]
Dale, M.A.; Ruhlman, M.K.; Baxter, B.T. Inflammatory cell phenotypes in AAAs: Their role and potential as targets for therapy.
Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1746–1755. [CrossRef]
J. Clin. Med. 2021, 10, 5907
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
18 of 20
Ait-Oufella, H.; Wang, Y.; Herbin, O.; Bourcier, S.; Potteaux, S.; Joffre, J.; Loyer, X.; Ponnuswamy, P.; Esposito, B.; Dalloz, M.; et al.
Natural regulatory T cells limit angiotensin II-induced aneurysm formation and rupture in mice. Arterioscler. Thromb. Vasc. Biol.
2013, 33, 2374–2379. [CrossRef]
Meng, X.; Yang, J.; Zhang, K.; An, G.; Kong, J.; Jiang, F.; Zhang, Y.; Zhang, C. Regulatory T cells prevent angiotensin II-induced
abdominal aortic aneurysm in apolipoprotein E knockout mice. Hypertension 2014, 64, 875–882. [CrossRef]
Yodoi, K.; Yamashita, T.; Sasaki, N.; Kasahara, K.; Emoto, T.; Matsumoto, T.; Kita, T.; Sasaki, Y.; Mizoguchi, T.; Sparwasser, T.; et al.
Foxp3+ regulatory T cells play a protective role in angiotensin II-induced aortic aneurysm formation in mice. Hypertension 2015,
65, 889–895. [CrossRef]
Yin, M.; Zhang, J.; Wang, Y.; Wang, S.; Bockler, D.; Duan, Z.; Xin, S. Deficient CD4+CD25+ T regulatory cell function in patients
with abdominal aortic aneurysms. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 1825–1831. [CrossRef]
Ait-Oufella, H.; Taleb, S.; Mallat, Z.; Tedgui, A. Recent advances on the role of cytokines in atherosclerosis. Arterioscler. Thromb.
Vasc. Biol. 2011, 31, 969–979. [CrossRef] [PubMed]
Pinderski, L.J.; Fischbein, M.P.; Subbanagounder, G.; Fishbein, M.C.; Kubo, N.; Cheroutre, H.; Curtiss, L.K.; Berliner, J.A.;
Boisvert, W.A. Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient
Mice by altering lymphocyte and macrophage phenotypes. Circ. Res. 2002, 90, 1064–1071. [CrossRef]
Robertson, A.K.; Rudling, M.; Zhou, X.; Gorelik, L.; Flavell, R.A.; Hansson, G.K. Disruption of TGF-beta signaling in T cells
accelerates atherosclerosis. J. Clin. Investig. 2003, 112, 1342–1350. [CrossRef] [PubMed]
Proto, J.D.; Doran, A.C.; Gusarova, G.; Yurdagul, A., Jr.; Sozen, E.; Subramanian, M.; Islam, M.N.; Rymond, C.C.; Du, J.;
Hook, J.; et al. Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity 2018, 49, 666–677.
[CrossRef] [PubMed]
Maganto-Garcia, E.; Tarrio, M.L.; Grabie, N.; Bu, D.X.; Lichtman, A.H. Dynamic changes in regulatory T cells are linked to levels
of diet-induced hypercholesterolemia. Circulation 2011, 124, 185–195. [CrossRef] [PubMed]
Mailer, R.K.W.; Gistera, A.; Polyzos, K.A.; Ketelhuth, D.F.J.; Hansson, G.K. Hypercholesterolemia enhances T cell receptor
signaling and increases the regulatory T cell population. Sci. Rep. 2017, 7, 15655. [CrossRef] [PubMed]
Mailer, R.K.W.; Gistera, A.; Polyzos, K.A.; Ketelhuth, D.F.J.; Hansson, G.K. Hypercholesterolemia induces differentiation of
regulatory T cells in the liver. Circ. Res. 2017, 120, 1740–1753. [CrossRef]
Amersfoort, J.; Schaftenaar, F.H.; Douna, H.; van Santbrink, P.J.; van Puijvelde, G.H.M.; Slutter, B.; Foks, A.C.; Harms, A.;
Moreno-Gordaliza, E.; Wang, Y.; et al. Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T
cells. Cardiovasc. Res. 2021, 117, 1309–1324. [CrossRef] [PubMed]
Noels, H.; Weber, C.; Koenen, R.R. Chemokines as therapeutic targets in cardiovascular disease. Arterioscler. Thromb. Vasc. Biol.
2019, 39, 583–592. [CrossRef] [PubMed]
Bonacina, F.; Martini, E.; Svecla, M.; Nour, J.; Cremonesi, M.; Beretta, G.; Moregola, A.; Pellegatta, F.; Zampoleri, V.;
Catapano, A.L.; et al. Adoptive transfer of CX3CR1 transduced-T regulatory cells improves homing to the atherosclerotic plaques
and dampens atherosclerosis progression. Cardiovasc. Res. 2021, 117, 2069–2082. [CrossRef]
Sakaguchi, S.; Vignali, D.A.; Rudensky, A.Y.; Niec, R.E.; Waldmann, H. The plasticity and stability of regulatory T cells. Nat. Rev.
Immunol. 2013, 13, 461–467. [CrossRef]
Ali, A.J.; Makings, J.; Ley, K. Regulatory T cell stability and plasticity in atherosclerosis. Cells 2020, 9, 2665. [CrossRef] [PubMed]
Butcher, M.J.; Filipowicz, A.R.; Waseem, T.C.; McGary, C.M.; Crow, K.J.; Magilnick, N.; Boldin, M.; Lundberg, P.S.; Galkina, E.V.
Atherosclerosis-driven treg plasticity results in formation of a dysfunctional subset of plastic IFNgamma+ Th1/tregs. Circ. Res.
2016, 119, 1190–1203. [CrossRef] [PubMed]
Li, J.; McArdle, S.; Gholami, A.; Kimura, T.; Wolf, D.; Gerhardt, T.; Miller, J.; Weber, C.; Ley, K. CCR5+T-bet+FoxP3+ effector CD4
T cells drive atherosclerosis. Circ. Res. 2016, 118, 1540–1552. [CrossRef]
Wigren, M.; Rattik, S.; Yao Mattisson, I.; Tomas, L.; Gronberg, C.; Soderberg, I.; Alm, R.; Sundius, L.; Ljungcrantz, I.;
Bjorkbacka, H.; et al. Lack of ability to present antigens on major histocompatibility complex class II molecules aggravates
atherosclerosis in ApoE−/− mice. Circulation 2019, 139, 2554–2566. [CrossRef] [PubMed]
Kimura, T.; Kobiyama, K.; Winkels, H.; Tse, K.; Miller, J.; Vassallo, M.; Wolf, D.; Ryden, C.; Orecchioni, M.; Dileepan, T.; et al.
Regulatory CD4(+) T cells recognize MHC-II-restricted peptide epitopes of apolipoprotein B. Circulation 2018, 138, 1130–1143.
[CrossRef]
Wolf, D.; Gerhardt, T.; Winkels, H.; Michel, N.A.; Pramod, A.B.; Ghosheh, Y.; Brunel, S.; Buscher, K.; Miller, J.; McArdle, S.; et al.
Pathogenic autoimmunity in atherosclerosis evolves from initially protective apolipoprotein B100-reactive CD4(+) T-regulatory
cells. Circulation 2020, 142, 1279–1293. [CrossRef]
Subramanian, M.; Thorp, E.; Hansson, G.K.; Tabas, I. Treg-mediated suppression of atherosclerosis requires MYD88 signaling in
DCs. J. Clin. Investig. 2013, 123, 179–188. [CrossRef]
Choi, J.H.; Cheong, C.; Dandamudi, D.B.; Park, C.G.; Rodriguez, A.; Mehandru, S.; Velinzon, K.; Jung, I.H.; Yoo, J.Y.; Oh, G.T.;
et al. Flt3 signaling-dependent dendritic cells protect against atherosclerosis. Immunity 2011, 35, 819–831. [CrossRef] [PubMed]
Takeda, M.; Yamashita, T.; Sasaki, N.; Hirata, K. Dendritic cells in atherogenesis: Possible novel targets for prevention of
atherosclerosis. J. Atheroscler. Thromb. 2012, 19, 953–961. [CrossRef]
J. Clin. Med. 2021, 10, 5907
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
19 of 20
Hermansson, A.; Johansson, D.K.; Ketelhuth, D.F.; Andersson, J.; Zhou, X.; Hansson, G.K. Immunotherapy with tolerogenic
apolipoprotein B-100-loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice. Circulation 2011, 123,
1083–1091. [CrossRef]
Takeda, M.; Yamashita, T.; Sasaki, N.; Nakajima, K.; Kita, T.; Shinohara, M.; Ishida, T.; Hirata, K. Oral administration of an active
form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with
tolerogenic functions. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 2495–2503. [CrossRef]
Wang, T.J.; Pencina, M.J.; Booth, S.L.; Jacques, P.F.; Ingelsson, E.; Lanier, K.; Benjamin, E.J.; D’Agostino, R.B.; Wolf, M.; Vasan, R.S.
Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008, 117, 503–511. [CrossRef] [PubMed]
Weiner, H.L.; da Cunha, A.P.; Quintana, F.; Wu, H. Oral tolerance. Immunol. Rev. 2011, 241, 241–259. [CrossRef] [PubMed]
Mallat, Z.; Gojova, A.; Brun, V.; Esposito, B.; Fournier, N.; Cottrez, F.; Tedgui, A.; Groux, H. Induction of a regulatory T cell type 1
response reduces the development of atherosclerosis in apolipoprotein E-knockout mice. Circulation 2003, 108, 1232–1237.
van Puijvelde, G.H.; Hauer, A.D.; de Vos, P.; van den Heuvel, R.; van Herwijnen, M.J.; van der Zee, R.; van Eden, W.; van Berkel,
T.J.; Kuiper, J. Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation 2006, 114,
1968–1976. [CrossRef]
van Puijvelde, G.H.; van Es, T.; van Wanrooij, E.J.; Habets, K.L.; de Vos, P.; van der Zee, R.; van Eden, W.; van Berkel, T.J.; Kuiper, J.
Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis. Arterioscler.
Thromb. Vasc. Biol. 2007, 27, 2677–2683. [CrossRef]
Yamashita, T.; Kasahara, K.; Emoto, T.; Matsumoto, T.; Mizoguchi, T.; Kitano, N.; Sasaki, N.; Hirata, K. Intestinal immunity
and gut microbiota as therapeutic targets for preventing atherosclerotic cardiovascular diseases. Circ. J. 2015, 79, 1882–1890.
[CrossRef]
Yoshida, N.; Emoto, T.; Yamashita, T.; Watanabe, H.; Hayashi, T.; Tabata, T.; Hoshi, N.; Hatano, N.; Ozawa, G.; Sasaki, N.; et al.
Bacteroides vulgatus and Bacteroides dorei reduce gut microbial lipopolysaccharide production and inhibit atherosclerosis. Circulation
2018, 138, 2486–2498. [CrossRef] [PubMed]
Atarashi, K.; Tanoue, T.; Shima, T.; Imaoka, A.; Kuwahara, T.; Momose, Y.; Cheng, G.; Yamasaki, S.; Saito, T.; Ohba, Y.; et al.
Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011, 331, 337–341. [CrossRef]
Atarashi, K.; Tanoue, T.; Oshima, K.; Suda, W.; Nagano, Y.; Nishikawa, H.; Fukuda, S.; Saito, T.; Narushima, S.; Hase, K.; et al. Treg
induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013, 500, 232–236. [CrossRef]
Furusawa, Y.; Obata, Y.; Fukuda, S.; Endo, T.A.; Nakato, G.; Takahashi, D.; Nakanishi, Y.; Uetake, C.; Kato, K.; Kato, T.; et al.
Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013, 504, 446–450.
[CrossRef] [PubMed]
Bartolomaeus, H.; Balogh, A.; Yakoub, M.; Homann, S.; Marko, L.; Hoges, S.; Tsvetkov, D.; Krannich, A.; Wundersitz, S.;
Avery, E.G.; et al. Short-chain fatty acid propionate protects from hypertensive cardiovascular damage. Circulation 2019, 139,
1407–1421. [CrossRef]
Belghith, M.; Bluestone, J.A.; Barriot, S.; Megret, J.; Bach, J.F.; Chatenoud, L. TGF-beta-dependent mechanisms mediate restoration
of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat. Med. 2003, 9, 1202–1208. [CrossRef] [PubMed]
Herold, K.C.; Hagopian, W.; Auger, J.A.; Poumian-Ruiz, E.; Taylor, L.; Donaldson, D.; Gitelman, S.E.; Harlan, D.M.; Xu, D.;
Zivin, R.A.; et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N. Engl. J. Med. 2002, 346, 1692–1698.
[CrossRef]
Steffens, S.; Burger, F.; Pelli, G.; Dean, Y.; Elson, G.; Kosco-Vilbois, M.; Chatenoud, L.; Mach, F. Short-term treatment with anti-CD3
antibody reduces the development and progression of atherosclerosis in mice. Circulation 2006, 114, 1977–1984. [CrossRef]
Ochi, H.; Abraham, M.; Ishikawa, H.; Frenkel, D.; Yang, K.; Basso, A.S.; Wu, H.; Chen, M.L.; Gandhi, R.; Miller, A.; et al. Oral
CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+ CD25− LAP+ T cells. Nat. Med. 2006, 12,
627–635. [CrossRef] [PubMed]
Ishikawa, H.; Ochi, H.; Chen, M.L.; Frenkel, D.; Maron, R.; Weiner, H.L. Inhibition of autoimmune diabetes by oral administration
of anti-CD3 monoclonal antibody. Diabetes 2007, 56, 2103–2109. [CrossRef]
Sasaki, N.; Yamashita, T.; Takeda, M.; Shinohara, M.; Nakajima, K.; Tawa, H.; Usui, T.; Hirata, K. Oral anti-CD3 antibody treatment
induces regulatory T cells and inhibits the development of atherosclerosis in mice. Circulation 2009, 120, 1996–2005. [CrossRef]
[PubMed]
Foks, A.C.; Frodermann, V.; ter Borg, M.; Habets, K.L.; Bot, I.; Zhao, Y.; van Eck, M.; van Berkel, T.J.; Kuiper, J.; van Puijvelde,
G.H. Differential effects of regulatory T cells on the initiation and regression of atherosclerosis. Atherosclerosis 2011, 218, 53–60.
[CrossRef] [PubMed]
Dinh, T.N.; Kyaw, T.S.; Kanellakis, P.; To, K.; Tipping, P.; Toh, B.H.; Bobik, A.; Agrotis, A. Cytokine therapy with interleukin2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development
and progression of atherosclerosis. Circulation 2012, 126, 1256–1266. [CrossRef]
Korn, T.; Reddy, J.; Gao, W.; Bettelli, E.; Awasthi, A.; Petersen, T.R.; Backstrom, B.T.; Sobel, R.A.; Wucherpfennig, K.W.;
Strom, T.B.; et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat.
Med. 2007, 13, 423–431. [CrossRef] [PubMed]
J. Clin. Med. 2021, 10, 5907
20 of 20
115. Kasahara, K.; Sasaki, N.; Yamashita, T.; Kita, T.; Yodoi, K.; Sasaki, Y.; Takeda, M.; Hirata, K. CD3 antibody and IL-2 complex
combination therapy inhibits atherosclerosis by augmenting a regulatory immune response. J. Am. Heart Assoc. 2014, 3, e000719.
[CrossRef]
116. Koreth, J.; Matsuoka, K.; Kim, H.T.; McDonough, S.M.; Bindra, B.; Alyea, E.P., 3rd; Armand, P.; Cutler, C.; Ho, V.T.;
Treister, N.S.; et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 2011, 365, 2055–2066.
[CrossRef]
117. Saadoun, D.; Rosenzwajg, M.; Joly, F.; Six, A.; Carrat, F.; Thibault, V.; Sene, D.; Cacoub, P.; Klatzmann, D. Regulatory T-cell
responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 2011, 365, 2067–2077. [CrossRef]
118. Zhao, T.X.; Kostapanos, M.; Griffiths, C.; Arbon, E.L.; Hubsch, A.; Kaloyirou, F.; Helmy, J.; Hoole, S.P.; Rudd, J.H.F.; Wood, G.; et al.
Low-dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndromes (LILACS): Protocol and
study rationale for a randomised, double-blind, placebo-controlled, phase I/II clinical trial. BMJ. Open 2018, 8, e022452. [CrossRef]
119. Zhao, T.X.; Newland, S.A.; Mallat, Z. 2019 ATVB Plenary Lecture: Interleukin-2 Therapy in Cardiovascular Disease: The Potential
to Regulate Innate and Adaptive Immunity. Arterioscler. Thromb. Vasc. Biol. 2020, 40, 853–864. [CrossRef]
120. Schwarz, T. Mechanisms of UV-induced immunosuppression. Keio J. Med. 2005, 54, 165–171. [CrossRef]
121. Morita, A. Current developments in phototherapy for psoriasis. J. Dermatol. 2018, 45, 287–292. [CrossRef] [PubMed]
122. Sasaki, N.; Yamashita, T.; Kasahara, K.; Fukunaga, A.; Yamaguchi, T.; Emoto, T.; Yodoi, K.; Matsumoto, T.; Nakajima, K.; Kita, T.;
et al. UVB exposure prevents atherosclerosis ...
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