Background. CD4+ T helper (Th) cells play critical roles in the development and progression of atherosclerosis and the onset of acute coronary syndromes (ACS, including acute myocardial infarction (AMI) and unstable angina pectoris (UAP)). In addition to Th1, Th2, and Th17 cells, Th22 and Th9 subsets have been identified in humans. In the present study, we investigated whether Th22 cells and Th9 cells are involved in the onset of ACS. Methods. The frequencies of Th22 and Th9 cells were detected using a flow cytometric analysis and their related cytokine and transcription factor were measured in the AMI, UAP, stable angina pectoris (SAP), and control groups. Results. The results revealed a significant increase in the peripheral Th22 number, AHR expression, and IL-22 levels in patients with ACS compared with those in the SAP and control groups. Although there was no difference in the peripheral Th9 number among the four groups, the PU.1 expression and IL-9 levels were significantly increased in patients with ACS compared with the SAP and control groups. Conclusions. Circulating Th22 and Th9 type responses may play a potential role in the onset of ACS symptom. 1. Introduction CD4+ T helper (Th) cells play major roles in the inflammatory process of atherosclerosis and the onset of acute coronary syndromes (ACS) including unstable angina pectoris (UAP) and acute myocardial infarction (AMI) [1–3]. CD4+ Th cells, accompanied by macrophages and dendritic cells, are easily detected in the shoulders of plaque and lead to thrombosis, embolization, and varying degrees of obstruction of myocardial perfusion [4–6]. CD4+ Th cells include effector T cells, which protect against pathogens, and regulatory T cells (Tregs), which protect against effector responses to autoantigens and against responses to exogenous antigens that are harmful to the host. Based on their cytokine secretion profile, effector T cells are functionally subdivided into three types, Th1, Th2, and Th17. The roles of four CD4+ Th cell lineages, Th1, Th2, Th17, and Treg cells, in atherosclerosis are widely studied [1, 2]. During the past two decades, the Th1/Th2 paradigm prevailed, and Th1 cells were thought to promote the pathology in atherosclerosis and Th2 cells were thought to attenuate the disease [7–9]. Recently, Th17, the third subpopulation of Th cells, was found to promote atherosclerotic lesion development in atherosclerotic-prone models and it was related to the onset of coronary artery disease in a number of studies [10–12]. The role of Th17 in atherosclerosis remains uncertain. Although
References
[1]
G. K. Hansson and A. Hermansson, “The immune system in atherosclerosis,” Nature Immunology, vol. 12, no. 3, pp. 204–212, 2011.
[2]
C. Lahoute, O. Herbin, Z. Mallat, and A. Tedgui, “Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets,” Nature Reviews Cardiology, vol. 8, no. 6, pp. 348–358, 2011.
[3]
C. M. Weyand, J. J. Goronzy, G. Liuzzo, S. L. Kopecky, and D. R. Holmes Jr., “T-cell immunity in acute coronary syndromes,” Mayo Clinic Proceedings, vol. 76, no. 10, pp. 1011–1020, 2001.
[4]
A.-K. L. Robertson and G. K. Hansson, “T cells in atherogenesis: for better or for worse?” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 11, pp. 2421–2432, 2006.
[5]
J. Frostegard, A. K. Ulfgren, P. Nyberg et al., “Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines,” Atherosclerosis, vol. 145, no. 1, pp. 33–43, 1999.
[6]
A. Yilmaz, M. Lochno, F. Traeg et al., “Emergence of dendritic cells in rupture-prone regions of vulnerable carotid plaques,” Atherosclerosis, vol. 176, no. 1, pp. 101–110, 2004.
[7]
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,” Journal of the American College of Cardiology, vol. 45, no. 12, pp. 1939–1945, 2005.
[8]
X. Cheng, Y. Chen, J. J. Xie et al., “Suppressive oligodeoxynucleotides inhibit atherosclerosis in ApoE(？/？) mice through modulation of Th1/Th2 balance,” Journal of Molecular and Cellular Cardiology, vol. 45, no. 2, pp. 168–175, 2008.
[9]
S. C. Whitman, P. Ravisankar, H. Elam, and A. Daugherty, “Exogenous interferon-γ enhances atherosclerosis in apolipoprotein E？/？ mice,” American Journal of Pathology, vol. 157, no. 6, pp. 1819–1824, 2000.
[10]
R. E. Eid, D. A. Rao, J. Zhou et al., “Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells,” Circulation, vol. 119, no. 10, pp. 1424–1432, 2009.
[11]
C. Erbel, L. Chen, F. Bea et al., “Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice,” The Journal of Immunology, vol. 183, no. 12, pp. 8167–8175, 2009.
[12]
E. Smith, K. M. Prasad, M. Butcher et al., “Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice,” Circulation, vol. 121, no. 15, pp. 1746–1755, 2010.
[13]
K. Danzaki, Y. Matsui, M. Ikesue et al., “Interleukin-17A deficiency accelerates unstable atherosclerotic plaque formation in apolipoprotein E-deficient mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 2, pp. 273–280, 2012.
[14]
M. J. Butcher, B. N. Gjurich, T. Phillips, and E. V. Galkina, “The IL-17A/IL-17RA axis plays a proatherogenic role via the regulation of aortic myeloid cell recruitment,” Circulation Research, vol. 110, no. 5, pp. 675–687, 2012.
[15]
F. Usui, H. Kimura, T. Ohshiro et al., “Interleukin-17 deficiency reduced vascular inflammation and development of atherosclerosis in Western diet-induced apoE-deficient mice,” Biochemical and Biophysical Research Communications, vol. 420, no. 1, pp. 72–77, 2012.
[16]
M. S. Madhur, S. A. Funt, L. Li et al., “Role of interleukin 17 in inflammation, atherosclerosis, and vascular function in apolipoprotein e-deficient mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 31, no. 7, pp. 1565–1572, 2011.
[17]
H. Ait-Oufella, B. L. Salomon, S. Potteaux et al., “Natural regulatory T cells control the development of atherosclerosis in mice,” Nature Medicine, vol. 12, no. 2, pp. 178–180, 2006.
[18]
A. Mor, D. Planer, G. Luboshits et al., “Role of naturally occurring CD4+ CD25+ regulatory T cells in experimental atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 4, pp. 893–900, 2007.
[19]
Y. Zhong, X. Wang, Q. Ji et al., “CD4+LAP+ and CD4+CD25+Foxp3+ regulatory T cells induced by nasal oxidized low-density lipoprotein suppress effector T cells response and attenuate atherosclerosis in ApoE？/？ mice,” Journal of Clinical Immunology, vol. 32, no. 5, pp. 1104–1117, 2012.
[20]
Z. Mallat, A. Gojova, V. Brun et al., “Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice,” Circulation, vol. 108, no. 10, pp. 1232–1237, 2003.
[21]
Q. W. Ji, M. Guo, J. S. Zheng et al., “Downregulation of T helper cell type 3 in patients with acute coronary syndrome,” Archives of Medical Research, vol. 40, no. 4, pp. 285–293, 2009.
[22]
V. Dardalhon, A. Awasthi, H. Kwon et al., “IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells,” Nature Immunology, vol. 9, no. 12, pp. 1347–1355, 2008.
[23]
M. Veldhoen, C. Uyttenhove, J. van Snick et al., “Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset,” Nature Immunology, vol. 9, no. 12, pp. 1341–1346, 2008.
[24]
S. Trifari, C. D. Kaplan, E. H. Tran, N. K. Crellin, and H. Spits, “Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells,” Nature Immunology, vol. 10, no. 8, pp. 864–871, 2009.
[25]
T. Duhen, R. Geiger, D. Jarrossay, A. Lanzavecchia, and F. Sallusto, “Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells,” Nature Immunology, vol. 10, no. 8, pp. 857–863, 2009.
[26]
R. Basu, D. B. O'Quinn, D. J. Silberger et al., “Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria,” Immunity, vol. 37, no. 6, pp. 1061–1075, 2012.
[27]
A. J？ger, V. Dardalhon, R. A. Sobel, E. Bettelli, and V. K. Kuchroo, “Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes,” Journal of Immunology, vol. 183, no. 11, pp. 7169–7177, 2009.
[28]
Z. J. Ye, M. L. Yuan, Q. Zhou et al., “Differentiation and recruitment of Th9 cells stimulated by pleural mesothelial cells in human Mycobacterium tuberculosis infection,” PloS ONE, vol. 7, no. 2, Article ID e31710, 2012.
[29]
M.-E. Truchetet, N. C. Brembilla, E. Montanari, Y. Allanore, and C. Chizzolini, “Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease,” Arthritis Research & Therapy, vol. 13, no. 5, p. R166, 2011.
[30]
L. Zhang, Y. G. Li, Y. H. Li et al., “Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis,” PloS ONE, vol. 7, no. 4, Article ID e31000, 2012.
[31]
Q. Xia, X. Xiang, S. Patel, R. Puranik, Q. Xie, and S. Bao, “Characterisation of IL-22 and interferon-gamma-inducible chemokines in human carotid plaque,” International Journal of Cardiology, vol. 154, no. 2, pp. 187–189, 2012.
[32]
R. T. Oliveira, R. M. Silva, F. H. Teo et al., “Detection of TCD4+ subsets in human carotid atheroma,” Cytokine, vol. 62, no. 1, pp. 131–140, 2013.
[33]
I. Gregersen, M. Skjelland, S. Holm et al., “Increased systemic and local interleukin 9 levels in patients with carotid and coronary atherosclerosis,” PLoS ONE, vol. 8, no. 8, Article ID e72769, 2013.
[34]
H. Chang, H. Hanawa, H. Liu et al., “Hydrodynamic-based delivery of an interleukin-22-Ig fusion gene ameliorates experimental autoimmune myocarditis in rats,” The Journal of Immunology, vol. 177, no. 6, pp. 3635–3643, 2006.
[35]
K. Wolk, E. Witte, K. Witte, K. Warszawska, and R. Sabat, “Biology of interleukin-22,” Seminars in Immunopathology, vol. 32, no. 1, pp. 17–31, 2010.
[36]
L. Geboes, L. Dumoutier, H. Kelchtermans et al., “Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice,” Arthritis and Rheumatism, vol. 60, no. 2, pp. 390–395, 2009.
[37]
X. Y. Yang, H. Y. Wang, X. Y. Zhao, L. J. Wang, Q. H. Lv, and Q. Q. Wang, “Th22, but not Th17 might be a good index to predict the tissue involvement of systemic lupus erythematosus,” Journal of Clinical Immunology, vol. 33, no. 4, pp. 767–774, 2013.
[38]
T. Liu, L. Peng, P. Yu et al., “Increased circulating Th22 and Th17 cells are associated with tumor progression and patient survival in human gastric cancer,” Journal of Clinical Immunology, vol. 32, no. 6, pp. 1332–1339, 2012.
[39]
D. Whiting, G. Hsieh, J. J. Yun et al., “Chemokine monokine induced by IFN-gamma/CXC chemokine ligand 9 stimulates T lymphocyte proliferation and effector cytokine production,” The Journal of Immunology, vol. 172, no. 12, pp. 7417–7424, 2004.
[40]
N. R. Madamanchi, S. Li, C. Patterson, and M. S. Runge, “Reactive oxygen species regulate heat-shock protein 70 via the JAK/STAT pathway,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 3, pp. 321–326, 2001.
[41]
A. H. Sprague and R. A. Khalil, “Inflammatory cytokines in vascular dysfunction and vascular disease,” Biochemical Pharmacology, vol. 78, no. 6, pp. 539–552, 2009.
[42]
A. Tedgui and Z. Mallat, “Cytokines in atherosclerosis: pathogenic and regulatory pathways,” Physiological Reviews, vol. 86, no. 2, pp. 515–581, 2006.
[43]
H. C. Chang, S. Sehra, R. Goswami et al., “The transcription factor PU. 1 is required for the development of IL-9-producing T cells and allergic inflammation,” Nature Immunology, vol. 11, no. 6, pp. 527–534, 2010.
[44]
M. H. Kaplan, “Th9 cells: differentiation and disease,” Immunological Reviews, vol. 252, no. 1, pp. 104–115, 2013.
[45]
H. Li and A. Rostami, “IL-9: basic biology, signaling pathways in CD4+ T cells and implications for autoimmunity,” Journal of Neuroimmune Pharmacology, vol. 5, no. 2, pp. 198–209, 2010.
[46]
V. Staudt, E. Bothur, M. Klein et al., “Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells,” Immunity, vol. 33, no. 2, pp. 192–202, 2010.
[47]
Y. Lu, S. Hong, H. Li et al., “Th9 cells promote antitumor immune responses in vivo,” The Journal of Clinical Investigation, vol. 122, no. 11, pp. 4160–4171, 2012.
