Circulating Th17 and Tc17 Cells and Their Imbalance with Regulatory T Cells Is Associated with Myocardial Infarction in Young Indian Patients

Abstract

Background: Activated inflammatory cells are found in coronary plaques as well as peripheral circulation in patients with acute coronary syndrome. We explored the circulating T cell profile, their reactivity to self-antigens and plasma cytokine levels in Indian patients with Myocardial Infarction. Methods and Results: Intracellular expression of interferon-γ Interleukin (IL)-4, IL-17, IL-10 and Foxp3 were determined in CD4+ and CD8+ T cells using flow cytometry in patients with ST elevated myocardial infarction (STEMI) (N = 79) and controls (N = 80). Cytokines were measured using Milliplex kit and T cell reactivity was studied by CFSE dilution. Statistical analysis was performed using SPSS software. Patients with myocardial infarction showed higher proportion of IL-17 expressing CD4+ and CD8+ T cells (Th17 and Tc17) and elevated levels of IL-6 and IL-17 in plasma with significant reduction in circulating Tregs. Th1, Th2 and CD4+CD28null cells were not significantly different in patients compared to healthy individuals. The ratio of Th17 and Tc17 to Tregs showed an independent association with STEMI with an adjusted odds ratio of 2.92 (95% CI: 1.73 - 4.92), P < 0.001 and 2.22 (95% CI: 1.42 - 3.44), P < 0.001 respectively. Reactivity to HSP60 and oxidized LDL with expansion of IL-17 expression was higher in patients compared with control. Young patients (<45 years) with no apparent risk factor could be distinguished from healthy controls by the increase in Th17 and ratio of Th17 and Tc17 to Tregs in peripheral blood. Conclusion: Our results suggest that an imbalance in both CD4+ and CD8+ T cells secreting IL-17 and Tregs is associated with acute myocardial infarction. HSP60 and Ox-LDL may contribute to this response and pathogenesis of AMI in Indian population.

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Ponnusamy, T. , Srikanth, K. , Manjunatha, R. , Kakkar, V. and Mundkur, L. (2015) Circulating Th17 and Tc17 Cells and Their Imbalance with Regulatory T Cells Is Associated with Myocardial Infarction in Young Indian Patients. World Journal of Cardiovascular Diseases, 5, 373-387. doi: 10.4236/wjcd.2015.512043.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] World Health Organization (2014) World Health Statistics 2014. World Health Organization, Geneva.
http://www.who.int/gho/publications/world_health_statistics/2014/en
[2] Sherer, Y. and Shoenfeld, Y. (2006) Mechanisms of Disease: Atherosclerosis in Autoimmune Diseases. Nature Clinical Practice Rheumatology, 2, 99-106.
http://dx.doi.org/10.1038/ncprheum0092
[3] Robertson, A.K. and Hansson, G.K. (2006) T Cells in Atherogenesis: For Better or for Worse? Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 2421-2432.
http://dx.doi.org/10.1161/01.ATV.0000245830.29764.84
[4] Khallou-Laschet, J., Caligiuri, G., Groyer, E., Tupin, E., Gaston, A.T., Poirier, B., Kronenberg, M., Cohen, J.L., Klatzmann, D., Kaveri, S.V. and Nicoletti, A. (2006) The Proatherogenic Role of T Cells Requires Cell Division and Is Dependent on the Stage of the Disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 353-358.
[5] George, J. (2008) Mechanisms of Disease: The Evolving Role of Regulatory T Cells in Atherosclerosis. Nature Clinical Practice Cardiovascular Medicine Nature Clinical Practice Cardiovascular Medicine, 5, 531-540.
http://dx.doi.org/10.1038/ncpcardio1279
[6] Hansson, G.K. and Berne, G.P. (2004) Atherosclerosis and the Immune System. Acta Paediatrica, 93, 63-69.
http://dx.doi.org/10.1111/j.1651-2227.2004.tb00241.x
[7] Hansson, G.K. and Libby, P. (2006) The Immune Response in Atherosclerosis: A Double-Edged Sword. Nature Reviews Immunology, 6, 508-519.
http://dx.doi.org/10.1038/nri1882
[8] Taleb, S., Tedgui, A. and Mallat, Z. (2008) Regulatory T-Cell Immunity and Its Relevance to Atherosclerosis. Journal of Internal Medicine, 263, 489-499.
http://dx.doi.org/10.1111/j.1365-2796.2008.01944.x
[9] Fontenot, J.D., Gavin, M.A. and Rudensky, A.Y. (2003) Foxp3 Programs the Development and Function of CD4+CD25+ Regulatory T Cells. Nature Immunology, 4, 330-336.
http://dx.doi.org/10.1038/ni904
[10] Dejaco, C., Duftner, C., Grubeck-Loebenstein, B. and Schirmer, M. (2006) Imbalance of Regulatory T Cells in Human Autoimmune Diseases. Immunology, 117, 289-300.
http://dx.doi.org/10.1111/j.1365-2567.2005.02317.x
[11] Tesmer, L.A., Lundy, S.K., Sarkar, S. and Fox, D.A. (2008) Th17 Cells in Human Disease. Immunological Reviews, 223, 87-113.
http://dx.doi.org/10.1111/j.1600-065X.2008.00628.x
[12] Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T.B., Oukka, M., Weiner, H.L. and Kuchroo, V.K. (2006) Reciprocal Developmental Pathways for the Generation of Pathogenic Effector TH17 and Regulatory T Cells. Nature, 441, 235-238.
http://dx.doi.org/10.1038/nature04753
[13] Eisenstein, E.M. and Williams, C.B. (2009) The Treg/Th17 Cell Balance: A New Paradigm for Autoimmunity. Pediatric Research, 65, 26R-31R.
http://dx.doi.org/10.1203/PDR.0b013e31819e76c7
[14] Noack, M. and Miossec, P. (2014) Th17 and Regulatory T Cell Balance in Autoimmune and Inflammatory Diseases. Autoimmunity Reviews, 13, 668-677.
http://dx.doi.org/10.1016/j.autrev.2013.12.004
[15] Cheng, X., Yu, X., Ding, Y.J., Fu, Q.Q., Xie, J.J., Tang, T.T., Yao, R., Chen, Y. and Liao, Y.H. (2008) The Th17/Treg Imbalance in Patients with Acute Coronary Syndrome. Clinical Immunology, 127, 89-97.
http://dx.doi.org/10.1016/j.clim.2008.01.009
[16] Eid, R.E., Rao, D.A., Zhou, J., Lo, S.F., Ranjbaran, H., Gallo, A., Sokol, S.I., Pfau, S., Pober, J.S. and Tellides, G. (2009) Interleukin-17 and Interferon-Gamma Are Produced Concomitantly by Human Coronary Artery-Infiltrating T Cells and Act Synergistically on Vascular Smooth Muscle Cells. Circulation, 119, 1424-1432.
http://dx.doi.org/10.1161/CIRCULATIONAHA.108.827618
[17] Han, S.F., Liu, P., Zhang, W., Bu, L., Shen, M., Li, H., Fan, Y.H., Cheng, K., Cheng, H.X., Li, C.X. and Jia, G.L. (2007) The Opposite-Direction Modulation of CD4+CD25+ Tregs and T Helper 1 Cells in Acute Coronary Syndromes. Clinical Immunology, 124, 90-97.
http://dx.doi.org/10.1016/j.clim.2007.03.546
[18] Mor, A., Luboshits, G., Planer, D., Keren, G. and George, J. (2006) Altered Status of CD4+CD25+ Regulatory T Cells in Patients with Acute Coronary Syndromes. European Heart Journal, 27, 2530-2537.
http://dx.doi.org/10.1093/eurheartj/ehl222
[19] Wang, Z., Lee, J., Zhang, Y., Wang, H., Liu, X., Shang, F. and Zheng, Q. (2011) Increased Th17 Cells in Coronary Artery Disease Are Associated with Neutrophilic Inflammation. Scandinavian Cardiovascular Journal, 45, 54-61.
http://dx.doi.org/10.3109/14017431.2010.491123
[20] Zhao, Z., Wu, Y., Cheng, M., Ji, Y., Yang, X., Liu, P., Jia, S. and Yuan, Z. (2011) Activation of Th17/Th1 and Th1, but Not Th17, Is Associated with the Acute Cardiac Event in Patients with Acute Coronary Syndrome. Atherosclerosis, 217, 518-524.
http://dx.doi.org/10.1016/j.atherosclerosis.2011.03.043
[21] del Rosario Espinoza Mora, M., Bohm, M. and Link, A. (2014) The Th17/Treg Imbalance in Patients with Cardiogenic Shock. Clinical Research in Cardiology, 103, 301-313.
http://dx.doi.org/10.1007/s00392-013-0656-0
[22] Zal, B., Kaski, J.C., Arno, G., Akiyu, J.P., Xu, Q., Cole, D., Whelan, M., Russell, N., Madrigal, J.A., Dodi, I.A. and Baboonian, C. (2004) Heat-Shock Protein 60-Reactive CD4+CD28null T Cells in Patients with Acute Coronary Syndromes. Circulation, 109, 1230-1235.
http://dx.doi.org/10.1161/01.CIR.0000118476.29352.2A
[23] Liuzzo, G., Goronzy, J.J., Yang, H., Kopecky, S.L., Holmes, D.R., Frye, R.L. and Weyand, C.M. (2000) Monoclonal T-Cell Proliferation and Plaque Instability in Acute Coronary Syndromes. Circulation, 101, 2883-2888.
http://dx.doi.org/10.1161/01.CIR.101.25.2883
[24] Gupta, M. and Brister, S. (2006) Is South Asian Ethnicity an Independent Cardiovascular Risk Factor? Canadian Journal of Cardiology, 22, 193-197.
http://dx.doi.org/10.1016/S0828-282X(06)70895-9
[25] Gupta, R., Joshi, P., Mohan, V., Reddy, K.S. and Yusuf, S. (2008) Epidemiology and Causation of Coronary Heart Disease and Stroke in India. Heart, 94, 16-26.
http://dx.doi.org/10.1136/hrt.2007.132951
[26] Hawkins, E.D., Hommel, M., Turner, M.L., Battye, F.L., Markham, J.F. and Hodgkin, P.D. (2007) Measuring Lymphocyte Proliferation, Survival and Differentiation Using CFSE Time-Series Data. Nature Protocols, 2, 2057-2067.
http://dx.doi.org/10.1038/nprot.2007.297
[27] Quah, B.J., Warren, H.S. and Parish, C.R. (2007) Monitoring Lymphocyte Proliferation in Vitro and in Vivo with the Intracellular Fluorescent Dye Car-boxyfluorescein Diacetate Succinimidyl Ester. Nature Protocols, 2, 2049-2056.
http://dx.doi.org/10.1038/nprot.2007.296
[28] Lopes-Virella, M.F., Koskinen, S., Mironova, M., Horne, D., Klein, R., Chassereau, C., Enockson, C. and Virella, G. (2000) The Preparation of Copper-Oxidized LDL for the Measurement of Oxidized LDL Antibodies by EIA. Atherosclerosis, 152, 107-115.
http://dx.doi.org/10.1016/S0021-9150(99)00456-6
[29] Tesfa, L., Volk, H.D. and Kern, F. (2003) A Protocol for Combining Proliferation, Tetramer Staining and Intracellular Cytokine Detection for the Flow-Cytometric Analysis of Antigen Specific T-Cells. Journal of Biological Regulators & Homeostatic Agents, 17, 366-370.
[30] Schmidt, T. and Sester, M. (2013) Detection of Antigen-Specific T Cells Based on Intracellular Cytokine Staining Using Flow-Cytometry. Methods in Molecular Biology, 1064, 267-274.
http://dx.doi.org/10.1007/978-1-62703-601-6_19
[31] Fink, E.L. (2009) The FAQs on Data Transformation. Communication Monographs, 76, 379-397.
http://dx.doi.org/10.1080/03637750903310352
[32] Swirski, F.K. and Nahrendorf, M. (2013) Leukocyte Behavior in Atherosclerosis, Myocardial Infarction, and Heart Failure. Science, 339, 161-166.
http://dx.doi.org/10.1126/science.1230719
[33] Liuzzo, G., Biasucci, L.M., Trotta, G., Brugaletta, S., Pinnelli, M., Digianuario, G., Rizzello, V., Rebuzzi, A.G., Rumi, C., Maseri, A. and Crea, F. (2007) Unusual CD4+CD28null T Lymphocytes and Recurrence of Acute Coronary Events. Journal of the American College of Cardiology, 50, 1450-1458.
http://dx.doi.org/10.1016/j.jacc.2007.06.040
[34] Liuzzo, G., Kopecky, S.L., Frye, R.L., O’Fallon, W.M., Maseri, A., Goronzy, J.J. and Weyand, C.M. (1999) Perturbation of the T-Cell Repertoire in Patients with Unstable Angina. Circulation, 100, 2135-2139.
http://dx.doi.org/10.1161/01.CIR.100.21.2135
[35] Hansson, G.K. (2005) Inflammation, Atherosclerosis, and Coronary Artery Disease. The New England Journal of Medicine, 352, 1685-1695.
http://dx.doi.org/10.1056/NEJMra043430
[36] Park, H., Li, Z., Yang, X.O., Chang, S.H., Nurieva, R., Wang, Y.H., Wang, Y., Hood, L., Zhu, Z., Tian, Q. and Dong, C. (2005) A Distinct Lineage of CD4 T Cells Regulates Tissue Inflammation by Producing Interleukin 17. Nature Immunology, 6, 1133-1141.
http://dx.doi.org/10.1038/ni1261
[37] Ma, T., Gao, Q., Zhu, F., Guo, C., Wang, Q., Gao, F. and Zhang, L. (2013) Th17 Cells and IL-17 Are Involved in the Disruption of Vulnerable Plaques Triggered by Short-Term Combination Stimulation in Apolipoprotein E-Knockout Mice. Cellular & Molecular Immunology, 10, 338-348.
http://dx.doi.org/10.1038/cmi.2013.4
[38] Gao, Q., Jiang, Y., Ma, T., Zhu, F., Gao, F., Zhang, P., Guo, C., Wang, Q., Wang, X., Ma, C., Zhang, Y., Chen, W. and Zhang, L. (2010) A Critical Function of Th17 Proinflammatory Cells in the Development of Atherosclerotic Plaque in Mice. The Journal of Immunology, 185, 5820-5827.
http://dx.doi.org/10.4049/jimmunol.1000116
[39] Ma, T., Gao, Q., Zhu, F., Guo, C., Wang, Q., Gao, F. and Zhang, L. (2013) Th17 Cells and IL-17 Are Involved in the Disruption of Vulnerable Plaques Triggered by Short-Term Combination Stimulation in Apolipoprotein E-Knockout Mice. Cellular & Molecular Immunology, 10, 338-348.
http://dx.doi.org/10.1038/cmi.2013.4
[40] Tae Yu, H., Youn, J.-C., Lee, J., Park, S., Chi, H.-S., Lee, J., Choi, C., Park, S., Choi, D., Ha, J.-W. and Shin, E.-C. (2014) Characterization of CD8+CD57+ T Cells in Patients with Acute Myocardial Infarction. Cellular & Molecular Immunology, 12, 466-473.
[41] Intlekofer, A.M., Banerjee, A., Takemoto, N., Gordon, S.M., Dejong, C.S., Shin, H., Hunter, C.A., Wherry, E.J., Lindsten, T. and Reiner, S.L. (2008) Anomalous Type 17 Response to Viral Infection by CD8+ T Cells Lacking T-Bet and Eomesodermin. Science, 321, 408-411.
http://dx.doi.org/10.1126/science.1159806
[42] Tzartos, J.S., Friese, M.A., Craner, M.J., Palace, J., Newcombe, J., Esiri, M.M. and Fugger, L. (2008) Interleukin-17 Production in Central Nervous System-Infiltrating T Cells and Glial Cells Is Associated with Active Disease in Multiple Sclerosis. American Journal of Pathology, 172, 146-155.
http://dx.doi.org/10.2353/ajpath.2008.070690
[43] Ortega, C., Fernandez, A.S., Carrillo, J.M., Romero, P., Molina, I.J., Moreno, J.C. and Santamaria, M. (2009) IL-17-Producing CD8+ T Lymphocytes from Psoriasis Skin Plaques Are Cytotoxic Effector Cells That Secrete Th17-Related Cytokines. Journal of Leukocyte Biology, 86, 435-443.
http://dx.doi.org/10.1189/JLB.0109046
[44] Ridker, P.M., Rifai, N., Stampfer, M.J. and Hennekens, C.H. (2000) Plasma Concentration of Interleukin-6 and the Risk of Future Myocardial Infarction among Apparently Healthy Men. Circulation, 101, 1767-1772.
http://dx.doi.org/10.1161/01.CIR.101.15.1767
[45] Jager, A. and Kuchroo, V.K. (2010) Effector and Regulatory T-Cell Subsets in Autoimmunity and Tissue Inflammation. Scandinavian Journal of Immunology, 72, 173-184.
http://dx.doi.org/10.1111/j.1365-3083.2010.02432.x
[46] Mor, A., Planer, D., Luboshits, G., Afek, A., Metzger, S., Chajek-Shaul, T., Keren, G. and George, J. (2007) Role of Naturally Occurring CD4+CD25+ Regulatory T Cells in Experimental Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 893-900.
http://dx.doi.org/10.1161/01.ATV.0000259365.31469.89
[47] Gotsman, I., Grabie, N., Gupta, R., Dacosta, R., Mac-Conmara, M., Lederer, J., Sukhova, G., Witztum, J.L., Sharpe, A.H. and Lichtman, A.H. (2006) Impaired Regulatory T-Cell Response and Enhanced Atherosclerosis in the Absence of Inducible Costimulatory Molecule. Circulation, 114, 2047-2055.
http://dx.doi.org/10.1161/CIRCULATIONAHA.106.633263
[48] Lutgens, E., Gijbels, M., Smook, M., Heeringa, P., Gotwals, P., Koteliansky, V.E. and Daemen, M.J. (2002) Transforming Growth Factor-Beta Mediates Balance between Inflammation and Fibrosis during Plaque Progression. Arteriosclerosis, Thrombosis, and Vascular Biology, 22, 975-982.
http://dx.doi.org/10.1161/01.ATV.0000019729.39500.2F
[49] Mallat, Z., Gojova, A., Marchiol-Fournigault, C., Esposito, B., Kamate, C., Merval, R., Fradelizi, D. and Tedgui, A. (2001) Inhibition of Transforming Growth Factor-Beta Signaling Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Mice. Circulation Research, 89, 930-934.
http://dx.doi.org/10.1161/hh2201.099415
[50] Wang, Y., Burns, W.R., Tang, P.C., Yi, T., Schechner, J.S., Zerwes, H.G., Sessa, W.C., Lorber, M.I., Pober, J.S. and Tellides, G. (2004) Interferon-Gamma Plays a Nonredundant Role in Mediating T Cell-Dependent Outward Vascular Remodeling of Allogeneic Human Coronary Arteries. The FASEB Journal, 18, 606-608.
[51] Dumitriu, I.E., Araguas, E.T., Baboonian, C. and Kaski, J.C. (2009) CD4+CD28null T Cells in Coronary Artery Disease: When Helpers Become Killers. Cardiovascular Research, 81, 11-19.
http://dx.doi.org/10.1093/cvr/cvn248
[52] Gupta, R. (2005) Burden of Coronary Heart Disease in India. Indian Heart Journal, 57, 632-638.
[53] Gupta, M., Singh, N. and Verma, S. (2006) South Asians and Cardiovascular Risk: What Clinicians Should Know. Circulation, 113, e924-e929.
http://dx.doi.org/10.1161/circulationaha.105.583815
[54] Sharma, M. and Ganguly, N.K. (2005) Premature Coronary Artery Disease in Indians and Its Associated Risk Factors. Vascular Health and Risk Management, 1, 217-225.
[55] Sekhri, T., Kanwar, R.S., Wilfred, R., Chugh, P., Chhillar, M., Aggarwal, R., Sharma, Y.K., Sethi, J., Sundriyal, J., Bhadra, K., Singh, S., Rautela, N., Chand, T., Singh, M. and Singh, S.K. (2014) Prevalence of Risk Factors for Coronary Artery Disease in an Urban Indian Population. BMJ Open, 4, e005346.
http://dx.doi.org/10.1136/bmjopen-2014-005346
[56] Joshi, P., Islam, S., Pais, P., Reddy, S., Dorairaj, P., Kazmi, K., Pandey, M.R., Haque, S., Mendis, S., Rangarajan, S. and Yusuf, S. (2007) Risk Factors for Early Myocardial Infarction in South Asians Compared with Individuals in Other Countries. JAMA, 297, 286-294.
http://dx.doi.org/10.1001/jama.297.3.286
[57] Capes, S.E., Hunt, D., Malmberg, K. and Gerstein, H.C. (2000) Stress Hyperglycaemia and Increased Risk of Death after Myocardial Infarction in Patients with and without Diabetes: A Systematic Overview. Lancet, 355, 773-778.
http://dx.doi.org/10.1016/S0140-6736(99)08415-9
[58] Dandona, P., Aljada, A. and Bandyopadhyay, A. (2003) The Potential Therapeutic Role of Insulin in Acute Myocardial Infarction in Patients Admitted to Intensive Care and in Those with Unspecified Hyperglycemia. Diabetes Care, 26, 516-519.
http://dx.doi.org/10.2337/diacare.26.2.516
[59] Mangan, P.R., Harrington, L.E., O’Quinn, D.B., Helms, W.S., Bullard, D.C., Elson, C.O., Hatton, R.D., Wahl, S.M., Schoeb, T.R. and Weaver, C.T. (2006) Transforming Growth Factor-Beta Induces Development of the TH17 Lineage. Nature, 441, 231-234.
http://dx.doi.org/10.1038/nature04754

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