RSS-Feed abonnieren
PDF herunterladen
DOI: 10.1055/a-2437-6111
Characterization of CD3+ T Lymphocytes in Human Coronary Thrombi with ST-segment Elevation Myocardial Infarction
Funding This work was supported by grants from the National Natural Science Foundation of China [No. 82030016 and 82230011 to X.C.; No. 82200320 to M.G.; No. 82170282 to N.X.; No. 82000443 to J.L.].
Abstract
Background The occurrence and development of ST-segment elevation myocardial infarction (STEMI) are accompanied by coronary atherothrombosis and occlusion, and immune responses play prominent roles in their pathogeneses. However, the causes of atherothrombosis remain elusive, and a comprehensive study of T cell-mediated immune responses in coronary thrombi from STEMI patients is lacking.
Objectives The aim of this study was to determine the heterogeneity and clonality of CD3+ T lymphocytes in STEMI patients at the single-cell level.
Methods Paired single-cell RNA and T cell receptor (TCR) sequencing was performed on CD3+ T lymphocytes in the coronary thrombi and peripheral blood of STEMI patients, as well as the blood from control subjects without coronary artery disease (CAD).
Results Compared with those in the peripheral blood of STEMI patients, the activation, cytotoxicity, proinflammatory, and prothrombotic characteristics of CD3+ T lymphocytes in coronary thrombi were decreased, and the clonality of CD3+ T cells was increased. Compared with those from non-CAD controls, T lymphocytes from STEMI patients exhibited an upregulation of genes related to recent TCR engagement, suggesting antigen-specific stimulation in STEMI. Antigen specificity prediction using an algorithm indicated the probability of T cells from different patients binding to similar antigens for clonal expansion during STEMI.
Conclusion This study provides a basis for exploring the cellular heterogeneity of CD3+ T lymphocytes in the coronary thrombi and peripheral blood of STEMI patients. Identifying the precise adaptive immune mechanisms driving atherothrombosis may lead to innovative therapies that selectively target the aberrant immune response, resulting in more effective treatments for STEMI.
Authors' Contribution
M.G., N.X., and X.C. designed the study. M.G., N.X., Y.L., S.N., and J.J. enrolled participants and supervised study participant recruitment. M.G., X.Z., M.L., N.L., and H.Y. collected the samples and performed the experiments. M.G., S.Z., and T.T. designed and performed the analysis. M.G. and N.X. prepared the manuscript and the figures. N.X., X.C., J.L., F.Y., B.L., H.L., and C.C. edited and revised the manuscript. X.C., W.W., D.H., and J.H. supervised the project. All the authors contributed to the interpretation of the results and the composition of the final manuscript. All the authors have read and approved the final version of the paper.
* These authors contributed equally to this work.
Publikationsverlauf
Eingereicht: 28. Februar 2024
Angenommen: 09. Oktober 2024
Artikel online veröffentlicht:
07. November 2024
© 2024. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Interpretation of the annual report on cardiovascular health and diseases in China 2021. Cardiol Discov 2023; 3 (04) 277-300
- 2 Sakakura K, Nakano M, Otsuka F, Ladich E, Kolodgie FD, Virmani R. Pathophysiology of atherosclerosis plaque progression. Heart Lung Circ 2013; 22 (06) 399-411
- 3 Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20 (05) 1262-1275
- 4 Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010; 30 (07) 1282-1292
- 5 Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res 2019; 124 (02) 315-327
- 6 Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes: the pathologists' view. Eur Heart J 2013; 34 (10) 719-728
- 7 Tabas I. Macrophage apoptosis in atherosclerosis: consequences on plaque progression and the role of endoplasmic reticulum stress. Antioxid Redox Signal 2009; 11 (09) 2333-2339
- 8 Klingenberg R, Brokopp CE, Grivès A. et al. Clonal restriction and predominance of regulatory T cells in coronary thrombi of patients with acute coronary syndromes. Eur Heart J 2015; 36 (17) 1041-1048
- 9 Lin YZ, Lu SH, Lu ZD. et al. Downregulation of CD4+LAP+ and CD4+CD25+ regulatory T cells in acute coronary syndromes. Mediators Inflamm 2013; 2013: 764082
- 10 Witztum JL, Lichtman AH. The influence of innate and adaptive immune responses on atherosclerosis. Annu Rev Pathol 2014; 9: 73-102
- 11 Matsuura E, Atzeni F, Sarzi-Puttini P, Turiel M, Lopez LR, Nurmohamed MT. Is atherosclerosis an autoimmune disease?. BMC Med 2014; 12: 47
- 12 Chistiakov DA, Orekhov AN, Bobryshev YV. Immune-inflammatory responses in atherosclerosis: role of an adaptive immunity mainly driven by T and B cells. Immunobiology 2016; 221 (09) 1014-1033
- 13 Liuzzo G, Goronzy JJ, Yang H. et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 2000; 101 (25) 2883-2888
- 14 Flego D, Liuzzo G, Weyand CM, Crea F. Adaptive immunity dysregulation in acute coronary syndromes: from cellular and molecular basis to clinical implications. J Am Coll Cardiol 2016; 68 (19) 2107-2117
- 15 Papalexi E, Satija R. Single-cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immunol 2018; 18 (01) 35-45
- 16 Winkels H, Ehinger E, Vassallo M. et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ Res 2018; 122 (12) 1675-1688
- 17 Cole JE, Park I, Ahern DJ. et al. Immune cell census in murine atherosclerosis: cytometry by time of flight illuminates vascular myeloid cell diversity. Cardiovasc Res 2018; 114 (10) 1360-1371
- 18 Cochain C, Vafadarnejad E, Arampatzi P. et al. Single-cell RNA-seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ Res 2018; 122 (12) 1661-1674
- 19 Lin JD, Nishi H, Poles J. et al. Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regression. JCI Insight 2019; 4 (04) e124574
- 20 Fernandez DM, Rahman AH, Fernandez NF. et al. Single-cell immune landscape of human atherosclerotic plaques. Nat Med 2019; 25 (10) 1576-1588
- 21 Depuydt MAC, Prange KHM, Slenders L. et al. Microanatomy of the human atherosclerotic plaque by single-cell transcriptomics. Circ Res 2020; 127 (11) 1437-1455
- 22 Chowdhury RR, D'Addabbo J, Huang X. et al. Human coronary plaque T cells are clonal and cross-react to virus and self. Circ Res 2022; 130 (10) 1510-1530
- 23 Depuydt MAC, Schaftenaar FH, Prange KHM. et al. Single-cell T cell receptor sequencing of paired human atherosclerotic plaques and blood reveals autoimmune-like features of expanded effector T cells. Nat Cardiovasc Res 2023; 2 (02) 112-125
- 24 Wang Z, Zhang X, Lu S. et al. Pairing of single-cell RNA analysis and T cell antigen receptor profiling indicates breakdown of T cell tolerance checkpoints in atherosclerosis. Nat Cardiovasc Res 2023; 2 (03) 290-306
- 25 Ramaiola I, Padró T, Peña E. et al. Changes in thrombus composition and profilin-1 release in acute myocardial infarction. Eur Heart J 2015; 36 (16) 965-975
- 26 Stuart T, Butler A, Hoffman P. et al. Comprehensive integration of single-cell data. Cell 2019; 177 (07) 1888-1902.e21
- 27 Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 2018; 36 (05) 411-420
- 28 Zhang L, Yu X, Zheng L. et al. Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. Nature 2018; 564 (7735) 268-272
- 29 Gaydosik AM, Tabib T, Domsic R, Khanna D, Lafyatis R, Fuschiotti P. Single-cell transcriptome analysis identifies skin-specific T-cell responses in systemic sclerosis. Ann Rheum Dis 2021; 80 (11) 1453-1460
- 30 Aran D, Looney AP, Liu L. et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol 2019; 20 (02) 163-172
- 31 Herder C, Peeters W, Illig T. et al; CARDIoGRAM Consortium. RANTES/CCL5 and risk for coronary events: results from the MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies. PLoS One 2011; 6 (12) e25734
- 32 Mirabelli-Badenier M, Braunersreuther V, Viviani GL. et al. CC and CXC chemokines are pivotal mediators of cerebral injury in ischaemic stroke. Thromb Haemost 2011; 105 (03) 409-420
- 33 Najem MY, Couturaud F, Lemarié CA. Cytokine and chemokine regulation of venous thromboembolism. J Thromb Haemost 2020; 18 (05) 1009-1019
- 34 Cenerenti M, Saillard M, Romero P, Jandus C. The era of cytotoxic CD4 T cells. Front Immunol 2022; 13: 867189
- 35 Serroukh Y, Gu-Trantien C, Hooshiar Kashani B. et al. The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes. eLife 2018; 7: 7
- 36 Tavakolian Ferdousie V, Mohammadi M, Hassanshahi G. et al. Serum CXCL10 and CXCL12 chemokine levels are associated with the severity of coronary artery disease and coronary artery occlusion. Int J Cardiol 2017; 233: 23-28
- 37 Leberzammer J, Agten SM, Blanchet X. et al. Targeting platelet-derived CXCL12 impedes arterial thrombosis. Blood 2022; 139 (17) 2691-2705
- 38 Dominguez-Villar M, Hafler DA. Regulatory T cells in autoimmune disease. Nat Immunol 2018; 19 (07) 665-673
- 39 Pita-López ML, Pera A, Solana R. Adaptive memory of human NK-like CD8+ T-cells to aging, and viral and tumor antigens. Front Immunol 2016; 7: 616
- 40 Wang J, Xu Y, Chen Z. et al. Liver immune profiling reveals pathogenesis and therapeutics for biliary atresia. Cell 2020; 183 (07) 1867-1883.e26
- 41 Shugay M, Bagaev DV, Zvyagin IV. et al. VDJdb: a curated database of T-cell receptor sequences with known antigen specificity. Nucleic Acids Res 2018; 46 (D1): D419-D427
- 42 Tickotsky N, Sagiv T, Prilusky J, Shifrut E, Friedman N. McPAS-TCR: a manually curated catalogue of pathology-associated T cell receptor sequences. Bioinformatics 2017; 33 (18) 2924-2929
- 43 Bending D, Zikherman J. Nr4a nuclear receptors: markers and modulators of antigen receptor signaling. Curr Opin Immunol 2023; 81: 102285
- 44 Glanville J, Huang H, Nau A. et al. Identifying specificity groups in the T cell receptor repertoire. Nature 2017; 547 (7661) 94-98
- 45 Kwong JC, Schwartz KL, Campitelli MA. et al. Acute myocardial infarction after laboratory-confirmed influenza infection. N Engl J Med 2018; 378 (04) 345-353
- 46 Warren-Gash C, Hayward AC, Hemingway H. et al. Influenza infection and risk of acute myocardial infarction in England and Wales: a CALIBER self-controlled case series study. J Infect Dis 2012; 206 (11) 1652-1659
- 47 Kimura T, Tse K, Sette A, Ley K. Vaccination to modulate atherosclerosis. Autoimmunity 2015; 48 (03) 152-160
- 48 Rossmann A, Henderson B, Heidecker B. et al. T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire. Exp Gerontol 2008; 43 (03) 229-237
- 49 Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6 (07) 508-519
- 50 Pessi T, Karhunen V, Karjalainen PP. et al. Bacterial signatures in thrombus aspirates of patients with myocardial infarction. Circulation 2013; 127 (11) 1219-1228 , e1–e6