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De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes.
Abstract
The inflammatory infiltrate in atherosclerotic plaque is composed of T cells and macrophages. CD4 + T cells with a unique phenotype, CD4 + CD28 null , are preferentially recruited into culprit lesions. These T cells are distinct from classic CD4 + CD28 + T cells in gene expression and function, including their ability to mediate cytolysis. In this study, we have investigated the regulation of CD4 + CD28 null T-cell cytolytic function. In patients with acute coronary syndromes (ACS), CD4 + CD28 null T cells express killer immunoglobulin-like receptors (KIRs). KIRs encompass a polymorphic family of receptors that recognize HLA class I molecules and have been implicated in self-tolerance. CD4 + CD28 null T-cell clones from patients with ACS and age-matched controls were compared for their KIR-expression profile. T-cell clones derived from the patients expressed a broader spectrum of KIRs ( P <0.001) with preference for the stimulatory variant, CD158j. Additionally, CD4 + T-cell clones from patients but not those from controls acquired de novo expression of the DAP12 molecule, an adapter chain that transmits CD158j-derived signals. Cumulative expression of CD158j and DAP12 endowed cytolytic competence on CD4 + CD28 null T cells, allowing them to kill in the absence of T-cell receptor triggering. Our data demonstrate that CD4 + CD28 null T cells in ACS are characterized by a unique gene expression profile. Consequently, these T cells acquire cytolytic capability that can bypass the need for T-cell receptor triggering and, thus, impose a threat to self-tolerance.
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“CD28− T cells are high producers for interferon-γ (IFN-γ), display cytotoxic functions and accumulate in inflammatory lesions [21–26].”
From T-cell aging in rheumatoid arthritis (2014) · cites this paper as [25]
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“They are highly resistant to apoptosis (Kovalcsik et al., 2015) and appear to accumulate in vulnerable coronary atherosclerotic plaques (Nakajima et al., 2003).”
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Backgroundon behalf of KIRIIND (KIR Infectious and Inflammatory Diseases) Collaborative Group, Tuttolomondo, A., Raimondo, D. D., Pecoraro, R., Casuccio, A., Bona, D. D., Aiello, A., Accardi, G., Arnao, V., Clemente, G., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1469-5 · Cited by 64
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“CD4+ CD28− KIR+ T cells are frequently detected in patients with acute coronary syndrome or rheumatoid arthritis [21, 22].”
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“Moreover, they display an increased production of proinflammatory cytokines (33, 36‐38) as well as cytotoxic capacity (37, 39, 40 ) raising the hypothesis that the expansion of CD4 C CD28 null T cells found in such diseases may have a pathogenic role in the development of these disorders (31, 35).”
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“…their clonal expansion, their accumulation in unstable plaques, their bias towards producing large amounts of IFN-γ, and their cytotoxic ability (Liuzzo et al., 1999; Liuzzo et al., 2000; Liuzzo et al., 2001; Nakajima et al., 2002; Nakajima et al., 2003; Pryshchep et al., 2006; Sato et al., 2006).”
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“…antigens to T-cells (DCs) 4, 6-8 , foam cell formation by taking up lipids (macrophages, SMCs, DCs) 9 , proinflammatory cytokine production (macrophages, T-cells) 3, 10-12 , fibrous cap formation (SMCs), cytotoxicity (T-cells) 13-15 , and extracellular matrix degradation (macrophages) 4 .”
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“In contrast, CD28 T cells are also reported to act independently of antigen recognition (22,47).”
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“Other studies were proposed to characterize specific T-cell subsets in different settings, such as investigating cytotoxic T-cells function in peripheral blood of ACS patients, [81], culturing T-cells stimulated with plaque homogenates supplemented with different growth factors [80], or evaluating T-lymphocytes infilt…”
BackgroundEpigenetic mechanisms of age-dependent KIR2DL4 expression in T cells
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“Stimulatory KIRs have been implicated in a number of autoimmune diseases such as rheumatoid vasculitis, type I diabetes, and psoriatic arthritis [2, 31, 32] and also in tissue-injurious, inflammatory responses such as atherosclerosis [ 33 ].”
BackgroundSelf-citationAge as a risk factor in vasculitis
Gloor, A. D., Berry, G. J., Goronzy, J. J., & Weyand, C. M. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00911-1 · Cited by 44
“cytotoxicity against endothelial cells [61].”
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Yadav, A. K., & Jha, V. (2011) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfr010 · Cited by 38
“Despite the loss of CD28, these cells remain functionally active and have the ability to release cytokines even in the absence of costimulatory pathway activation [17,18].”
BackgroundNeopterin, CD4+CD28− lymphocytes and the extent and severity of coronary artery disease
Alber, H. F., Duftner, C., Wanitschek, M. M., Dörler, J., Schirmer, M., Suessenbacher, A., Frick, M., Dichtl, W., Pachinger, O. M., & Weidinger, F. F. (2008) · International Journal of Cardiology · doi:10.1016/j.ijcard.2008.03.010 · Cited by 37
“This is probably due to the additional role of these cells in plaque destabilization by having cytolytic functions [45] and apoptotic effects on vascular wall cells[46], which may explain their more evident elevation in unstable angina.”
BackgroundZal, B., Kaski, J. C., Akiyu, J. P., Cole, D., Arno, G., Poloniecki, J. D., Madrigal, J. A., Dodi, A. I., & BABOONIAN, C. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.8.5233 · Cited by 36
“Although a previous report has described this phenomenon in redirected cytotoxicity assays (9), this is the first substantive evidence that cells presenting a specific autologous Ag are targeted by these 2DS2 2DL2 2DL3 T lymphocytes.”
BackgroundResultInfluentialStem cell aging and autoimmunity in rheumatoid arthritis
Weyand, C. M., & Goronzy, J. J. (2004) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2004.07.006 · Cited by 35
Self-citationPalma, R. D., Cirillo, P. L., Ciccarelli, G., Barra, G., Conte, S., Pellegrino, G., Pasquale, G. D., Nassa, G., Pacifico, F., Leonardi, A., et al. (2016) · International Journal of Cardiology · doi:10.1016/j.ijcard.2016.04.177 · Cited by 33
Biswas, M., Suvarna, R., Vimal Krishnan, S., Devasia, T., Belle, V. S., & Prabhu, K. (2022) · F1000Research · doi:10.12688/f1000research.123245.1 · Cited by 31
“The study further reported de novo expression of DAP12 (adapter chain transmitting CD158j signals which activates MAPK [mitogen activated protein kinase] cascade) in CD4 T cells of patients, thus furnishing chronic cytolytic stimulation and competence of CD4CD28 T cells even in absence of exogenous antigen mediated T…”
BackgroundKiller cells in atherosclerosis
Kyaw, T. S., Tipping, P. G., Toh, B., & Bobik, A. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.05.009 · Cited by 30
Local and Systemic Cellular Immunity in Early Renal Artery Atherosclerosis
Kotliar, C., Juncos, L. I., Inserra, F., de Cavanagh, E. M. V., Chuluyán, E., Aquino, J. B., Hita, A., Navari, C., & Sanchez, R. A. (2011) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.06270611 · Cited by 29
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Öztaş, E., Özler, S., Tokmak, A., Yılmaz, N., Çelik, H. T., Kazancı, F. H., Danışman, N., Ergin, M., & Yakut, H. İ. (2016) · European Journal of Obstetrics & Gynecology and Reproductive Biology · doi:10.1016/j.ejogrb.2016.01.009 · Cited by 25
“diseases including acute coronary syndromes [29,30].”
Immunosuppression in Atherosclerosis
Goronzy, J. J., & Weyand, C. M. (2006) · Circulation · doi:10.1161/circulationaha.106.656751 · Cited by 25
Self-citationThe tortoise and the hare: slowly evolving T‐cell responses take hastily evolving KIR
van Bergen, J., & Koning, F. (2010) · Immunology · doi:10.1111/j.1365-2567.2010.03337.x · Cited by 24
Xu, R., Cao, M., Wu, X., Wang, X., Ruan, L., Quan, X., Lü, C., He, W., & Zhang, C. (2011) · Clinical Immunology · doi:10.1016/j.clim.2011.10.009 · Cited by 23
Two opposite signaling outputs are driven by the KIR2DL1 receptor in human CD4+ T cells
Fourmentraux-Neves, E., Jalil, A., Rocha, S. D., Pichon, C., Chouaı̈b, S., Bismuth, G., & Caignard, A. (2008) · Blood · doi:10.1182/blood-2007-12-127779 · Cited by 23
Zhao, T. V., Hu, Z., Ohtsuki, S., Jin, K., Wu, B., Berry, G. J., Frye, R. L., Goronzy, J. J., & Weyand, C. M. (2022) · Nature Cardiovascular Research · doi:10.1038/s44161-022-00096-8 · Cited by 22
Self-citationCan We Talk about CD4+CD28– Lymphocytes as a Risk Factor for Ischemic Stroke?
Nowik, M., Nowacki, P., Grabarek, J., Drechsler, H., Białecka, M. A., Widecka, K., Stankiewicz, J., & Safranow, K. (2007) · European Neurology · doi:10.1159/000102163 · Cited by 22
“It is also known that CD4+CD28– lymphocytes are capable of an immediate reaction upon contact with antigen [ ,”
BackgroundExcess recurrent cardiac events in rheumatoid arthritis patients with acute coronary syndrome
Douglas, K., Pace, A. V., Treharne, G. J., Saratzis, A. N., Nightingale, P., Erb, N., Banks, M., & Kitas, G. D. (2006) · PubMed Central · Cited by 22
Characteristics of Expanded CD4+CD28nullT Cells in Patients with Chronic Hepatitis B
Wang, Y., Bai, J., Li, F., Wang, H., Fu, X., Zhao, T., Xu, W., Zhang, J., Ni, B., & Wu, Y. (2009) · Immunological Investigations · doi:10.1080/08820130902943105 · Cited by 20
Chronic autoimmune-mediated inflammation: a senescent immune response to injury
Hart, B. A. ‘., Chalan, P., Koopman, G., & Boots, A. M. H. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.11.010 · Cited by 20
Immunomodulation and vaccination for atherosclerosis
Zhou, X., & Hansson, G. K. (2004) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.4.4.599 · Cited by 20
Cimmino, G., Conte, S., Morello, A., D’Elia, S., Marchese, V., & Golino, P. (2012) · Expert Review of Cardiovascular Therapy · doi:10.1586/erc.12.157 · Cited by 19
Cytotoxic CD4+ T cells: origin, biological functions, diseases and therapeutic targets
Lai, L., Ran, S., Li, Y., Cui, J., Zhang, X., Yu, J., Zou, Y., Cheng, Z., Xia, J., & Wu, J. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02533-z · Cited by 24
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Targets of Immune Regeneration in Rheumatoid Arthritis
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Self-citationCytomegalovirus in Plasma of Acute Coronary Syndrome Patients
Nikitskaya, E., Grivel, J., Maryukhnich, E., Lebedeva, А., Ivanova, O., Savvinova, P. P., Shpektor, A., Margolis, L. B., & Vasilieva, E. (2016) · Acta Naturae · doi:10.32607/20758251-2016-8-2-102-107 · Cited by 16
Remtoula, N., Bensussan, A., & Marie‐Cardine, A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.5.2767 · Cited by 16
“Similarly, KIR expression was reported on CD4 CD28 T cells from patients with acute coronary syndromes (ACS), with again a preference for the stimulatory variant CD158j (8).”
BackgroundRole of unusual CD4+ CD28− T cells in acute coronary syndrome
Sun, W., Zheng, L., & Huang, L. (2011) · Molecular Biology Reports · doi:10.1007/s11033-011-1103-9 · Cited by 14
“transduction, and mediate the cytotoxic effect and cytokine production [ 24 ].”
BackgroundBlood cytotoxic/inflammatory mediators in non‐eosinophilic asthma
Hodge, S. J., Hodge, G. L., Simpson, J. L., Yang, I. A., Upham, J. W., James, A., Gibson, P. G., & Reynolds, P. N. (2015) · Clinical & Experimental Allergy · doi:10.1111/cea.12634 · Cited by 13
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Distress and expression of natural killer receptors on lymphocytes
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Comprehensive approach to high-resolution KIR typing
Lebedeva, T., Ohashi, M., Zannelli, G., Cullen, R., & Yu, N. (2007) · Human Immunology · doi:10.1016/j.humimm.2007.07.002 · Cited by 12
Anti-Inflammatory Strategies for Plaque Stabilization after Acute Coronary Syndromes
Baruch, A., van Bruggen, N., Kim, J. B., & Lehrer‐Graiwer, J. (2013) · Current Atherosclerosis Reports · doi:10.1007/s11883-013-0327-7 · Cited by 12
Metadata
- Authors
- Nakajima, T., Goek, O., Zhang, X., Kopecky, S. L., Frye, R. L., Goronzy, J. J., & Weyand, C. M.
- Affiliations
- Mayo Clinic (US)
- From the Departments of Medicine (T.N., O.G., X.Z., S.L.K., R.L.F., J.J.G., C.M.W.) and Immunology (J.J.G., C.M.W.), Mayo Clinic, Rochester, Minn.
- Venue
- Circulation Research
- Published
- 2003-07-25
- Volume
- 93
- Issue
- 2
- Pages
- 106-113
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2114639295
- Cited by
- 127
- References
- 44
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 2 · 2017: 3 · 2016: 6 · 2015: 2 · 2014: 4 · 2013: 5 · 2012: 6
- FWCI
- 3.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mayo Foundation for Medical Education and Research (R01 AR42527, R01 AR41974)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL063919, R01 HL 63919)
- National Eye Institute (R01EY011916, R01 EY 11916)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR041974, R01 AR 41974, R01AR042527, R01AR42527)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- killer cell immunoglobulin-like receptors, CD4+CD28null T cells, acute coronary syndrome, DAP12, T cell cytotoxicity, atherosclerosis, self-tolerance, inflammatory cell infiltration
- MeSH terms
- Acute Disease, Aged, Arteriosclerosis, Cells, Cultured, Clone Cells, Coronary Disease, Cytotoxicity Tests, Immunologic, Female, Flow Cytometry, Multigene Family, Humans, Male, Membrane Proteins, Proteins, Receptors, Immunologic, T-Lymphocytes, Cytotoxic, Signal Transduction, CD4-Positive T-Lymphocytes, T-Lymphocyte Subsets, CD28 Antigens, Protein Isoforms, Adaptor Proteins, Signal Transducing, Receptors, KIR
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