Immunity in Atherosclerosis: Focusing On T And B Cells Part 2
May 16, 2023
2.2. Circulating T-Cell Subpopulations
In patients with coronary artery disease, a lymphocyte subpopulation profile in the thoracic lymph nodes appeared to differ from the blood profile. This includes a higher share of B cells, a lower share of CD8+ T cells, a twice higher CD4/CD8 ratio, and CD4+CD69+ cell saturation, as well as Tregs [37,38]. In the peripheral blood of patients with cardiovascular diseases, a higher share of effector memory T cells (TEM cells or TEM) characterized as CD3+CD4+CD45RA−CD45RO+CCR7− were found, which relate to the degree of atherosclerotic lesions in the coronary and brain carotid regions [39]. In comparison with these results, other studies have demonstrated a CCR7− T cell elevation in patients with coronary artery disease [40], and T cell memory increase in patients with subclinical carotid atherosclerosis [41].
There is a complex interplay between coronary artery disease and immunity. On the one hand, an abnormal response of the immune system may lead to the development of coronary artery disease. For example, in patients with autoimmune diseases (such as rheumatoid arthritis, systemic lupus erythematosus, etc.), the immune system may attack the walls of blood vessels, causing vasculitis and hardening of the arteries. On the other hand, coronary artery disease itself can also affect the immune system. Studies have shown that the immune system may be abnormal in patients with coronary artery disease, manifested as immune dysregulation and inflammation. In addition, the interaction of viral infection and the immune system may also influence the development of coronary artery disease.
For example, influenza virus infection may lead to increased inflammation in the body, accelerating arteriosclerosis and thrombosis. Conversely, strengthening the immune system may help prevent the development of coronary artery disease. Several studies have shown that consistent physical activity and a healthy diet can boost the immune system and reduce the risk of coronary artery disease. Taken together, there is a two-way effect between the immune system and coronary artery disease, and further research is needed to deepen our understanding of this relationship. At the same time, we see the importance of immunity, so we need to pay attention to the improvement of immunity in daily life. Cistanche can significantly improve immunity. Cistanche is rich in various antioxidant substances, such as vitamin C, carotenoids, etc. These ingredients can scavenge free radicals, reduce oxidative stress, and improve the resistance of the immune system.
TEM appeared as a subset of T cells with the strongest bond with atherosclerosis in carotid and coronary vessels at various disease phases. An essential correlation was spotted between TEM and total plasma cholesterol, as well as LDL cholesterol. Despite the link between TEM and carotid artery atherosclerosis, there was no dependence on the classical cardiovascular risk factors, which proves the validity of the adaptive immune response in cardiovascular disorders [42]. After the removal of the antigen that triggered the immune response, TEM cells and central memory T cells (TCM) are stored in the memory pool. They store the memory of (1) antigen specificity, (2) the whole range of cytokines they have produced, and (3) the site where their effector function is required. With repeated exposure to the TEM antigen in inflamed peripheral tissues (in this particular case an atherosclerotic plaque), it quickly shows effector effects. This is mainly due to the CCR5 and CXCR3 expression [43].
HLA-DR expression is a sign of effector function, and some studies have shown an elevation in activated HLA-DR+ T cells in patients with coronary heart disease [44]. It was found that Th1 cells are more common in the blood of patients suffering from acute coronary syndrome [45]. However, it remains to be revealed whether this represents an acute reaction to myocardial injury or an underlying CAD. It was also found that a subset of INF-γ-secreting Th17 cells, specifically Th1/Th17 cells, is caused by the progression of ACS, which proves the significance of IFN-γ in atherosclerosis [11].
Although Th17 was linked with a high-risk level of cardiovascular disease, this association turned out to be inconsistent [24]. Recent studies have shown a negative correlation between circulating Th2 cells, the thickness of the common medium carotid intima (IMT), and the cardiovascular events threat, as well as a negative bond between the number of Th1 cells and the progression of complications associated with atherosclerosis [46]. Over the ACS period, the traditional immunological synapse mediated by antigen–TCR involvement (signal 1) and co-stimulatory receptors such as CD28 (signal 2) is the circulation of unsound T cells [47].
Essentially, CD3+CD4+TCR zeta-dim, a subset of T cells with reduced levels of the TCR zeta subunit, also referred to as CD247, binds the involved TCR-CD3 complex to downstream intracellular signal transduction pathways. Patients with ACS have been shown to have higher levels of CD4+CD28null T cells [48]. Notably, an association was found between higher circulating levels of CD4+CD28null cells and a poor prognosis in ACS relapse. TCR zeta and CD28 chain regulation lowering usually happens following antigen involvement or in reaction to inflammatory stimuli as a feedback mechanism aimed at setting the immune response [11].
Whereas intact TCR signaling is highly important for upholding immune homeostasis through the generation and functioning of regulatory T cell subsets, changes in signal pathways can lead to an increase in TCR zeta-dim T cells. These can weaken modulator feedback signals, thereby potentially limiting the sensitivity of CD4+CD28null T cells to suppression. TCR zeta-dim T cells and CD4+CD28null T cells can react to stimuli isolated from the antigen-mediated TCR pathway [49]. In addition, human circulating or intraplaque CD4+CD28null T cells from patients with ACS exhibit IL-12 receptors even when antigen stimulation is deficient. This increases the expression of the CCR5 chemokine receptor CD161 and the C-type lectin receptor CD161, which are involved in the regulation of the tissue homing of effector T cells after IL-12 stimulation.
Therefore, CD4+CD28null T cells could function like NK cells with anti-inflammatory activity, even in the irreconcilable state of enlarged tissue trafficking and homing after an IL-12-inducing host infection connected with accrual in inflammatory lesions. Therefore, it is generally assumed that both antigen-dependent and autonomous mechanisms are crucial for obtaining responses in subsets of memory T cells with CD28 and/or TCR zeta-chain defects, thus contributing to the pro-inflammatory and pro-atherosclerotic response [50].
During atherogenesis, adaptive immunity has both stimulating and suppressive effects on plaques [51]. As for the anti-inflammatory or anti-atherosclerotic side of T-cell function, analysis of circulating Tregs gave contrary results. ACS patients have lower levels of CD4+CD25+ forkhead box protein 3 (FoxP3+ ) circulating in T cells, and Tregs detached from the blood of the same patients showed a lowered ability to suppress oxLDL-induced CD4+CD25 proliferation [31].
However, in patients with stable CAD, no significant association with the spread of atherosclerotic disease was detected. No link between the stable degree and progression of CAD and the levels of circulating Tregs, designated as CD4+CD25hiCD127lo, was shown. This proved an association between an ST-elevation myocardial infarction (STEMI) T and a high level of Tregs [33].
More distinctly, inflammatory activation in ST-elevation myocardial infarction (STEMI), confirmed by elevated IL-6, can explain the proportional compensatory balance of Treg, similar to the observed elevation in IL-10 [52].
On the contrary, patients with acute coronary syndrome have shown a decrease in the level of Tregs circulating without elevation of ST levels [33]. Ultimately, since CCR5 not only controls effector T cells but also directs Tregs and moves them into inflamed nonlymphoid tissue, assuming that CCR5+ Tregs constitute a subgroup of ‘effector’ Tregs cells, the levels of circulating CCR5+ Tregs were evaluated in both subclinical carotid artery patients and patients with CAD. The tricky role of Tregs in atherosclerosis is currently being studied. This is proved by new data on the atheroprotective role of this subset of T cells, as acquired in mouse models [53].
3. B-Cells
T cells’ role in atherosclerosis has been studied for decades, but B cells have only recently become an object of curiosity. Hints of B cell involvement in the pathogenesis of atherosclerotic lesions were observed during animal studies [54]. However, lately, such hints also began to appear in humans. Along with the whole blood gene expression profiles of Framingham Heart Study participants, a network integrative data analysis of genomewide linkage studies showed the presence of B-cell immune responses as provocative factors for coronary artery disease [55].
Unlike T cells, just a small amount of B cells can be found locally in atheroma. At the same time, a multitude of B cells could be detected in the atherosclerotic vessels' adventitial layer, where they exhibit a structural organization close to the tertiary lymphoid organ, which is associated with the presence of a chronic immune response [56].
It was found that, in atherosclerotic lesions, B cells are oligoclonal and undergo antigenic proliferation [11]. Being Th cell-dependent, the antigen-driven B-cell response slows down and leads to the formation of high-affinity antibodies which are exposed to class switching.
The whole process happens in structures of special purpose inside the lymphoid organs—the germinal centers. It has been shown that a specific subset of Th cells or T follicular helper cells (Tfh) is responsible for the location of the germ center, as well as for supplying B cells with the assistance necessary for the proliferation and maturation of affinity [57]. It was established that the Tfh cells do not express fewer cytokines; they also provide a diversity of surface receptors, such as CD40L (CD154) or OX-40, in comparison to other subsets of Th cells [14]. Research on the subject of Tfh cells and their role in atherosclerosis is still ongoing. The B cells liable for this type of response emerge from the bone marrow and are referred to as B2 cells [58].
The antibodies secreted by B cells include all classes of human immunoglobulins (Ig), i.e., IgM, IgG, IgE, and IgA. In the blood serum of patients with atherosclerosis, IgG antibodies directed against oxidation-specific epitopes can easily be found (in particular, the aldehyde-modified peptide sequences of apolipoprotein B-100) [59]. It has also been revealed that self-reactive IgG against transhelin (TAGLN), a cytoskeletal protein, is secreted by B2 cells located in carotid artery plaques [60]. It is noteworthy that these antibodies cross-react with the antigenic determinants of the bacterial wall of gram-negative bacteria related to the Enterobacteriaceae family, which again indicates the infection’s possible role in atherosclerosis promotion [61].
Additional studies are being conducted to further understand the role of the connection with the cardiovascular risk of IgG and IgM against oxidation-specific epitopes (OSEs) and other antigens that can be detected in atherosclerotic plaques. Experimental studies have revealed that, in addition to the production of atherogenic antibodies in B2 cells, they can aggravate atherogenesis. This is due to antibody-independent mechanisms that enhance the effect of pro-inflammatory cytokines [62].
Immunoglobulin IgA can be detected on mucous membrane surfaces, where it contributes to the major defense line against pathogens at reduced levels of concentration within the circulation. Despite the lack of data regarding the role of IgA in atherosclerosis, there may be a link between high serum IgA titers and progressive vascular diseases, as well as myocardial infarction. So far, no mechanism has been proposed to clarify this relationship. However, the latest information on the role of the gut microbiome in cardiovascular diseases provides new insights into the role of IgA in atherosclerosis [63].
In addition to B2 cells, a small subset of B1 cells also exists. It consists of long-lived, non-circulating cells that are mostly detected in the spleen, peritoneum, or pleural cavity [64]. These cells secrete poorly specific natural IgM antibodies, creating a rapid and T-cell-independent humoral response. Secreted B1 antibodies are polyreactive and are the main defense against pathogens. Natural IgM antibodies represent an essential ratio of IgM in noninfected humans, and up to 30% of them are targeted particularly against OSEs [65]. Some clinical studies have demonstrated that the titers of such naturally occurring oxidation-specific antibody IgMs correlate, on the contrary, with atherosclerotic load, which is estimated by carotid BMI [66], as well as with the risk of stroke and acute myocardial infarction. The atheroprotective mechanism of natural IgMs has yet to be determined. However, some experimental studies have demonstrated that these antibodies inhibit the internalization of ox-LDL by macrophages and restrain the storage of apoptotic cells by enhancing efferocytosis.
4. T-Cell Based Therapy
Various compounds have been shown to regulate Tregs and thus have efficacy in the treatment of atherosclerosis in animal models. Data on several of the most investigated drugs are summarized in Table 1. Therefore, pharmacological regulation of the numbers and immunosuppressive activity of Tregs may provide valuable treatment options for atherosclerotic diseases.
Atherosclerosis treatment options involving antibodies and cytokines are of particular interest. IL-2 stimulates the proliferation and differentiation of T cells and Treg effectors. However, low doses of IL-2 give a strong result in the atherosclerosis treatment, due to the selective expansion of Tregs with essential sensitivity to IL-2. This method was, for example, used in the clinical treatment of systemic lupus erythematosus [75]. Administration of antibodies (both oral and intravenous) against CD3 suppresses atherogenesis and the possible development of atherosclerotic plaques, causing Tregs expansion and decreasing the number of CD4+ T cells in mice [76]. Successful suppression of atherosclerosis is also possible with treatment using anti-CD3 antibodies and the IL-2 complex [76]. Integrin αvβ8 mediates TGF-β activation. Thereby, manipulation of the avß8 integrin can modulate Trg function to interrupt atherosclerotic disease mediated by effector T cells [77]. G-CSF (granulocyte colony-stimulating factor) modifies immunity and enhances immune diseases in animals, elevates the amount of Tregs and IL-10, and lowers IFN-γ levels in ApoE−/− mice [78].
In atherosclerosis, physical therapy can play a protective role. As an illustration, ultraviolet B radiation weakens the development of atherosclerosis in mice that are inclined to atherosclerosis, due to the increased function of Tregs and the regulation of the effector response of T cells [79].
5. B-Cell Based Therapy
5.1. Rituximab
It is widely thought that rituximab eliminates B-lymphocytes; potentially through complement-dependent and antibody-dependent cell cytotoxicity and induction of B-cell apoptosis. Recent studies examining the influence of rituximab on the cardiovascular system are not extensive. Hypothetically, selective suppression of the effect of B2 cells on the vascular wall of patients with rheumatoid arthritis can be the endpoint of endothelial dysfunction and atherosclerosis prevention. A couple of experimental reports have been published on the positive effect of rituximab on the lipid profile and early markers of atherosclerosis (enhancement of endothelial function) in patients with atherosclerosis [80].
Therefore, several findings suggest that, in incidents of productive lowering of rheumatoid arthritis activity, a lower index of atherogenicity and improved endothelial function are found. However, the rituximab effect on the promotion of atherosclerosis, and the corresponding cardiovascular events in patients with rheumatoid arthritis, requires further study [81,82].
It is assumed that statin therapy is a long-term strategy for primary and secondary prevention of cardiovascular diseases [83]. A five-year follow-up showed that the high-dose administration of statins, such as atorvastatin and simvastatin, can cause commensurable cardioprotective and hypolipidemic effects both in patients with rheumatoid arthritis and in the general population. Even though, at the initial stage, patients with rheumatoid arthritis had a lower total cholesterol level, it has been established that statin usage suspension for more than three months in patients with rheumatoid arthritis is caused by an elevated risk of myocardial infarction by 67% [84].
DREAM—the Dutch Rheumatoid Arthritis Monitoring study, provided evidence of a reduction in the effect of antiretroviral therapy while using concomitantly with statins. After six months, patients with rheumatoid arthritis who received combined statins and rituximab (n = 23) had a higher DAS28 score, in contrast to patients who did not take statins (control group, n = 64), adjusted for gender, baseline DAS28 level, and rheumatoid factor positivity [85]. Compared to the control group, the period of usefulness of rituximab in patients receiving statins was shorter—seven months as opposed to nine months. This study points to the need for limiting the concomitant treatment with statins and rituximab in patients with rheumatoid arthritis. Treatment of patients suffering from lymphoma gave the opposite results. For almost four years, the use of antiretroviral therapy and statins equally did not hurt clinical outcomes. Statins’ influence on the effectiveness of rituximab is a clinical problem, and confirmation of its prognostic importance requires further studies [86].
5.2. Modulating B-Cell Receptor Signaling
BCR signaling plays a significant role in the control of B cell activation, proliferation, and differentiation. Therefore, strict regulation by costimulatory receptors is required. Ibrutinib is used for cancer therapy and suppresses Bruton tyrosine kinase (Btk) below the BCR. As another option, BCR signaling can be negatively regulated by using mAb epratuzumab, which activates the CD22 inhibitory receptor. Originally, Epratuzumab was created to treat systemic red lupus [87]. Currently, there is no preclinical data on the significance of these factors in the formation of atherosclerosis. Since the specificity of BCR and the power of the BCR signal are crucial for determining decisions about the fate of B cell development, drugs modulating the BCR signal can affect the distribution of subsets of B cells, which in turn can affect atherogenesis. We recently demonstrated that low-dose treatment with ibrutinib leads to margin zone lowering and is linked with an increase in the number of FOB cells [88]. Therefore, it seems that powerful BCR signaling promotes the development of marginal zone (MZ) B cells. Therapeutic modulation of BCR signaling can guide the differentiation of B2 cells towards the atheroprotective B cell fate.
It has also recently been reported that MZB cells have thermal protective activity. Using a genetic model of MZB cell deficiency, it has been shown that the role of MZB in the negative regulation of proatherogenic TFH cells, via the PDL1 (programmed cell death ligand 1) axis, programs cell death 1 [89]. Before this, it was assumed that a potential atheroprotective role might appear through the secretion of OSE-specific antibodies. However, the contribution of B cells could not be excluded. It is interesting to study the additional effect of BSR signaling on subsets of B cells and atherosclerosis in patients undergoing BSR-modulating therapy. Clinically, ibrutinib is linked with a high risk of atrial fibrillation and hypertension [90].
5.3. Targeting B-Cell Costimulation and Immune Checkpoint Inhibitors
The synergy between B and T cells is vital for adaptive immunity. B cells provide antigens and send costimulatory signals to T cells. The two most notable methods have been extensively investigated in experimental atherosclerosis: CD40-CD40L dyad and CD80/CD86-CD28/ CTLA4 system (cytotoxic T-lymphocyte-associated protein). Preclinical studies of CD40 or CD40L deficiency indicate predominantly proatherogenic functions of this dyad [91]. However, it has been hypothesized that T-cell and CD40-dependent B-cell responses are proatherogenic circulating CD40+ B cells correlated with a reduced risk of stroke, which may be related to the importance of CD40 in Breg differentiation. Although CD40/CD40L inhibitors have a powerful anti-inflammatory effect in preclinical studies, their clinical use has been complicated by severe side effects. CD80 and CD86 on B cells interact with both the CD28 costimulatory receptor and the CTLA4 inhibitory receptor on T cells [92]
Since CD86 generates the induction of Th1 immunity, experimental studies suggest a predominantly proatherogenic function of CD80/CD86,75,76. At the same time, CD86+ B cell levels correlate with the degree of stenosis and the frequency of stroke in humans. However, CD80/CD86 signaling is also potentially required for the induction of atheroprotective regulatory T cells. For the treatment of rheumatoid arthritis, the CTLA4Ig (abatacept) design was approved, preventing CD80/CD86 from interacting with CD28 and activating T cells. Despite the positive effect of CVD on cardiovascular parameters in preclinical studies, cardiovascular parameters have not been evaluated in clinical trials [93].
In contrast, many cell types, which include antigen-presenting cells and tumor cells, express T-cell-inhibiting ligands. They target immune checkpoint inhibitors (ICIs), which are often used in cancer therapy. ISCs are clinically approved; they target programmed cell death 1 (nivolumab, pembrolizumab), PD L1 (atezolizumab, durvalumab, and nivolumab), and CTLA4 (ipilimumab). However, they have potentially detrimental effects on cardiovascular disease, and cardiovascular adverse events have been reported [94].
Interestingly, high T cell activity after checkpoint suppression could also contribute to T cell-mediated effects on B cells. Elevated B cell activation and plasmablast levels have been reported in patients treated with immune checkpoint inhibition (ICI), which carries an increased risk of immune-related side effects. Even though ICI has possible proatherogenic effects, most likely through its effect on T cells, consequential effects on B cells should not be missed [95].
6. Conclusions
Atherosclerosis is the leading contributor to mortality rates worldwide. The most important components of the pathogenesis of atherosclerosis are, without doubt, lipid metabolism alterations and inflammation. When considering inflammation, the crucial role is played by immune cells, of which T and B cells must be noted. The impact of T cells is well-studied, especially in contrast to B cells, which became a topic of interest relatively recently. This may be explained by the low level of B cells in the atheroma itself—T cells are presented there in all their diversity.
Special research interest lies in the scope of therapeutic targeting. Various approaches have proven their effectiveness in atheroprotection via T cells, especially Tregs regulation. Such approaches include the use of well-known drugs, antibodies, and cytokine treatment, as well as ultraviolet B radiation. When considering B cells as a target, rituximab seems both interesting and promising.
Author Contributions:
Writing—original draft preparation, A.V.P.; writing—review and editing, A.N.O., E.E.B., A.V.S., T.V.P. All authors have read and agreed to the published version of the manuscript.
Funding:
This research was funded by the Russian Science Foundation, grant number 18-15-00254.
Institutional Review Board Statement:
Not applicable.
Informed Consent Statement:
Not applicable.
Conflicts of Interest:
The authors declare no conflict of interest.
References
1. Virani, S.S.; Alonso, A.; Aparicio, H.J.; Benjamin, E.J.; Bittencourt, M.S.; Callaway, C.W.; Carson, A.P.; Chamberlain, A.M.; Cheng, S.; Delling, F.N.; et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation 2021, 143, e254–e743. [CrossRef] [PubMed]
2. Tokgozoglu, L.; Hekimsoy, V.; Costabile, G.; Calabrese, I.; Riccardi, G. Diet, Lifestyle, Smoking. In Handbook of Experimental Pharmacology; Springer: Berlin/Heidelberg, Germany, 2020. [CrossRef]
3. Anand, S.S.; Hawkes, C.; de Souza, R.J.; Mente, A.; Dehghan, M.; Nugent, R.; Zulyniak, M.A.; Weis, T.; Bernstein, A.M.; Krauss, R.M.; et al. Food Consumption and Its Impact on Cardiovascular Disease: Importance of Solutions Focused on the Globalized Food System: A Report From the Workshop Convened by the World Heart Federation. J. Am. Coll. Cardiol. 2015, 66, 1590–1614. [CrossRef]
4. Conti, P.; Shaik-Dasthagirisaeb, Y. Atherosclerosis: A chronic inflammatory disease mediated by mast cells. Cent. Eur. J. Immunol. 2015, 40, 380–386. [CrossRef]
5. Borén, J.; Chapman, M.J.; Krauss, R.M.; Packard, C.J.; Bentzon, J.F.; Binder, C.J.; Daemen, M.J.; Demer, L.L.; Hegele, R.A.; Nicholls, S.J.; et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: Pathophysiological, genetic, and therapeutic insights: A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 2020, 41, 2313–2330. [CrossRef] [PubMed]
6. Zhong, C.; Yang, X.; Feng, Y.; Yu, J. Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis. Front. Immunol. 2020, 11, 284. [CrossRef] [PubMed]
7. Herrero-Fernandez, B.; Gomez-Bris, R.; Somovilla-Crespo, B.; Gonzalez-Granado, J.M. Immunobiology of Atherosclerosis: A Complex Net of Interactions. Int. J. Mol. Sci. 2019, 20, 5293. [CrossRef]
8. Crux, N.B.; Elahi, S. Human Leukocyte Antigen (HLA) and Immune Regulation: How to Do Classical and Non-Classical HLA Alleles Modulate Immune Response to Human Immunodeficiency Virus and Hepatitis C Virus Infections? Front. Immunol. 2017, 8, 832. [CrossRef]
9. Pennock, N.D.; White, J.T.; Cross, E.W.; Cheney, E.E.; Tamburini, B.A.; Kedl, R.M. T cell responses: Naive to memory and everything in between. Adv. Physiol. Educ. 2013, 37, 273–283. [CrossRef]
10. van Duijn, J.; Kuiper, J.; Slütter, B. The many faces of CD8+ T cells in atherosclerosis. Curr. Opin. Lipidol. 2018, 29, 411–416. [CrossRef] [PubMed]
11. Ammirati, E.; Moroni, F.; Magnoni, M.; Camici, P.G. The role of T and B cells in human atherosclerosis and atherothrombosis. Clin. Exp. Immunol. 2015, 179, 173–187. [CrossRef]
12. Rhoads, J.P.; Major, A.S. How Oxidized Low-Density Lipoprotein Activates Inflammatory Responses. Crit. Rev. Immunol. 2018, 38, 333–342. [CrossRef]
13. Piñon-Esteban, P.; Núñez, L.; Moure, R.; Marrón-Liñares, G.M.; Flores-Rios, X.; Aldama-Lopez, G.; Salgado-Fernandez, J.; Calviño-Santos, R.; Rebollal-Leal, F.; Pan-Lizcano, R.; et al. Presence of bacterial DNA in thrombotic material of patients with myocardial infarction. Sci. Rep. 2020, 10, 16299. [CrossRef]
14. Cano, R.L.E.; Lopera, H.D.E. Introduction to T and B lymphocytes. In Autoimmunity: From Bench to Bedside [Internet]; Anaya, J.M., Shoenfeld, Y., Rojas-Villarraga, A., Levy, R.A., Cervera, R., Eds.; El Rosario University Press: Bogota, Colombia, 2013; Chapter 5. Available online: https://www.ncbi.nlm.nih.gov/books/NBK459471/ (accessed on 25 May 2021).
15. Szentes, V.; Gazdag, M.; Szokodi, I.; Dézsi, C.A. The Role of CXCR3 and Associated Chemokines in the Development of Atherosclerosis and During Myocardial Infarction. Front. Immunol. 2018, 9, 1932. [CrossRef] [PubMed]
16. Schäfer, S.; Zernecke, A. CD8+ T Cells in Atherosclerosis. Cells 2020, 10, 37. [CrossRef]
17. Lei, T.Y.; Ye, Y.Z.; Zhu, X.Q.; Smerin, D.; Gu, L.J.; Xiong, X.X.; Zhang, H.F.; Jian, Z.H. The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke. J. Neuroinflamm. 2021, 18, 25. [CrossRef] [PubMed]
18. Tabas, I.; Lichtman, A.H. Monocyte-Macrophages and T Cells in Atherosclerosis. Immunity 2017, 47, 621–634. [CrossRef]
19. Amemiya, K.; Dankmeyer, J.L.; Bearss, J.J.; Zeng, X.; Stonier, S.W.; Soffler, C.; Cote, C.K.; Welkos, S.L.; Fetterer, D.P.; Chance, T.B.; et al. Dysregulation of TNF-α and IFN-γ expression is a common host immune response in a chronically infected mouse model of melioidosis when comparing multiple human strains of Burkholderia pseudomallei. BMC Immunol. 2020, 21, 5. [CrossRef]
20. Wu, M.Y.; Li, C.J.; Hou, M.F.; Chu, P.Y. New Insights into the Role of Inflammation in the Pathogenesis of Atherosclerosis. Int. J. Mol. Sci. 2017, 18, 2034. [CrossRef]
21. Raphael, I.; Nalawade, S.; Eagar, T.N.; Forsthuber, T.G. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 2015, 74, 5–17. [CrossRef]
22. McLeod, O.; Silveira, A.; Valdes-Marquez, E.; Björkbacka, H.; Almgren, P.; Gertow, K.; Gådin, J.R.; Bäcklund, A.; Sennblad, B.; Baldassarre, D.; et al. Genetic loci on chromosome 5 are associated with circulating levels of interleukin-5 and eosinophil count in a European population with a high risk for cardiovascular disease. Cytokine 2016, 81, 1–9. [CrossRef]
23. Bax, L.; van der Graaf, Y.; Rabelink, A.J.; Algra, A.; Beutler, J.J.; Mali, W.P. SMART Study Group. Influence of atherosclerosis on age-related changes in renal size and function. Eur. J. Clin. Investig. 2003, 33, 34–40. [CrossRef]
24. Taleb, S.; Tedgui, A.; Mallat, Z. IL-17 and Th17 cells in atherosclerosis: Subtle and contextual roles. Arter. Thromb. Vasc. Biol. 2015, 35, 258–264. [CrossRef]
25. Fatkhullina, A.R.; Peshkova, I.O.; Koltsova, E.K. The Role of Cytokines in the Development of Atherosclerosis. Biochemistry 2016, 81, 1358–1370. [CrossRef]
26. Bano, A.; Pera, A.; Almoukayed, A.; Clarke, T.H.S.; Kirmani, S.; Davies, K.A.; Kern, F. CD28 null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection. F1000Research 2019, 8, 327. [CrossRef]
27. Dumitriu, I.E. The life (and death) of CD4+ CD28(null) T cells in inflammatory diseases. Immunology 2015, 146, 185–193. [CrossRef]
28. Simons, K.H.; de Jong, A.; Jukema, J.W.; de Vries, M.R.; Arens, R.; Quax, P.H.A. T cell co-stimulation and co-inhibition in cardiovascular disease: A double-edged sword. Nat. Rev. Cardiol. 2019, 16, 325–343. [CrossRef]
29. Xu, A.; Liu, Y.; Chen, W.; Wang, J.; Xue, Y.; Huang, F.; Rong, L.; Lin, J.; Liu, D.; Yan, M.; et al. TGF-β-Induced Regulatory T Cells Directly Suppress B Cell Responses through a Noncytotoxic Mechanism. J. Immunol. 2016, 196, 3631–3641. [CrossRef]
30. Rohm, I.; Atiskova, Y.; Drobnik, S.; Fritzenwanger, M.; Kretzschmar, D.; Pistulli, R.; Zanow, J.; Krönert, T.; Mall, G.; Figulla, H.R.; et al. Decreased regulatory T cells in vulnerable atherosclerotic lesions: Imbalance between pro- and anti-inflammatory cells in atherosclerosis. Mediat. Inflamm. 2015, 2015, 364710. [CrossRef]
31. Ou, H.X.; Guo, B.B.; Liu, Q.; Li, Y.K.; Yang, Z.; Feng, W.J.; Mo, Z.C. Regulatory T cells as a new therapeutic target for atherosclerosis. Acta Pharm. Sin. 2018, 39, 1249–1258. [CrossRef] 32. Li, F.; Guo, X.; Chen, S.Y. Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis. Front. Cardiovasc. Med. 2017, 4,
32. [CrossRef] [PubMed]
33. Foks, A.C.; Lichtman, A.H.; Kuiper, J. Treating atherosclerosis with regulatory T cells. Arter. Thromb. Vasc. Biol. 2015, 35, 280–287. [CrossRef]
34. Bayati, F.; Mohammadi, M.; Valadi, M.; Jamshidi, S.; Foma, A.M.; Sharif-Paghaleh, E. The Therapeutic Potential of Regulatory T Cells: Challenges and Opportunities. Front. Immunol. 2021, 11, 585819. [CrossRef]
35. Tse, K.; Tse, H.; Sidney, J.; Sette, A.; Ley, K. T cells in atherosclerosis. Int. Immunol. 2013, 25, 615–622. [CrossRef] [PubMed]
36. Wu, L.; Van Kaer, L. Natural killer T cells in health and disease. Front. Biosci. 2011, 3, 236–251. [CrossRef]
37. Kott, K.A.; Vernon, S.T.; Hansen, T.; de Dreu, M.; Das, S.K.; Powell, J.; Fazekas de St Groth, B.; Di Bartolo, B.A.; McGuire, H.M.; Figtree, G.A. Single-Cell Immune Profiling in Coronary Artery Disease: The Role of State-of-the-Art Immunophenotyping with Mass Cytometry in the Diagnosis of Atherosclerosis. J. Am. Heart Assoc. 2020, 9, e017759. [CrossRef]
38. Riazi Rad, F.; Ajdary, S.; Omranipour, R.; Alimohammadian, M.H.; Hassan, Z.M. Comparative analysis of CD4+ and CD8+ T cells in tumor tissues, lymph nodes and the peripheral blood from patients with breast cancer. Iran. Biomed. J. 2015, 19, 35–44. [CrossRef]
39. Rattik, S.; Engelbertsen, D.; Wigren, M.; Ljungcrantz, I.; Östling, G.; Persson, M.; Nordin Fredrikson, G.; Bengtsson, E.; Nilsson, J.; Björkbacka, H. Elevated circulating effector memory T cells but similar levels of regulatory T cells in patients with type 2 diabetes mellitus and cardiovascular disease. Diabetes Vasc. Dis. Res. 2019, 16, 270–280. [CrossRef]
40. Gencer, S.; Evans, B.R.; van der Vorst, E.P.C.; Döring, Y.; Weber, C. Inflammatory Chemokines in Atherosclerosis. Cells 2021, 10, 226. [CrossRef]
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