Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Ministry of Science and Higher Education of Russian Federation T regulatory lymphocytes (Treg) participate in resolution of inflammation and are essential in post-infarct myocardial healing. The crucial mediator of Treg activity is transcription factor FoxP3. Nuclear localization of FoxP3 is an obligatory requirement for anti-inflammatory properties of the cells. FoxP3 is also expressed in conventional T-lymphocytes at the stage of their activation. Data on functional state of FoxP3 in chronic and acute coronary syndromes are absent. Purpose Our aim was to comparatively evaluate the level of FoxP3 nuclear translocation in subpopulations of FoxP3+ T-lymphocytes in patients with chronic and acute coronary syndromes. Methods We have recruited 14 patients with chronic coronary syndrome (CCS) (8 males; 6 females; 63.2 ± 9.0 y.o.) and 5 patients with acute anterior ST-segment elevation myocardial infarction (STEMI) (4 males; 1 female; 61.4 ± 11.2 y.o.). Reperfusion of the infarct-related artery (IRA) has been achieved in all STEMI patients (the mean time of recanalization constituted 5 hours), and coronary angioplasty and IRA stenting were performed. Health status was evaluated and functional class of chronic heart failure was assessed according to the 6-minute walk test. Peripheral blood mononuclear cells were isolated from heparinized blood of CCS patients and STEMI patients during the first day after the event. Frequency of T regulatory and T conventional lymphocytes and degree of FoxP3 nuclear translocation in them were evaluated by imaging flow cytometry. Results Numbers of T regulatory lymphocytes in STEMI patients were lower than in patients with CCS, while numbers of T conventional lymphocytes were higher. However these differences did not reach the level of statistical significance: 7.2 (6.2; 8.4)% vs. 6.7 (3.8; 7.0)% of T regulatory lymphocytes (p = 0.298) and 1.6 (1.3; 1.8)% vs. 2.1 (1.0; 2.8)% of T conventional cells (p = 0.754), in CCS and in STEMI patients, respectively. Meanwhile, STEMI patients displayed significantly lower nuclear translocation of FoxP3 in lymphocytes compared to CCS patients: 74.8 (64.9; 92.9)% vs. 98.2 (96.8; 98.7)% in T regulatory cells (p = 0.026) and 58.7 (33.9; 67.7)% vs. 88.3 (73.1; 96.9)% in T conventional lymphocytes (p = 0.034). Conclusions Our study is the first one to comparatively describe the FoxP3 nuclear translocation in patients with chronic coronary syndrome and STEMI. We showed that STEMI is primarily associated with the decrease of nuclear localization of FoxP3 rather than with changes in numbers of FoxP3+ T-lymphocytes in peripheral blood. The revealed phenomenon demonstrates that alterations of the balance between the suppressive and inflammatory activities of T-lymphocytes are observed already in the early inflammatory phase of STEMI, long before their expected clonal expansion.

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The key cellular and molecular factors being involved in the resolution of inflammation following acute myocardial infarction remain poorly understood. T-regulatory (Treg) lymphocytes are characterized by the extreme potential to regulate the strength and direction of immune responses during the myocardial injury. The functional activity of Treg-lymphocytes depends upon the transcription factor forkhead box protein P3 (FoxP3). It may be also expressed in conventional T-lymphocytes at the stage of their activation. Nuclear localization of FoxP3 is a prerequisite factor determining its ability to impact the suppressive functions of Treglymphocytes.The aim of the present study was comparative evaluation of FoxP3+T-lymphocytes frequency and counts, combined with estimation of FoxP3 subcellular localization, in patients with acute myocardial infarction and chronic coronary syndrome and examination of changes of these parameters in the short-term follow-up of patients with myocardial infarction. The study included 14 patients with chronic coronary syndrome (8 males; 6 females; 63.2±9.0 y.o.) and 5 patients with acute anterior ST-segment elevation myocardial infarction (4 males; 1 female; 61.4±11.2 y.o.) at days 1, 3 and 7 after the event. The frequency of FoxP3+ conventional and regulatory T-lymphocytes was evaluated in peripheral blood mononuclear cells together with estimation of the level of FoxP3 nuclear localization by imaging flow cytometry.Patients with infarction were characterized by the decreased counts of FoxP3+Treg-lymphocytes compared to patients with chronic coronary syndrome, and exhibited even further decrease in the counts of FoxP3+Tregcells at day 7 after infarction, while frequency of Treg and conventional T-lymphocytes did not differ significantly. The level of FoxP3 nuclear translocation was lower both in Treg and conventional T-lymphocytes in patients at day 1 post-infarction compared to patients with chronic coronary syndrome. Absolute counts of FoxP3+Tregs with nuclear FoxP3 localization remained significantly lower both at days 1 and 7 post-infarction compared to patients with chronic coronary syndrome.Thus, here we demonstrated that FoxP3 nuclear localization experiences decrease in the course of acute myocardial infarction and may serve as a more sensitive marker of changes in Treg-lymphocyte functioning than simple evaluation of their frequency.