mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-EOS-2910mimmun-2910Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESВлияние стрептококковой аргининдеиминазы на функциональную активность CD4+ и CD8+ популяций Т-лимфоцитов периферической крови человекаEffect of streptococcal arginine deiminase on the function of CD4+ and CD8+T lymphocytesСтариковаЭ. А.StarikovaE. A.

Старикова Э.А. – к.б.н., старший научный сотрудник отдела иммунологии; доцент кафедры иммунологии; доцент кафедрыклеточной биологии и гистологии, Институт медицинского образования

197376, Россия, Санкт-Петербург, ул. Акад. Павлова, 12

Тел.: 8 (812) 234-68-68

Starikova E.A., PhD (Biology), Senior Research Associate, Department of Immunology; Associate Professor, Department of Immunology; Associate Professor, Department of Cell Biology and Histology, Institute of Medical Education

12 Acad. Pavlov St St. Petersburg 197376 Russian Federation

Phone: +7 (812) 234-68-68

Starickova@yandex.ruМаммедоваДж. Т.MammedovaJ. T.

Маммедова Дж.Т. – научный сотрудник отдела иммунологии

Санкт-Петербург

Mammedova J.T., Research Associate, Department of Immunology

St. Petersburg

ОжигановаА.OzhiganovaA.

Ожиганова А. – младший научный сотрудник отдела иммунологии

Санкт-Петербург

Ozhiganova A., Junior Research Associate, Department of Immunology, Institute of Experimental Medicine

St. Petersburg

ЛебедеваА. М.LebedevaA. M.

Лебедева А.М. – к.б.н., научный сотрудник отдела иммунологии

Санкт-Петербург

Lebedeva A.M., PhD (Biology), Research Associate, Department of Immunology

St. Petersburg

ЛевешкоТ. А.LeveshkoT. A.

Левешко Т.А. – лаборант-исследователь отдела иммунологии

Санкт-Петербург

Leveshko T.A., Laboratory Assistant-Researcher, Department of Molecular Microbiology

St. Petersburg

БуроваЛ. А.BurovaL. A.

Бурова Л.А. – д.м.н., ведущий научный сотрудник отдела молекулярной микробиологии

Санкт-Петербург

Burova L.A., PhD, MD (Medicine), Leading Research Associate, Department of Molecular Microbiology

St. Petersburg

КудрявцевИ. В.KudryavtsevI. V.

Кудрявцев И.В. – к.б.н., заведующий лабораторией клеточной иммунологии отдела иммунологии; доцент кафедры иммунологии

Санкт-Петербург

Kudryavtsev I.V., PhD (Biology), Head, Laboratory of Cellular Immunology, Department of Immunology; Associate Professor, Department of Immunology

St. Petersburg

ФГБНУ «Институт экспериментальной медицины»; ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФ; Институт медицинского образования ФГБУ «Национальный медицинский исследовательский центр имени В.А. Алмазова» Министерства здравоохранения РФРоссияInstitute of Experimental Medicine; First St. Petersburg State I. Pavlov Medical University; Institute of Medical Education, V. Almazov National Medical Research CentreRussian FederationФГБНУ «Институт экспериментальной медицины»РоссияInstitute of Experimental MedicineRussian FederationФГБНУ «Институт экспериментальной медицины»; ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФРоссияInstitute of Experimental Medicine; First St. Petersburg State I. Pavlov Medical UniversityRussian Federation202413102023263503512Copyright © Старикова Э.А., Маммедова Д.Т., Ожиганова А., Лебедева А.М., Левешко Т.А., Бурова Л.А., Кудрявцев И.В., 20242024Старикова Э.А., Маммедова Д.Т., Ожиганова А., Лебедева А.М., Левешко Т.А., Бурова Л.А., Кудрявцев И.В.Starikova E.A., Mammedova J.T., Ozhiganova A., Lebedeva A.M., Leveshko T.A., Burova L.A., Kudryavtsev I.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2910

Метаболизм аргинина играет важную роль в регуляции функций клеток иммунной системы у млекопитающих. Патогенные микробы используют механизм истощения аргинина для подавления иммунного ответа при инфекции. Аргининдеиминаза – микробный аргинин-гидролизующий фермент, необходимый для выживания при низком рН в очаге инфекции или внутри фаголизосом, а также в условиях низкого содержания глюкозы. Влияние бактериальной аргининдеиминазы на функции клеток адаптивного иммунного ответа остается слабо изученным. Цель исследования состояла в изучении влияния стрептококковой аргининдеиминазы на пролиферацию и аутофагию CD4+ и CD8+ популяций Т-лимфоцитов периферической крови человека.

Действие фермента на клетки изучали с использованием супернатантов разрушенных ультразвуком Streptococcus pyogenes M49-16 и его изогенного мутанта с инактивированным геном arcA (Streptococcus pyogenes M49-16delarcA). Исследование проводили с использованием крови здоровых доноров. Фракцию мононуклеарных лейкоцитов выделяли путем центрифугирования на градиенте плотности Фиколла. Для оценки пролиферации использовали метод, основанный на окрашивании внутриклеточных белков прижизненным флуоресцентным красителем carboxyfluorescein succinimidyl ester (CFSE). Исследование уровня аутофагии в клетках проводили с использованием флуоресцентного красителя Lysotracker Green DND-26. Для анализа пролиферации и аутофагии Т-хелперов (CD3+CD4+) и цитотоксических Т-лимфоцитов (CD3+CD4-) клеточные суспензии, окрашивали антителами против CD4, CD45RA, и CD3. Долю клеток в состоянии некроза определяли путем их окрашивания флуоресцентным ДНК-связывающим красителем DAPI. Нормальность распределения оценивали тестом Шапиро–Уилка. Данные были проанализированы с использованием критерия Краскела–Уоллиса с последующим применением критерия Манна–Уитни для попарных сравнений и выражены в виде медианы и межквартильных диапазонов (Q0,25-Q0,75).

Сравнение эффектов супернатантов разрушенных стрептококков исходного и мутантного штаммов, которые отличались по экспрессии одного гена аргининдеиминазы, показало, что бактериальный фермент не оказывал влияния на функции неактивированных лимфоцитов. Однако стрептококковая аргининдеиминаза полностью подавляла стимулированную anti-CD2/CD3/CD28 антителами пролиферацию CD4+ и CD8+Т-лимфоцитов. Эти эффекты сопровождались снижением в клетках уровня аутофагии. В то же время аргининдеиминаза не обладала цитотоксическими эффектами в отношении лимфоцитов. Введение супрафизиологических концентраций L-аргинина исследуемые восстанавливало клеточные функции. Различий между исследуемыми параметрами CD4+ и CD8+ популяций Т-лимфоцитов выявлено не было.

Полученные данные показывают, что антипролиферативное действие аргининдеиминазы может быть связано со способностью фермента ингибировать аутофагию и доказывают способность бактериального фермента подавлять адаптивные иммунные реакции организма-хозяина.

Arginine metabolism plays an important role in regulating the functions of immune cells in mammals. Pathogenic microbes use the mechanism of arginine depletion to suppress the immune response during infection. Arginine deiminase is a microbial arginine-hydrolyzing enzyme important for survival at low pH in the focus of infection, or in phagolysosomes, as well as under low-glucose conditions. The effect of bacterial arginine deiminase on the functions of adaptive immune cells remains poorly understood. The aim of our study was to evaluate the effect of streptococcal arginine deiminase on the proliferation and autophagy of CD4+ and CD8+ human peripheral blood T lymphocytes.

The enzyme effects were studied with supernates of ultrasonic lysates from parental Streptococcus pyogenes M49-16, and its isogenic mutant with inactivated arcA gene (Streptococcus pyogenes M49-16delarcA). The study was performed with blood samples of healthy donors. The fraction of mononuclear leukocytes was isolated by centrifugation in a Ficoll density gradient. To evaluate proliferation levels, a method based on the staining of intracellular proteins with vital fluorescent dye carboxyfluorescein succinimidyl ester (CFSE) was used. The level of autophagy was studied using the fluorescent Lysotracker Green DND-26 dye. To analyze the proliferation and autophagy of T helper cells (CD3+CD4+) and cytotoxic T lymphocytes (CD3+CD4-), the obtained cell suspensions were stained with antibodies against CD4, CD45RA, and CD3. The proportion of necrotic cells was determined by staining with a fluorescent DNA-binding DAPI dye. The normality of the distribution was assessed by Shapiro–Wilk test. The data were analyzed using Kruskal–Wallis criterion, followed by Mann–Whitney criterion for pairwise comparisons and expressed as median and interquartile ranges (Q0.25-Q0.75).

When comparing the effects of supernatants from the parental and mutant streptococcal strains, which differed in expression of arginine deiminase gene, we have shown that the bacterial enzyme had no effect on the functions of inactive lymphocytes. However, streptococcal arginine deiminase completely suppressed proliferation of CD4+ and CD8+T lymphocytes stimulated with anti-CD2/CD3/CD28 antibodies. These effects were accompanied by a decrease in the autophagy levels. At the same time, arginine deiminase did not exert cytotoxic effects upon lymphocytes. L-arginine applied at the doses exceeding physiological levels caused restoration of the cellular functions. There were no differences between the studied parameters of CD4+ and CD8+T lymphocyte subsets.

The obtained data show that the antiproliferative effect of arginine demimnase may be associated with ability of the enzyme to inhibit autophagy and confirm an opportunity of the bacterial enzyme to suppress host adaptive immune responses.

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The authors declare that there are no conflicts of interest present.