mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2019-4-669-688mimmun-1759Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESФЕНОТИПИЧЕСКИЕ И ФУНКЦИОНАЛЬНЫЕ ХАРАКТЕРИСТИКИ МИКРОВЕЗИКУЛ, ПРОДУЦИРУЕМЫХ NK-КЛЕТКАМИPHENOTYPIC AND FUNCTIONAL CHARACTERISTICS OF MICROVESICLES PRODUCED BY NATURAL KILLER CELLShttps://orcid.org/0000-0002-5749-2531СоколовД. И.SokolovD. I.

д.б.н., заведующий лабораторией межклеточных взаимодействий, отдел иммунологии и межклеточных взаимодействий; доцент

199034, Россия, Санкт-Петербург, Менделеевская линия, 3

Тел.: 8 (812) 323-75-45, 328-98-50Факс: 8 (812) 323-75-45

PhD, MD (Biology), Head, Cell Interactions Laboratory; Associate Professor

199034, Russian Federation, St. Petersburg, Mendeleevskaya line, 3

Phone: 7 (812) 323-75-45, 328-98-50Fax: 7 (812) 323-75-45

falcojugger@yandex.ruМарковаК. Л.MarkovaK. L.

младший научный сотрудник лаборатории межклеточных взаимодействий, отдел иммунологии и межклеточных взаимодействий

Санкт-Петербург

 

Junior Research Associate, Cell Interactions Laboratory, Department of Immunology and Cell Interactions

St. Petersburg

kseniyabelyakova129@gmail.comМихайловаВ. А.MikhailovaV. A.

к.б.н., старший научный сотрудник лаборатории межклеточных взаимодействий, отдел иммунологии и межклеточных взаимодействий; ассистент кафедры иммунологии

Санкт-Петербург

PhD (Biology), Senior Research Associate, Cell Interactions Laboratory, Department of Immunology and Cell Interactions; Assistant Professor,Department of Immunology

St. Petersburg

mva_spb@mail.ruВязьминаЛ. П.VyazminaL. P.

лаборант-исследователь лаборатории межклеточных взаимодействий, отдел иммунологии и межклеточных взаимодействий

Санкт-Петербург

Researcher, Cell Interactions Laboratory, Department of Immunology and Cell Interactions

St. Petersburg

larisa.viazmina@gmail.comМилютинаЮ. П.MilyutinaYu. P.

старший научный сотрудник лаборатории межклеточных взаимодействий, отдел иммунологии и межклеточных взаимодействий

Санкт-Петербург

Senior Research Associate, Cell Interactions Laboratory, Department of Immunology and Cell Interactions

St. Petersburg

milyutina1010@mail.ruКозыреваА. Р.KozyrevaA. R.

лаборант-исследователь лаборатории межклеточных взаимодействий, отдел иммунологии и межклеточных взаимодействий

Санкт-Петербург

researcher, Cell Interactions Laboratory, Department of Immunology and Cell Interactions

St. Petersburg

anastasiasheveleva075@gmail.comЖдановаА. А.ZhdanovaA. A.

младший научный сотрудник лаборатории межклеточных взаимодействий, отдел иммунологии и межклеточных взаимодействий

Санкт-Петербург

researcher, Cell Interactions Laboratory, Department of Immunology and Cell Interactions

St. Petersburg

annafiamma@yandex.ruМалыгинаД. А.MalyginaD. A.

младший научный сотрудник лаборатории межклеточных взаимодействий, отдел иммунологии и межклеточных взаимодействий

Санкт-Петербург

researcher, Cell Interactions Laboratory, Department of Immunology and Cell Interactions

St. Petersburg

malygina.darja@yandex.ruОнохинК. В.OnokhinK. V.

сотрудник кафедры цитологии и гистологии

Санкт-Петербург

Research Associate, Department of Cytology and Histology

St. Petersburg

 

kirya80x@gmail.comИвановаА. Н.IvanovaA. N.

научный сотрудник ресурсного научного центра «Развитие молекулярных и клеточных технологий»

Санкт-Петербург

Research Associate

St. Petersburg

alyx@bk.ruКореневскийА. В.KorenevskyA. V.

ведущий научный сотрудник лаборатории межклеточных взаимодействий, отдел иммунологии и межклеточных взаимодействий

Санкт-Петербург

Leading Research Associate, Cell Interactions Laboratory, Department of Immunology and Cell Interactions

St. Petersburg

a.korenevsky@yandex.ruСельковС. А.SelkovS. A.

д.м.н., профессор, руководитель отдела иммунологии и межклеточных взаимодействий; профессор

Санкт-Петербург

PhD, MD, Professor (Medicine), Head, Immunology and Cell Interactions Department; Professor

St. Petersburg

selkovsa@mail.ruФГБНУ "НИИ акушерства, гинекологии и репродуктологии им.Д.О.Отта", ГБОУ ВПО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФРоссияD. Ott Research Institute of Obstetrics, Gynecology and Reproductology, First St. Petersburg State I. Pavlov Medical UniversityRussian FederationФГБНУ «Научно-исследовательский институт акушерства, гинекологии и репродуктологии им. Д.О.Отта»РоссияD. Ott Research Institute of Obstetrics, Gynecology and ReproductologyRussian FederationФГБНУ «Научно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта»РоссияD. Ott Research Institute of Obstetrics, Gynecology and ReproductologRussian FederationФГБОУ ВО «Санкт-Петербургский государственный университет»РоссияSaint Petersburg State UniversityRussian FederationРесурсный научный центр «Развитие молекулярных и клеточных технологий» ФГБОУ ВО «Санкт-Петербургский государственный университет»РоссияResearch and resource center for Molecular and Cell Technologies, Saint Petersburg State UniversityRussian FederationФГБНУ «Научно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта», ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФРоссияD. Ott Research Institute of Obstetrics, Gynecology and Reproductolog, First St. Petersburg State I. Pavlov Medical UniversityRussian Federation201923082019214препринт669688Copyright © Соколов Д.И., Маркова К.Л., Михайлова В.А., Вязьмина Л.П., Милютина Ю.П., Козырева А.Р., Жданова А.А., Малыгина Д.А., Онохин К.В., Иванова А.Н., Кореневский А.В., Сельков С.А., 20192019Соколов Д.И., Маркова К.Л., Михайлова В.А., Вязьмина Л.П., Милютина Ю.П., Козырева А.Р., Жданова А.А., Малыгина Д.А., Онохин К.В., Иванова А.Н., Кореневский А.В., Сельков С.А.Sokolov D.I., Markova K.L., Mikhailova V.A., Vyazmina L.P., Milyutina Y.P., Kozyreva A.R., Zhdanova A.A., Malygina D.A., Onokhin K.V., Ivanova A.N., Korenevsky A.V., Selkov S.A.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/1759

Среди множества клеток-источников микровезикул (МВ) особый интерес представляют естественные киллеры (NK-клетки) - субпопуляция лимфоцитов, осуществляющая контактный цитолиз вирус-инфицированных и опухолевых клеток. Каждая из популяций NK-клеток обладает уникальным репертуаром рецепторов на своей поверхности, а, следовательно, и функциями. Функционирование NK-клеток регулируется широким диапазоном активирующих и ингибирующих рецепторов, которые экспрессируются на их поверхности. Экзоцитоз содержимого литических гранул при контакте с клеткой мишенью – самый распространённый механизм цитолиза мишени NK-клетками. В настоящее время имеются косвенные данные о способности NK-клеток продуцировать МВ, так как такие МВ с фенотипом CD56, а также МВ лейкоцитарного происхождения с различным фенотипом обнаружены в плазме периферической крови. Целью настоящего исследования явилось изучение фенотипа, состава и функциональной активности микровезикул, образуемых NK-клетками. Сравнительный анализ спонтанной экспрессии рецепторов при помощи проточной цитофлуориметрии показал, что МВ, как и клетки-источники (NK-клетки линии NK-92), обладают сходным профилем экспрессии молекул CD56 и CD16, но отличаются более выраженной экспрессией CD119 и CD11b и менее выраженной экспрессией CD18. Культивирование клеток линии NK-92 в присутствии индукторов (TNFα, IL-1β, IFNγ, PMA) приводило к изменению фенотипа как самих клеток, так и МВ, образуемых ими. По данным проведенного WesternBlot Analisis в присутствии указанных индукторов также изменялось содержание перфорина и гранзима B (GrB) в составе МВ. Анализ цитотоксической активности клеток линии NK-92 в отношении клеток линии K562 показал, что МВ, полученные от активированных TNFα клеток линии NK-92 повышают цитотоксичность активированных же TNFα клеток линии NK-92 по сравнению с уровнем их цитотоксичности в отношении клеток линии K562 без МВ, что совпадает с обнаруженным нами повышенным содержанием GrB в МВ, полученных от активированных TNFα клеток линии NK-92. Суммируя полученные данные следует отметить, что в зависимости от типа индуктора NK-клетки линии NK-92 продуцируют микрочастицы разные по фенотипу и составу. Изменение состава МВ может приводить к изменению их функциональной активности, в частности, к усилению цитотоксической активности NK-клеток.

Natural killer (NK) cells are of special interest among a multitude of microvesicle (MV) source cells. NK cells are a lymphocyte subpopulation performing contact cytolysis of virus-infected cells and tumor cells. Each of the NK cell populations has a unique receptor repertoire on its surface and, thus, unique functions. During their contact with a target cell, the most common mechanism of cytolysis is an exocytosis of lytic granules. However, some indirect evidence suggests that MV with CD56 phenotype and leukocyte-derived MV with various phenotypes are present in the peripheral blood plasma.This research is aimed to study the phenotype, composition and cytotoxic activity of microvesicles produced by NK cells. The analysis of receptor expression showed that MV, as well as source cells of the NK-92 cell line, had a similar CD56 molecule expression profile. The expression profile in MV differs from the same in source cells by higher CD119 and CD11b expression and by lower CD18 expression. Culturing of NK-92 cells in the presence of PMA, IL-1β, TNFα, IFNγ resulted in alterations of cell phenotypes and MV. Immunoblots revealed a change of perforin and granzyme B (GrB) in MV. The analysis of the cytotoxic activity of NK-92 cells in a natural killer in vitro assay employing K562 target cells demonstrated that MV obtained from TNFα-activated cells of the NK-92 cell line increased the cytotoxicity of the same TNFα-activated NK-92 cells regarding cytotoxicity levels. This coincides with the previously revealed increased content of GrB in MV obtained from TNFα-activated cells of the NK-92 cell line. To sum up depending on the cytokine NK-92 cells produce MV that differ in their phenotype, composition and activity. Any changes in MV composition can result in changes in their functional activity: in particular, changes can increase the cytotoxic activity of NK cells of the NK-92 cell line. Thus, besides a well-known and proved way for GrB delivery to a target cell, we can suggest an additional way – the transportation of GrB within MV.

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