akusherstvoObstetrics, Gynecology and ReproductionАкушерство, Гинекология и Репродукция2313-73472500-3194IRBIS LLC10.17749/2313-7347/ob.gyn.rep.2025.674akusherstvo-2566Research ArticleREVIEW ARTICLEНАУЧНЫЙ ОБЗОРUterine natural killer cells and pregnancy outcomes: mechanisms, biomarkers, and therapeutic targetsМаточные естественные киллеры и исходы беременности: механизмы, биомаркеры и терапевтические мишениhttps://orcid.org/0009-0007-1748-9411ДжегутановА. А.DzhegutanovA. A.

Джегутанов Амир Арсенович 

355017 Ставрополь, ул. Мира, д. 310

Amir A. Dzhegutanov

310 Mira Str., Stavropol 355017

dzhegutanov.amir1@gmail.comhttps://orcid.org/0009-0006-1459-7946ШерышеваК. А.SheryshevaK. A.

Шерышева Кристина Андреевна 

450008 Уфа, ул. Ленина, д. 3

Kristina A. Sherysheva

3 Leninа Str., Ufa 450008

https://orcid.org/0009-0002-1990-538XМуталиповА. Р.MutalipovA. R.

Муталипов Алмаз Русланович 

450008 Уфа, ул. Ленина, д. 3

Almaz R. Mutalipov

3 Leninа Str., Ufa 450008

https://orcid.org/0009-0007-2010-018XАхкамоваЛ. А.AkhkamovaL. A.

Ахкамова Лейсан Алмазовна 

450008 Уфа, ул. Ленина, д. 3

Leysan A. Akhkamova

3 Leninа Str., Ufa 450008

https://orcid.org/0009-0007-4243-3751ГимазетдиноваР. Ф.GimazetdinovaR. F.

Гимазетдинова Ралина Флюровна

460000 Оренбург, ул. Советская, д. 6

Ralina F. Gimazetdinova

6 Sovetskaya Str., Orenburg 460000

https://orcid.org/0009-0004-4002-3650ПятковаА. В.PyatkovaA. V.

Пяткова Алина Владимировна

117513 Москва, ул. Островитянова, д. 1

Alina V. Pyatkova

1 Ostrovityanova Str., Moscow 117513

https://orcid.org/0009-0008-3093-517XЛевытченковаЕ. Н.LevytchenkovaE. N.

Левытченкова Екатерина Николаевна

443099 Самара, ул. Чапаевская, д. 89

Ekaterina N. Levytchenkova

89 Chapaevskaya Str., Samara 443099

https://orcid.org/0009-0003-9170-9508ГалеевВ. Д.GaleevV. D.

Галеев Вадим Димович

450008 Уфа, ул. Ленина, д. 3

Vadim D. Galeev

3 Leninа Str., Ufa 450008

https://orcid.org/0009-0002-5729-5834ЛиВ.LiV.

Ли Виктория

620028 Екатеринбург, ул. Репина, д. 3

Victoria Li

3 Repina Str., Еkaterinburg 620028

https://orcid.org/0009-0006-0288-6775ЗыряновА. В.ZyryanovA. V.

Зырянов Александр Владиславович

620028 Екатеринбург, ул. Репина, д. 3

Aleksandr V. Zyryanov

3 Repina Str., Еkaterinburg 620028

https://orcid.org/0009-0006-4637-574XЧарыеваС.CharyevaS.

Чарыева Сельби

300012 Тула, проспект Ленина, д. 92 

Selbi Charyeva

92 Lenin Avenue, Tula 300012

https://orcid.org/0009-0005-3056-5955АбосовМ. А.AbosovM. A.

Абосов Мирзоумархон Анварджонович

300012 Тула, проспект Ленина, д. 92 

Mirzoumarkhon A. Abosov

92 Lenin Avenue, Tula 300012

https://orcid.org/0009-0003-6551-6032ИдрисовА. И.IdrisovA. I.

Идрисов Айнур Ильдарович

450008 Уфа, ул. Ленина, д. 3

Ainur I. Idrisov

3 Leninа Str., Ufa 450008

https://orcid.org/0009-0006-8067-1980КрицынаВ. И.KritsynaV. I.

Крицына Виктория Ильинична

344022 Ростов-на-Дону, Нахичеванский переулок, д. 29

Victoria I. Kritsyna

29 Nakhichevansky Lane, Rostov-on-Don 344022

ФГБОУ ВО «Ставропольский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияStavropol State Medical University, Ministry of Health of the Russian FederationRussian FederationФГБОУ ВО «Башкирский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияBashkir State Medical University, Ministry of Health of the Russian FederationRussian FederationФГБОУ ВО «Оренбургский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияOrenburg State Medical University, Ministry of Health of the Russian FederationRussian FederationФГАОУ ВО «Российский национальный исследовательский медицинский университет имени Н.И. Пирогова (Пироговский университет)» Министерства здравоохранения Российской ФедерацииРоссияPirogov Russian National Research Medical University (Pirogov University), Ministry of Health of the Russian FederationRussian FederationФГБОУ ВО «Самарский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияSamara State Medical University, Ministry of Health of the Russian FederationRussian FederationФГБОУ ВО «Уральский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияUral State Medical University, Ministry of Health of the Russian FederationRussian FederationФГБОУ ВО «Тульский государственный университет»РоссияTula State UniversityRussian FederationФГБОУ ВО «Ростовский государственный медицинский университет» Министерства здравоохранения Российской ФедерацииРоссияRostov State Medical University, Ministry of Health of the Russian FederationRussian Federation20200310202500Online First2566Copyright © Dzhegutanov A.A., Sherysheva K.A., Mutalipov A.R., Akhkamova L.A., Gimazetdinova R.F., Pyatkova A.V., Levytchenkova E.N., Galeev V.D., Li V., Zyryanov A.V., Charyeva S., Abosov M.A., Idrisov A.I., Kritsyna V.I., 20202020Джегутанов А.А., Шерышева К.А., Муталипов А.Р., Ахкамова Л.А., Гимазетдинова Р.Ф., Пяткова А.В., Левытченкова Е.Н., Галеев В.Д., Ли В., Зырянов А.В., Чарыева С., Абосов М.А., Идрисов А.И., Крицына В.И.Dzhegutanov A.A., Sherysheva K.A., Mutalipov A.R., Akhkamova L.A., Gimazetdinova R.F., Pyatkova A.V., Levytchenkova E.N., Galeev V.D., Li V., Zyryanov A.V., Charyeva S., Abosov M.A., Idrisov A.I., Kritsyna V.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.gynecology.su/jour/article/view/2566

Uterine natural killer cells (uNK) represent the dominant population of immune cells in the decidual tissue during early pregnancy, playing a key role in embryo implantation, spiral artery remodeling, and the establishment of proper uteroplacental blood flow. Unlike peripheral natural killer cells (pNK), uNK cells exhibit limited cytotoxicity and pronounced regulatory functions mediated through the production of cytokines, growth factors, and adhesion molecules. An imbalance in uNK cell activation or inhibition is associated with developing several pregnancy complications, including recurrent pregnancy loss, preeclampsia, and infertility associated with endometriosis. Here, we analyze current concepts assessing uNK cell phenotype and functional activity, crosstalk with trophoblasts and regulatory T cells (Treg), as well as the role for key receptors – NKp46 (natural killer protein 46), NKp44 (natural killer protein 44), NKp30 (natural killer protein 30), CD16 (cluster of differentiation 16), NKG2A (natural killer group 2 member A receptor), and cognate ligand HLA-E (human leukocyte antigen E). Special attention is paid to biomarkers reflecting uNK cell status and their prognostic value in reproductive medicine. Therapeutic approaches aimed at modulating uNK cell activity are also considered. In particular, it has been shown that the use of glucocorticoids (e.g., prednisolone) reduces endometrial CD56⁺ uNK cell counts and is applied in patients with recurrent pregnancy loss and repeated implantation failure. Granulocyte colony-stimulating factor (G-CSF) is capable of stimulating angiogenesis, enhancing endometrial receptivity, and increasing the clinical pregnancy rate in women with impaired uNK function. Monoclonal antibodies targeting activating NK cell receptors (NKp46, NKp44, NKp30, CD16) are considered an experimental approach to alleviate excessive uNK cytotoxicity in endometriosis and recurrent miscarriage. Another promising direction relies on applying targeted intervention in immune checkpoints, particularly modulating interaction between the NKG2A receptor and its ligand HLA-E, which may optimize spiral artery remodeling and uteroplacental blood flow.

Маточные естественные киллеры (англ. uterine natural killer cells, uNK) представляют собой доминирующую популяцию иммунных клеток децидуальной ткани на ранних сроках беременности, играя ключевую роль в процессах имплантации, ремоделирования спиральных артерий и формирования адекватного маточно-плацентарного кровотока. В отличие от периферических NK-клеток (англ. peripheral natural killer cells, pNK), uNK-клетки обладают ограниченной цитотоксичностью и выраженными регуляторными функциями, опосредованными через продукцию цитокинов, факторов роста и молекул адгезии. Дисбаланс в их активации или ингибировании ассоциирован с развитием ряда осложнений беременности, включая повторную потерю беременности, преэклампсию и бесплодие при эндометриозе. В статье проанализированы современные представления о фенотипе и функциональной активности uNK-клеток, их взаимодействии с трофобластом и регуляторными Т-клетками (англ. regulatory T cells, Treg), а также рассмотрено значение ключевых рецепторов — NKp46 (англ. natural killer protein 46; белок натуральных киллеров 46), NKp44 (англ. natural killer protein 44; белок натуральных киллеров 44), NKp30 (англ. natural killer protein 30; белок натуральных киллеров 30), CD16 (англ. cluster of differentiation 16; кластер дифференцировки 16), NKG2A (англ. natural killer group 2 member A receptor; рецептор натуральных киллеров группы 2, член A), а также их лиганда — HLA-E (англ. human leukocyte antigen E; антиген лейкоцитов человека Е). Особое внимание уделено биомаркерам, отражающим состояние uNK-клеток, и их прогностической ценности в репродуктивной медицине. Рассмотрены терапевтические подходы, направленные на модуляцию активности uNK-клеток. В частности, показано, что применение глюкокортикоидов (например, преднизолона) снижает количество CD56⁺ uNK-клеток в эндометрии и используется у пациенток с привычным невынашиванием беременности и повторными неудачами имплантации. Гранулоцитарный колониестимулирующий фактор (англ. granulocyte colony-stimulating factor, G-CSF) способен стимулировать ангиогенез, повышать рецептивность эндометрия и увеличивать частоту наступления клинической беременности у женщин с нарушениями функции uNK. Моноклональные антитела к активирующим рецепторам NK-клеток (NKp46, NKp44, NKp30, CD16) рассматриваются как экспериментальный метод для снижения избыточной цитотоксичности uNK при эндометриозе и привычных выкидышах. Перспективным направлением также является таргетное воздействие на иммунные контрольные точки, в частности модуляция взаимодействия рецептора NKG2A с его лигандом HLA-E, что может оптимизировать ремоделирование спиральных артерий и маточно-плацентарный кровоток.

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