1. На главную
  2. Электронные версии
  3. Российский физиологический журнал им. И.М. Сеченова
  4. T. 109, № 5, 2023

Российский физиологический журнал им. И.М. Сеченова, 2023, T. 109, № 5, стр. 572-587

Экспрессия молекул Tim-3 и CD9 на натуральных киллерах (NK) и Т-лимфоцитах с функциями NK (NKT) периферической крови в разные сроки физиологической беременности

Е. Г. Орлова 1, *, О. А. Логинова 1, О. Л. Горбунова 1, Н. В. Каримова 2, С. В. Ширшев 1

1 Институт экологии и генетики микроорганизмов УрО РАН
Пермь, Россия

2 ООО Централизованная клинико-диагностическая лаборатория
Пермь, Россия

* E-mail: orlova_katy@mail.ru

Поступила в редакцию 06.03.2023
После доработки 21.03.2023
Принята к публикации 22.03.2023

Аннотация

При физиологически протекающей беременности натуральные киллеры (NK) и Т-лимфоциты с функциями NK (NKT) являются ведущими эффекторами иммунной толерантности организма матери к полуаллогенному плоду, а также выполняют фетотрофическую функцию. Молекулы Tim-3 (T-cell Ig and mucin domain-containing protein 3) и CD9 играют критическую роль в реализации иммунорегуляторной и фетотрофической функций NK и NKT, однако их экспрессия на клетках периферической крови не изучена. Цель работы – исследовать экспрессию Tim-3, CD9 на субпопуляциях NK и NKT периферической крови в разные сроки физиологически протекающей беременности. Объектом исследования являлась периферическая кровь условно-здоровых женщин в I и III триместрах физиологически протекающей беременности. Группу сравнения составили условно-здоровые небеременные женщины в I фазе менструального цикла. Экспрессию молекул Tim-3, CD9 анализировали методом проточной цитофлюориметрии на регуляторных NK (CD16–CD56bright) и NKT (CD16–CD56+), цитотоксических NK (CD16+CD56dim/–) и NKT (CD16+CD56+). Установлено, что в I триместре беременности количество и соотношение регуляторных и цитотоксических NK и NKT не менялось. Экспрессия Tim-3 увеличивалась на всех субпопуляциях NK и NKT за исключением цитотоксических CD16+CD56dimNK. Экспрессия CD9 возрастала на всех субпопуляциях NK, а на NKT не отличалась от небеременных. При этом на регуляторных NK и NKT в I триместре беременности выявлена прямая корреляция экспрессии CD9 и Tim-3. В III триместре количество регуляторных CD16–CD56brightNK увеличивалось, а цитотоксических CD16+CD56dimNK и регуляторных CD16–CD56+NKТ снижалось по сравнению с небеременными. Количество CD16+CD56–NK не менялось по триместрам беременности. Экспрессия Tim-3 усиливалась на всех субпопуляциях NK и цитотоксических NKТ, а CD9 повышалась только на регуляторных NK. Таким образом, экспрессия молекул Tim-3 и CD9 на разных субпопуляциях NK и NKT менялась по триместрам, что играет важную роль в регуляции их фенотипа и функций при беременности.

Ключевые слова: натуральные киллеры, T-лимфоциты с функциями натуральных киллеров, Tim-3, СD9, беременность

Список литературы

  1. Saito S, Nakashima A, Myojo-Higuma S, Shiozaki A (2008) The balance between cytotoxic NK cells and regulatory NK cells in human pregnancy. J Reprod Immunol 77(1): 14–22. https://doi.org/10.1016/j.jri.2007.04.007

  2. Shojaei Z, Jafarpour R, Mehdizadeh S, Bayatipoor H, Pashangzadeh S, Motallebnezhad M (2022) Functional prominence of natural killer cells and natural killer T cells in pregnancy and infertility: A comprehensive review and update. Pathol Res Pract 238: 154062. https://doi.org/10.1016/j.prp.2022.154062

  3. Di Santo JP (2008) Functionally distinct NK-cell subsets: developmental origins and biological implications. Eur J Immunol 38(11): 2948–2951. https://doi.org/10.1002/eji.200838830

  4. Veenstra van Nieuwenhoven AL, Bouman A, Moes H, Heineman MJ, de Leij LF, Santema J, Faas MM (2002) Cytokine production in natural killer cells and lymphocytes in pregnant women compared with women in the follicular phase of the ovarian cycle. Fertil Steril 77(5): 1032–1037. https://doi.org/10.1016/s0015-0282(02)02976-x

  5. Wijaya RS, Read SA, Schibeci S, Han S, Azardaryany MK, van der Poorten D, Lin R, Yuen L, Lam V, Douglas MW, George J, Ahlenstiel G. (2021). Expansion of dysfunctional CD56–CD16+ NK cells in chronic hepatitis B patients. Liver Int: Offic J Int Associat Study Liver, 41(5): 969–981. https://doi.org/10.1111/liv.14784

  6. Orrantia A, Terrén I, Izquierdo-Lafuente A, Alonso-Cabrera JA, Sandá V, Vitallé J, Moreno S, Tasias M, Uranga A, González C, Mateos JJ, García-Ruiz JC, Zenarruzabeitia O, Borrego F (2020) A NKp80-Based Identification Strategy Reveals that CD56neg NK Cells Are Not Completely Dysfunctional in Health and Disease. Science 23(7): 101298. https://doi.org/10.1016/j.isci.2020.101298

  7. Cocker ATH, Liu F, Djaoud Z, Guethlein LA, Parham P (2022) CD56-negative NK cells: Frequency in peripheral blood, expansion during HIV-1 infection, functional capacity and KIR expression. Front Immunol 13: 992723. https://doi.org/10.3389/fimmu.2022.992723

  8. Whettlock EM, Woon EV, Cuff AO, Browne B, Johnson MR, Male V (2022) Dynamic Changes in Uterine NK Cell Subset Frequency and Function Over the Menstrual Cycle and Pregnancy. Front Immunol 13: 880438. https://doi.org/10.3389/fimmu.2022.880438

  9. Koopman LA, Kopcow HD, Rybalov B, Boyson JE, Orange JS, Schatz F, Masch R, Lockwood CJ, Schachter AD, Park PJ, Strominger JL (2003) Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 198(8): 1201–1212. https://doi.org/10.1084/jem.20030305

  10. Михайлова ВА, Белякова КЛ, Сельков СА, Соколов ДИ (2017) Особенности дифференцировки NK-клеток: CD56dim и CD56bright NK-клетки во время и вне беременности. Мед иммунол 19(1): 19–26. [Mikhailova VA, Belyakova KL, Selkov SA, Sokolov DI (2017) Features of NK cell differentiation: CD56dim and CD56bright NK cells during and outside pregnancy. Med Immunol 19(1): 19–26. (In Russ)]. https://doi.org/10.15789/1563-0625-2017-1-19-26

  11. Sotnikova N, Voronin D, Antsiferova Y, Bukina E (2014) Interaction of decidual CD56+ NK with trophoblast cells during normal pregnancy and recurrent spontaneous abortion at early term of gestation. Scand J Immunol 80(3): 198–208. https://doi.org/10.1111/sji.12196

  12. Du X, Zhu H, Jiao D, Nian Z, Zhang J, Zhou Y, Zheng X, Tong X, Wei H, Fu B (2022) Human-induced CD49a+NK Cells promote fetal growth. Front Immunol 13: 821542. https://doi.org/10.3389/fimmu.2022.821542

  13. Khademi M, Illés Z, Gielen AW, Marta M, Takazawa N, Baecher-Allan C, Brundin L, Hannerz J, Martin C, Harris RA, Hafler DA, Kuchroo VK, Olsson T, Piehl F, Wallström ET (2004) Cell Ig-and mucin-domain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J Immunol 172(11): 7169–7176. https://doi.org/10.4049/jimmunol.172.11.7169

  14. Sun J, Yang M, Ban Y, Gao W, Song B, Wang Y, Zhang Y, Shao Q, Kong B, Qu X (2016) Tim-3 Is upregulated in NK cells during early pregnancy and inhibits NK cytotoxicity toward trophoblast in galectin-9 dependent pathway. PloS One 11(1): e0147186. https://doi.org/10.1371/journal.pone.0147186

  15. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK (2005)The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol 6(12): 1245–1252. https://doi.org/10.1038/ni1271

  16. Hou H, Liu W, Wu S, Lu Y, Peng J, Zhu Y, Lu Y, Wang F, Sun Z (2014) Tim-3 negatively mediates natural killer cell function in LPS-induced endotoxic shock. PLoS One 9(10): e110585. https://doi.org/10.1371/journal.pone.0110585

  17. Meggyes M, Lajko A, Palkovics T, Totsimon A, Illes Z, Szereday L, Miko E (2015). Feto-maternal immune regulation by TIM-3/galectin-9 pathway and PD-1 molecule in mice at day 14.5 of pregnancy. Placenta 36(10): 1153–1160. https://doi.org/10.1016/j.placenta.2015.07.124

  18. Cerdeira AS, Rajakumar A, Royle CM, Lo A, Husain Z, Thadhani RI, Sukhatme VP, Karumanchi SA, Kopcow HD (2013). Conversion of peripheral blood NK cells to a decidual NK-like phenotype by a cocktail of defined factors. J Immunol (Baltimore, Md: 1950), 190(8): 3939–3948. https://doi.org/10.4049/jimmunol.1202582

  19. Reyes R, Cardeñes B, Machado-Pineda Y, Cabañas C (2018) Tetraspanin CD9: A key regulator of cell adhesion in the immune system. Front Immunol 9: 863. https://doi.org/10.3389/fimmu.2018.00863

  20. Lee CL, Vijayan M, Wang X, Lam KKW, Koistinen H, Seppala M, Li RHW, Ng EHY, Yeung WSB, Chiu PCN (2019) Glycodelin-A stimulates the conversion of human peripheral blood CD16-CD56bright NK cell to a decidual NK cell-like phenotype. Hum Reprod 34(4): 689–701. https://doi.org/10.1093/humrep/dey378

  21. Орлова ЕГ, Логинова ОА, Горбунова ОЛ, Каримова НВ, Ширшев СВ (2022) Особенности экспрессии молекул Tim-3, CD9, CD49a лимфоцитами периферической крови при физиологической беременности. [Электронный ресурс] Вестн уральской мед акад науки 19(5): 461–473. [Orlova EG, Loginova ОА, Gorbunova ОL, Karimova NV, Shirshev SV (2022) Features of TIM-3, CD9, CD49a molecule expressions by peripheral blood lymphocytes during physiological pregnancy. [Online] Vestn Ural Med Akad Nauki 19(5): 461–473. (In Russ)]. https://doi.org/10.22138/2500-0918-2022-19-5-461-473

  22. Moore T, Dveksler GS (2014) Pregnancy-specific glycoproteins: complex gene families regulating maternal-fetal interactions. Int J Dev Biol 58(2–4): 273–280. https://doi.org/10.1387/ijdb.130329gd

  23. Kronenberg M, Gapin L (2002) The unconventional lifestyle of NKT cells. Nat Rev Immunol 2: 557–568. https://doi.org/dx.doi.org/10.1038/nri854

  24. Vitelli-Avelar DM, Sathler-Avelar R, Dias JC, Pascoal VP, Teixeira-Carvalho A, Lage PS, Elói-Santos SM, Corrêa-Oliveira R, Martins-Filho OA (2005) Chagasic patients with indeterminate clinical form of the disease have high frequencies of circulating CD3+CD16–CD56+ natural killer T cells and CD4+CD25 high regulatory T lymphocytes. Scand J Immunol 62(3): 297–308. https://doi.org/10.1111/j.1365-3083.2005.01668.x

  25. Yuan J, Li J, Huang SY, Sun X (2015) Characterization of the subsets of human NKT-like cells and the expression of Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion. J Reprod Immunol 110: 81–88. https://doi.org/10.1016/j.jri.2015.05.001

  26. Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L (2004) NKT cells: what’s in a name? Nature Rev Immunol 4(3): 231–237. https://doi.org/10.1038/nri1309

  27. Borzychowski AM, Croy BA, Chan WL, Redman CWG, Sargent IL (2005) Changes in systemic type 1 and type 2 immunity in normal pregnancy and preeclampsia may be mediated by natural killer cells. Eur J Immunol 35: 3054–3063. https://doi.org/10.1002/eji.200425929

  28. Boyson JE, Rybalov B, Koopman LA, Exley M, Balk SP, Racke FK, Schatz F, Masch R, Wilson SB, Strominger JL (2002) CD1d and invariant NKT cells at the human maternal-fetal interface. Proc Natl Acad Sci U S A 9(21): 13741–13746. https://doi.org/10.1073/pnas.162491699

  29. Shi Y, Ling B, Zhou Y, Gao T, Feng D, Xiao M, Feng L (2007) Interferon-gamma expression in natural killer cells and natural killer T cells is suppressed in early pregnancy. Cell Mol Immunol 4(5): 389–394.

  30. Southcombe J, Redman C, Sargent I (2010) Peripheral blood invariant natural killer T cells throughout pregnancy and in preeclamptic women. J Reprod Immunol 87(1–2): 52–59. https://doi.org/10.1016/j.jri.2010.07.003

  31. Van den Heuvel MJ, Peralta CG, Hatta K, Han VK, Clark DA (2007) Decline in number of elevated blood CD3+ CD56+ NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy. Am J Reprod Immunol 58(5): 447–459. https://doi.org/10.1111/j.1600-0897.2007.00529.x

  32. Hosseini S, Shokri F, Pour SA, Khoshnoodi J, Jeddi-Tehrani M, Zarnani AH (2019) Diminished frequency of menstrual and peripheral blood NKT-like cells in patients with unexplained recurrent spontaneous abortion and infertile women. Reprod Sci 26(1): 97–108. https://doi.org/10.1177/1933719118766261

  33. Ito K, Karasawa M, Kawano T, Akasaka T, Koseki H, Akutsu Y, Kondo E, Sekiya S, Sekikawa K, Harada M, Yamashita M, Nakayama T, Taniguchi M (2000) Involvement of decidual Vα14 NKT cells in abortion. Proc Natl Acad Sci U S A 97(2): 740–744. https://doi.org/10.1073/pnas.97.2.740

  34. Lajko A, Meggyes M, Polgar B, Szereday L (2018) The immunological effect of Galectin-9/TIM-3 pathway after low dose Mifepristone treatment in mice at 14.5 day of pregnancy. PLoS One 13(3): e0194870. https://doi.org/10.1371/journal.pone.0194870

  35. Trittel S, Vashist N, Ebensen T, Chambers BJ, Guzmán CA, Riese P (2019) Invariant NKT cell-mediated modulation of ILC1s as a tool for mucosal immune intervention. Front Immunol 10: 1849. https://doi.org/10.3389/fimmu.2019.01849

  36. Ширшев СВ (2009) Иммунология материнско-фетальных взаимодействий. Екатеринбург. УрО РАН. [Shirshev SV (2009) Immunology of maternal-fetal interactions. Ekaterinburg. (In Russ)].

  37. Szekeres-Bartho J (2009) Progesterone-mediated immunomodulation in pregnancy: its relevance to leukocyte immunotherapy of recurrent miscarriage. Immunotherapy (5): 873–882. PMID: https://doi.org/10.2217/imt.09.5420636029

  38. Gutierrez C (1979) Purification of human T and B cells by a discontinuous density gradient of percoll. J Immunol Methods 29(1): 57–63. https://doi.org/10.1016/0022-1759(79)90125-x

  39. De Andrés C, Fernández-Paredes L, Tejera-Alhambra M, Alonso B, Ramos-Medina R, Sánchez-Ramón S (2017) Activation of Blood CD3+CD56+CD8+ T cells during pregnancy and multiple sclerosis. Front Immunol 8: 196. https://doi.org/10.3389/fimmu.2017.00196

  40. Zhou J, Zhao X, Wang Z, Wang J, Sun H, Hu Y (2013) High circulating CD3+CD56+CD16+ natural killer-like T cell levels predict a better IVF treatment outcome. J Reprod Immunol 97(2): 197–203. https://doi.org/10.1016/j.jri.2012.12.006

  41. Meggyes M, Miko E, Polgar B, Bogar B, Farkas B, Illes Z, Szereday L (2014) Peripheral blood TIM-3 positive NK and CD8+ T cells throughout pregnancy: TIM-3/galectin-9 interaction and its possible role during pregnancy. PloS One 9(3): e92371. https://doi.org/10.1371/journal.pone.0092371

  42. Williams PJ, Searle RF, Robson SC. Innes BA, Bulmer JN (2009) Decidual leucocyte populations in early to late gestation normal human pregnancy. J Reprod Immunol 82(1): 24–31. https://doi.org/10.1016/j.jri.2009.08.001

  43. Gemelli M, Noonan DM, Carlini V, Pelosi G, Barberis M, Ricotta R, Albini A (2022) Overcoming resistance to checkpoint Inhibitors: natural killer cells in non-small cell lung cancer. Front Oncol 12: 886440. https://doi.org/10.3389/fonc.2022.886440

  44. Meggyes M, Nagy DU, Saad Al Deen I, Parkanyi B, Szereday L (2023) CD8+ and CD8– NKT cells exhibit phenotypic changes during pregnancy. Immunol Invest 52(1): 35–57. https://doi.org/10.1080/08820139.2022.2119863

  45. Mikhailova VA, Kudryavtsev IV, Serebryakova MK, Milyutina YP, Demidova ES, Panina AN, Bazhenov DO, Belikova ME, Selkov SA, Sokolov DI (2020) Trophoblast cell influence on peripheral blood natural killer cell proliferation and phenotype in non-pregnant women and women in early pregnancy. Immunobiology 225(3): 151910. https://doi.org/10.1016/j.imbio.2020.151910

  46. Arruvito L, Giulianelli S, Flores AC, Paladino N, Barboza M, Lanari C, Fainboim L (2008) NK cells expressing a progesterone receptor are susceptible to progesterone-induced apoptosis. J Immunol 180(8): 5746–5753. https://doi.org/10.4049/jimmunol.180.8.5746

  47. Shirshev SV, Nekrasova IV, Gorbunova OL, Orlova EG (2017) Hormonal regulation of NK cell cytotoxic activity. Dokl Biol Sci 472(1): 28–30. https://doi.org/10.1134/S0012496617010021

  48. Shirshev SV, Nekrasova IV, Gorbunova OL, Orlova EG, Maslennikova IL (2017) MicroRNA in hormonal mechanisms of regulation of NK cell function. Dokl Biochem Biophys 474(1): 168–172. https://doi.org/10.1134/S160767291703005X

  49. Mikhailova V, Grebenkina P, Khokhlova E, Davydova A, Salloum Z, Tyshchuk E, Zagainova V, Markova K, Kogan I, Selkov S, Sokolov D (2022) Pro- and Anti-Inflammatory Cytokines in the Context of NK Cell-Trophoblast Interactions. Int J Mol Sci 23(4): 2387. https://doi.org/10.3390/ijms23042387

  50. Van den Heuvel MJ, Chantakru S, Xuemei X, Evans SS, Tekpetey F, Mote PA, Clarke CL, Croy BA (2005) Trafficking of circulating pro-NK cells to the decidualizing uterus: regulatory mechanisms in the mouse and human. Immunol Invest 34(3): 273–293. https://doi.org/10.1081/imm-200064488

  51. Shinomiya N, Tsuru S, Tsugita M, Katsura Y, Takemura T, Roku-tanda M, Nomoto K (1991) Thymic depletion in pregnancy: kinetics ofthymocytes and immunologic capacities of the hosts. J Clin Lab Immunol 34: 11–22.

  52. Montaldo E, Vacca P, Chiossone L, Croxatto D, Loiacono F, Martini S, Ferrero S, Walzer T, Moretta L, Mingari MC (2016) Unique eomes(+) NK cell subsets are present in uterus and decidua during early pregnancy. Front Immunol 6: 646. https://doi.org/10.3389/fimmu.2015.00646

  53. Albini A, Gallazzi M, Palano MT, Carlini V, Ricotta R, Bruno A, Stetler-Stevenson WG, Noonan DM (2021) TIMP1 and TIMP2 downregulate TGFβ induced decidual-like phenotype in natural killer cells. Cancers (Basel) 13(19): 4955. https://doi.org/10.3390/cancers13194955

Дополнительные материалы отсутствуют.

Инструменты

следующая статья выпуска предыдущая статья выпуска содержание выпуска

Российский физиологический журнал им. И.М. Сеченова

Архивы выпусков Информация о журнале Отправить рукопись в журнал