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104
Medical Immunology (Russia)/ Медицинская иммунология ОбЗОРЫ Meditsinskaya Immunologiya
2017, Т. 19, № 1, стр. 19-26 D * 2017, Vol. 19, No 1, pp. 19-26
© 2017, СПб РО РААКИ KeVWWS © 2017, SPb RAACI
ОСОБЕННОСТИ ДИФФЕРЕНЦИРОВКИ NK-КЛЕТОК: CD56dim И CD56bright NK-КЛЕТКИ ВО ВРЕМЯ И ВНЕ БЕРЕМЕННОСТИ
Михайлова В.А.1, 2, Белякова К.Л.1, Сельков С.А.1, Соколов Д.И.1, 2' 3
1ФГБНУ«Научно-исследовательский институт акушерства, гинекологии ирепродуктологии имени Д.О. Отта», Санкт-Петербург, Россия
2 ГБОУ ВПО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФ, Санкт-Петербург, Россия
3 ФГБНУ «Институт экспериментальной медицины», Санкт-Петербург, Россия
Резюме. NK-клетки представляют собой лимфоциты, способные к контактному цитолизу вирус-инфицированных клеток и опухолевых клеток и являющиеся источником цитокинов, стимулирующих другие клетки иммунной системы и способствующих развитию иммунного ответа. Дифференци-ровка NK-клеток связана с последовательным приобретением стволовыми клетками специфичных для NK-клеток рецепторов и становлением функциональных характеристик натуральных киллеров. Целью настоящего обзора было рассмотрение CD56dim и CD56bright популяций NK-клеток в процессе их дифференцировки. В обзоре описаны поверхностные рецепторы NK-клеток и экспрессия ими транскрипционных факторов на разных стадиях дифференцировки, представлена сравнительная характеристика данных о влиянии цитокинов и клеток микроокружения на процесс дифференцировки NK-клеток, рассмотрено явление существования NK-клеток, подобных клеткам памяти. Особый интерес представляет дифференцировка NK-клеток матки, так как эти клетки являются особой популяцией NK-клеток, которая преобладает среди лимфоцитов децидуальной оболочки при беременности и принимает участие в процессе образования и ремоделирования плаценты. В обзоре рассмотрены особенности дифференцировки NK-клеток матки, учитывая возможность образования этой популяции NK-клеток как из NK-клеток периферической крови, так и пролиферации in situ. Изучение особенностей функционального состояния NK-клеток матки позволит в дальнейшем приблизиться к пониманию роли NK-клеток при беременности и нарушению оказываемой NK-клетками регуляции в зоне маточно-плацентарного контакта при патологии беременности.
Ключевые слова: NK-клетки, дифференцировка, беременность, поверхностные рецепторы, цитокины, NK-клетки матки, децидуальные NK-клетки
PECULIARITIES OF NK CELLS DIFFERENTIATION: CD56dim AND CD56bright NK CELLS AT PREGNANCY AND IN NON-PREGNANT STATE
Mikhailova V.A.a' b, Belyakova K.L.a, Selkov S.A.a, Sokolov D.I.a' b' c
a D. Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russian Federation b The First St. Petersburg I. Pavlov State Medical University, St. Petersburg, Russian Federation c Institute of Experimental Medicine, St. Petersburg, Russian Federation
Abstract. Natural killer (NK) cells represent a lymphocyte subpopulation which is capable of contact cytolysis of virus-infected cells and tumor cells, being a source of cytokines which stimulate other immune
Адрес для переписки: Address for correspondence:
Соколов Дмитрий Игоревич Sokolov Dmitry I.
ФГБНУ «Научно-исследовательский институт D. Ott Research Institute of Obstetrics, Gynecology and
акушерства, гинекологии и репродуктологии имени Reproductology
Д.О. Отта» 199034, Russian Federation, St. Petersburg, Mendeleevskaya
199034, Россия, Санкт-Петербург, Line, 3.
Менделеевская линия, 3. Phone: 7 (812) 328-98-50.
Тел.: 8(812) 328-98-50. E-mail:[email protected]
E-mail: [email protected]
Образец цитирования: For citation:
ВА Михайлова, К.Л. Белякова, СА Сельков, Д.И. Соколов VA M^m^M КЕ Bdyak°vm S.A ^Icov D.L Sokolov
«Особенности дифференцировки NK-клеток: CD56dim "Peculiarities of NKcells differentiation: CDWm rnd CD56bnght
и CD56"ight NK-клетки во время и вне беременности» NK cells at pregnancy and in non-pregnant state", Medical
//Медицинская иммунология, 2017. Т. 19, № 1. С. 19-26. Immunology (Russia)/Meditsinskaya Immunologiya, 2017,
doi: 10.15789/1563-0625-2017-1-19-26 Vol. 19, no. 1, pp. 19-26.
doi: 10.15789/1563-0625-2017-1-19-26
© Михайлова В.А и соавт., 2017 DOI: http://dx.doi.org/10.15789/1563-0625-2017-1-19-26
cells and promote immune response. NK cell differentiation is connected with a consequent acquisition of specific NK cell receptors by stem cells and formation of functional characteristics inherent to natural killer cells. The aim of this review was to describe the CD56dim and CD56bright populations of NK cells in the course of their differentiation. The authors describe NK surface receptors and expression of transcription factors at various steps of the NK differentiation. We present comparative characteristics of data concerning cytokines and cellular microenvironment influence upon NK cell differentiation, and examine a phenomenon of existing memory-like NK cells. Uterine NK cell differentiation is of special interest, since these cells represent a special NK cell population which prevails among decidual lymphocytes during pregnancy and participates in the process of placental formation and development. This review considers some features of uterine NK cell differentiation, taking into account a possibility of formation of this NK cell population from both peripheral blood NK pool, and in situ proliferation. Moreover, functional studies of the uterine NK cells allow to get closer to understanding the role of NK cells during pregnancy and abnormality of utero-placental bed regulation by NK cells in cases of pregnancy failure.
Keywords: NK cells, differentiation, pregnancy, cell surface receptors, cytokines, uterine NK cells, decidual NK cells
Introduction
Natural killer (NK) are a part of innate immunity system and represent lymphocytes, which are capable of contact cytolysis of virus infected cells and tumor cells and are the source of cytokines stimulating other cells of the immune system and promoting immune response development [3]. NK cells in humans are present naturally in most organs and tissues, including bone marrow, thymus, lymph nodes, blood, skin, intestines, liver, lungs, uterus [6, 37]. NK cells are often addressed as CD3-CD56+ lymphocytes although the expression pattern of NK cells includes variety of receptors including killer immunoglobulin-like receptors (KIR) [38], CD16 (Fcy-receptor III), which mediates antibody-dependent cellular cytotoxity [25, 32], natural killer group (NKG) receptors, cytotoxic receptors NKp30, NKp44, NKp46 [20]. NK cells differentiation and development is connected with the consequent change of repertoire of receptors present in the cell and their acquisition of functional properties. Studying different aspects of NK cell differentiation in humans especially during pregnancy is of special interest, because NK cells functional and phenotypic specifics are closely connected with healthy pregnancy.
1. Development of NK cells main populations
1.1. NK cells populations' development in fetus
Mainly NK cells are present in tissues as intraepithelial lymphocytes, however, NK cells can also form cell clusters, such as in Peyer's glands and mesenterial lymph nodes [6]. In peripheral blood, mature NK cells are characterized by broad spectrum expression of KIR, having both activation and inhibitory activity [2]. NK cell differentiation and their expression of KIR begin at early stages of fetus development [14]. Mainly, NK cells locate in such fetus organs as liver and lungs, also NK cells are present in fetal spleen. Less NK cells are found in bone marrow and mesenterial lymph nodes [14]. Fetus NK cells are characterized by phenotype
CD7+CD161+CD3-CD14-CD19-CD45+, and also by high expression of CD56 [19], as the result of which it seems to be impossible to divide fetus NK cell populations into CD56dim and CD56bright cells1 as in adults [14]. NK cell differentiation in fetus is evaluated by level of NKG2A and CD16 receptors expression. It has been demonstrated that the ratio of NK cell populations NKG2A+CD16- (that can be corresponded to CD56bright population in adults), NKG2A+CD16+ and NKG2A- CD16+ (that can be corresponded to CD56dim population in adults) does not change at the gestational age from 15 weeks to 22 weeks, which indicates that NK cell differentiation takes place before the 15th week of pregnancy [14]. The character of KIR receptor expression by fetus NK cells varies depending on cell localization: the highest expression of KIR is found in NK cells, localized in fetus lungs. Like in adult organisms, an expression of large repertoire of KIR is connected with NK cell differentiation: the highest density of KIR is typical for NK cell populations NKG2A+CD16+ and NKG2A-CD16+. The expression of CD57, which is a marker of terminal stages of NK cell differentiation, is set for NKG2A-CD16+ [14], which indicates higher maturity level of these cells.
Comparing fetal NK cells and peripheral blood NK cells in an adult person, it was stated that NK cells of both groups can induce death of cells, which were not expressing MHC-1 locus molecules. However, compared to adult NK cells, fetal NK cells are characterized by lower cytotoxic activity [14, 19], but higher ability to respond to cytokine stimulation (IL-12, IL-18) [14]. Fetal NK cells localized in lungs contain perforin and granzyme B, while perforin and granzyme B content increases as NK cells differentiate from NKG2A+CD16- in NKG2A-CD16+, which indicates maturation of functional apparatus of fetal NK cells during differentiation [14].
1 dim — low expression of receptor; bright — high expression of receptor
1.2. NK cells populations' development in adults
1.2.1. Characteristics of two main populations of NK cells (CD56brigh1 and CD56dim)
Inadult organisms, themainsource ofhematopoietic stem cells, which can differentiate in NK cells, is bone marrow [2, 20]. NK cells can circulate [6] and continue their differentiation in spleen, tonsils and lymph nodes [20]. In secondary lymphoid tissue, NK cell progenitors pass differentiation to the stage of immature NK cells [20], which, in turn, develop into NK cells with phenotype CD56dimCD16bright, prevailing in blood flow, and CD56brightCD16dim NK cells, placed in liver, endometrium, decidua and lymph nodes [3]. Recently CD56brightCD16dim NK cells are viewed as precursors of CD56dimCD16bright NK cells [37]. While differentiation NK cells acquire functional receptors, connected with their cytotoxic function. In the beginning an expression of CD94/ NKG2A, NKp46, NKG2D receptors is observed, and then an expression of KIR and CD16 receptors [37].
CD56dimCD16bright NK cells, present in peripheral blood and spleen, are characterized by increased cytotoxic activity and expression of broad spectrum of KIR, as well as cytotoxic receptors NKp30, NKp44, NKp46 [20]. While culturing of CD56dimCD16bright NK cells with K562 cells, an increase of IFNy, TNFa, MIP-1a, MIP-ip production by NK cells was demonstrated [9].
The CD56brightCD16dim population of NK cells is mainly present in lymph nodes and tonsils, and in blood, it makes up less than 10% of NK cell population [20]. For CD56brightCD16dim NK cells, reduced cytotoxic activity and reduced expression of NKp46 receptors is typical [20]. In presence of K562 the CD56brightCD16dim population of NK cells does not significantly change cytokine production, however, with combined stimulation by IL-12 and IL-18 cytokines, it demonstrates an increased production of IFNy compared to CD56dimCD16brightNK cells [9]. Often the CD56brightCD16dim population of NK cells is
combined with CD56briglltCD16"NK cells, indicating the general population CD56brightCD16-/dim, and noting that the defining marker of these populations is CD56, while CD16 does not mediate the main functional properties of these cells [6, 20, 35]. As the result of activation both in vivo (after etering lymph node with afferent lymph) and in vitro NK cells with CD56bright CD16dim phenotype can acquire an increased content of perforin and a phenotype of CD56dimCD16brightNK cells: KIR+ IL-7R- c-kit (CD117-) CXCR3"CCR7" CD62L- [6]. Table 1 shows information about the surface receptor expression by NK-cells at different stages of differentiation.
1.2.2. Transcription factors in NK cells development process
Differentiation of NK cell is characterized by expression of a certain set of transcription factors. Using the analysis of expressed mRNA in the in vitro model of human NK cells differentiation obtained from umbilical vein, it was determined that at the stage of transfer from stem cells to NK cell progenitors, E4BP4 and TOX transcription factors participate [28]. While differentiation of NK cell progenitors into mature NK cells an expression of the transcription factors Ikaros, EGF1 and PU.1 is observed [28]. There is a high expression of transcription factors EGR-2, ID-2, and T-bet at all stages of NK cell differentiation. An expression of Gata-3 transcription factor in NK cell progenitors decreases for the short time and then restores to the initial level. High expression of EGR-2, ID-2, T-bet, and Gata-3 factors is connected with their participation in all stages of NK cell differentiation and in acquisition of functional properties by NK cells [28]. Transcription factor IRF-2, apparently, participates in maintenance of differentiated NK cell pool, because a defect of this protein results in an increase of intensity of NK cell apoptosis [28]. It was also demonstrated in vitro that, as the result of IL-12 impact on mature NK cells, an expression of transcription factor ID3 mRNA
TABLE 1. SURFACE RECEPTORS OF HUMAN NK-CELLS DEFINING THE STAGES OF THEIR DIFFERENTIATION
Differentiation stage Localization Surface receptors
Hematopoietic stem cell Bone marrow [2, 20] CD34+CD38dimCD45RA-CD10- [37]
Stage 1 Bone marrow [2, 20] CD34+CD117-CD94-CD16-CD45RA+CD10+ [20, 37]
Stage 2 Secondary lymphoid tissue [20] CD34+CD117+CD94-CD16-CD45RA+CD10-CD161+Integrinp7bright [10, 20, 37]
Stage 3 Secondary lymphoid tissue [20] CD34-CD117+CD94-CD16-CD11a+CD161+NKp44-CD56-[13,10, 37]
Stage 4 CD56bright Liver, uterine endometrium, decidua, lymph nodes [3, 20] CD34-CD117+/-CD94bri9htCD16-/dim CD11a+CD56brightNKp46dim [3, 20, 37]
Stage 5 CD56dim Peripheral blood, spleen [3, 20] CD34-CD117-CD94+/-CD16+/brightKIR+/-CD56dimNKp30+NKp44+NKp46+CXCR3-CCR7-CD62L-[3, 6, 20, 37]
Stage 6 (Memory cell) Peripheral blood [30] NKG2A+CD94+NKp46+CD69+ [30]
increases, while an expression of Gata3 and TOX reduces [18].
1.2.3. Non-linear character of NK cells populations' development
Despite the attempts to determine a sequence of NK cell developmental stages, current data on nonlinear character of NK cell differentiation appear in literature, in particular, depending on their localization and microenvironment. In the experiments on mice, transformed by human plasmids of cytokines IL-15 and Flt-3L, it was demonstrated that from common progenitor of myeloid cells, for which CD56-CD36"CD33+CD34+NKG2D"NKp46-phenotype is typical, myeloid progenitors of NK cells with CD56dimCD36+CD33+CD34-NKG2D-NKp46-phenotype are differentiated. Then, these progenitors of NK cells acquire a phenotype of CD56brightCD36-CD33-CD34-NKG2D+NKp46+NK cells [7]. The investigation also determined presence of myeloid progenitors of NK cells in humans in umbilical vein blood, as well as in fetal bone marrow and in bone marrow of an adult human [7]. Furthermore, it described presence of special populations of NK cell progenitors with DX5-CD49a+ phenotype, which were formed in the liver from CD45.1+NK1.1-CD3-CD19-NK cells of the spleen and were not detected in bone marrow [26].
1.2.4. Phenomenon of "memory-like NK cells"
Currently, a possibility of existence of memory-like
NK cells, which may be formed both by CD56bright and CD56dim NK cells [30] and be a final stage of NK cell differentiation, is discussed in literature [37]. The term memory-like NK cells, which means NK cells similar to memory cells, is used in literature. Some scientists point out three possible variants of memory-like NK cells, which differ by mechanism of formation and functional characteristics: virus dependent induction, cytokine induction, and existence of specialized population of memory-like NK cells in liver [24]. A capacity of NK cells, previously activated by IL-12 and IL-18 cytokines, after a certain period of time (from 7 to 21 days) at repeated cytokine stimulation to produce an increased number of IFNy compared to control was described [30]. At the same time, NK cell cytotoxicity evaluated by CD107a does not differ between the so-called memory NK cells and intact NK cells [30]. As NK cells have no antigen-induced differentiation, the term "memory NK cells" seems to be incorrect. Based on hypothetical mechanisms of memory-like NK cell induction, the most correct term seems to be "pre-activated NK cells". Currently, no markers unique to pre-activated NK cells were detected, however, a correlation between capacity to produce IFNy by pre-activated CD56bright NK cells and expression of NKG2A/CD94 receptor is determined, as well as correlation between capacity
to produce IFNy by pre-activated NK cells of both populations (CD56bright and CD56dim) and expression of NKp46 receptor [30]. It should be noted that the population of pre-activated CD56bright NK cells secrete more IFNy than CD56dim NK cells after repeated stimulation both by cytokines and cells of leukemia cell line K562 [30]. These factors indicate alteration of functional properties of NK cells as the result of preliminary activation by cytokines and preservation of these alterations during a few days. There are evidences of pre-activation of NK cells not only in vitro, but also in vivo: in humans an adaptive change of NK cells properties induced by cytomegalovirus (CMV) infection occurs, it implies change in cytokine secretion and activating receptor NKG2C expression [29]. The mechanisms determining a phenomenon of pre-activation for NK cells are poorly known. Currently it is shown that pre-activated NK cells do not differ from intact NK cells by their content of phosphorylated forms of proteins STAT4 and STAT3, as well as by their content of IFNy mRNA, which indicates the presence of post-transcriptional and post-translational mechanisms of memory induction at NK cells [30].
Thus, NK cell differentiation process in humans is connected with activation of transcriptional factors E4BP4, TOX, Ikaros, EGF1, PU.1, EGR-2, ID-2, IRF-2, T-bet, Gata-3 [28], and consequential change of repertoire of cell surface receptors, particularly acquirement of receptors CD56, CD94/NKG2A, NKp46, NKG2D, NKp30, NKp44, receptors KIR, CD16 [14, 20, 28]. Currently, two main populations of human NK cells are distinguished: CD56dimCD16bright and CD56brightCD16dim [3]. They are also supposed to represent two consequent stages of NK cell differentiation and their possible transfer from CD56brightCD16dim to CD56dimCD16bright cells [37]. Generally, the role of NK cells is realized in elimination virus-infected and tumor cells from organism, however, at such physiological state as pregnancy NK cells actively participate in the process of blastocyst implantation and placenta development. Despite investigations conducted of NK cell participation in pregnancy development, peculiarities of NK cell differentiation in placenta are poorly described.
2. Phenotype and functions of uterine NK cells at pregnancy
2.1. Presence of NK cells in uterus
NK cells make up a special population of uterine cells that significantly changes their representation in uterus depending on menstrual cycle phase and pregnancy. According to some data, decidual NK cells and endometrium NK cells differ little by phenotypic characteristics [22]. For endometrium NK cells an expression of activation receptors NKp46 and NKG2D
and lack or low expression of CD16, NKp44, NKp30 is typical while for decidual NK cells an expression of NKp46, NKG2D, NKp30, NKp44 is typical [23]. At pregnancy an IL-15 secretion by placenta is set [4], in presence of which activation of endometrial NK cells, their secretion of IFNy and IP-10, higher expression of NKp46, NKp30, NKp44, NKG2D take place [23]. Thus, endometrial NK cells at pregnancy can change their phenotype and start a population of decidual cells. Then, during the first trimester, an increase of uterine NK cell numbers takes place, which make up from 50% to 90% of lymphoid cells, present in uterus [11]. Such alteration of NK cell number in the zone of uteroplacental bed may be due to migration of NK cells from peripheral blood [2, 27] through expressing receptors to chemokines produced by cells of decidua [1].
2.2. Peculiarities of uterine NK cell differentiation at pregnancy
According to literature data, the final stages of NK cell differentiation represent transfer from CD56bright to CD56dim phenotype [37]. Apparently, this process has a reversible nature, as decidua NK cells differ from CD56bright NK cells of peripheral blood by expression of inhibiting receptors, for which CD56bright CD16dim/" phenotype, CD94 expression, and high content of cytolytic granules are typical [6, 20]. Also as opposed to NK cells of peripheral blood decidual NK cells to a far greater extent can bind HLA-G, expressed at trophoblast cells [34]. Probably, as the result of influence of cytokines, secreted in the zone of uteroplacental bed, alteration of CD56dim phenotype of NK cells of peripheral blood and their acquisition of CD56bright phenotype of decidual NK cells [2]. Such alteration of NK cell phenotype in placenta at pregnancy is a continuation of NK cell differentiation in situ.
2.2.1. Oxygen supply modifiers NK cells differentiation at pregnancy
Significant influence on differentiation of NK cells of peripheral blood into decidua NK cells is exerted by modifying oxygen supply to tissue. At early gestational age after blastocyst invasion, but before rearrangement of spiral arteries, the cells, present in fetal-placental complex, are in hypoxic conditions [15]. During the first trimester, the oxygen partial pressure in fetal-placental complex makes up about 20 mm of mercury (2%) and increases to about 60 mm of mercury (10%) through the 12th week of pregnancy. In decidua oxygen, partial pressure at the beginning of pregnancy constitutes 50 mm of mercury (8%) and in the end of the first trimester it increases up to 70 mm of mercury (12%), in proximity of spiral arteries it reaches 90-100 mm of mercury (20%) [36]. In the experiments with NK cells obtained in vitro from human hematopoietic stem cells, it was detected that in hypoxic conditions (1% O2) NK cells decrease expression of NKp30 and NKG2D activation markers
[38]. At 10% 02 decidual NK cells restore expression of NKG2D receptor, and at 21% 02 decidual NK cells reduce CD56 expression compared to culturing conditions at 10% 02 [36]. At combined culturing of trophoblast cells line (SGHPL-4) and decidual NK cells with 10% O2, the higher invasive activity of trophoblast and higher trophoblast capacity to form capillary-like structures is determined [36], which reflects the situation in vivo, when in the end of first trimester trophoblast invasion into uterus spiral arteries and establishment of uteroplacental blood supply takes place [16]. Thus, decidual cells, being in dynamic hypoxic conditions in placenta, can change their phenotype, reducing expression of receptors mediating cytotoxicity, and provide for regulation of uteroplacental bed development.
2.2.2. Cellular and cytokine microenvironment influences NK cells differentiation at pregnancy
Differentiation of NK cells of peripheral blood into decidua NK cells is influenced by cellular and cytokine microenvironment. Thus, combined culturing of NK cells of peripheral blood with decidual stromal cells results in reduction of NKp44, NKp30, NKG2D, DNAM-1 expression by NK cells of peripheral blood [8] and approaching of NK cell phenotype to the phenotype typical for decidual NK cells. Furthermore, binding of chemokine CXCL12 (SDF-1), secreted by placenta cells, leads to reduction of expression of NKp44, perforin by NK cells of peripheral blood, decrease of cytotoxicity, increase of expression of inhibiting receptor KIR2DL1 [27]. In the experiments in vitro, the TGF-p secreted by decidual cells causes reduction of CD16 expression by NK cells of peripheral blood, approximating their phenotype to decidual NK cells [5, 17]. Probably, decidual NK cells can maintain their differentiation due to autocrine impact of cytokine TGF-p, because, according to literature data, during pregnancy the number of decidual NK cells, characterized by capacity to secrete TGF-p, increases [31].
At the same time, probably, not all NK cells of peripheral blood can migrate into the uterus and change their phenotype. It was demonstrated that among decidual cells compared to NK cells of peripheral blood many more cells expressed receptor CD25 [33]. At that, more than half of cells present in decidua and expressing CD25 are NK cells, while in peripheral blood, T-lymphocytes make up the majority of CD25+ cells [33]. For NK cells of peripheral blood with CD3"CD56brightCD25+ phenotype the reduced expression of inhibiting receptors and increased expression of activation receptors is typical, as well as reduced content of perforin and granzyme B and increased expression of IFNy and TGF-p [33]. It is supposed that these NK cells can migrate into the uterus and their main function is to secrete cytokines and maintain cytokine microenvironment in the zone of uteroplacental bed at pregnancy [33]. However, at
Preactivated NK cells
BM - bone marrow; SLT - secondary lymphoid tissue; PB - peripheral blood; SP - spleen; LN - lymph nodes; L - liver; EM - endpmetrium; D - decidua; CMV - cytomegalovirus
Figure 1. Peculiarities of CD56dim and CD56bright NK cells differentiation
incubation of CD25+ NK cells with trophoblast, NK cells increased expression of NKp30, NKp44, NKp46 receptors [33], which indicates induction of CD25+ NK cell activation by trophoblast.
In uterus mucous membrane, the presence of NK cell progenitors at the intermediate stage of differentiation was determined, while no NK cell progenitors at early stages of differentiation were found [21]. Uterus NK cell progenitors at the intermediate stage have phenotype CD45+CD3-CD19-CD117+CD94~CD7+/~CD69+CD122dimCD127+/~ NKp44+/"NKG2D" [21], which makes them similar to NK cell progenitors at the intermediate stage present in secondary lymphoid tissue [10, 13, 37]. Furthermore, NK cell progenitors at the intermediate stage in uterus [21], like in secondary lymphoid tissue [12], can secrete IL-22, which indicates the occurrence of NK cell differentiation process in uterus not only from
NK cells of peripheral blood after migration, but also from NK cell progenitors placed in uterus.
Thus, uterine NK cells represent the terminal stage of NK cell differentiation, which resemble the stage of CD56bright NK cell differentiation. For uterine NK cells expression of CD56, NKp46, NKG2D, NKp30, NKp44, secretion of IFNy and TGF-p is typical. Without pregnancy, endometrial NK cells are present in the uterus; following pregnancy endometrial NK cells change their phenotype and differentiate into decidual NK cells. Significant growth of decidua NK cell numbers at pregnancy takes place through migration of NK cells from peripheral blood and respective alteration of their phenotype although differentiation of uterine NK cells can also occur in situ. Figure 1 shows paths of differentiation of CD56dim and CD56bright NK cells.
Conclusion
Currently, there is a great deal of evidence on phenotypic peculiarities of NK cells, which can determine functional features of different populations of NK cells. Summarizing these phenotypical and functional characteristics of NK cells populations can help in further distinguishing stages of NK cells differentiation process. Determining NK cell differentiation markers and examining peculiarities of NK cell functional characteristics promoted discovering NK cell capacity for pre-activation and retention of this condition during a long period of time. Further investigation of so-called pre-activated NK cells, or memory-like NK cells, may contribute in understanding of fundamental immunologic processes. Appearance of data about possible nonlinear nature of NK cell differentiation, as well as about influence of microenvironment cells on NK cell differentiation process, indicates the necessity of further investigations in this direction. Examining expression patterns of NK cell receptors at pregnancy is of special interest, as in this case, discovering reversibility of NK cell differentiation at the final stages of this process is possible, as well as the dependence of uterus NK cell functional peculiarities from the repertoire of expressed receptors. Further study and analysis of peculiarities of the NK cell functional state will allow us to come close to understanding the NK cell role at pregnancy and disorder of NK cell regulation in the zone of uteroplacental bed at pathologic pregnancy.
Список литературы / References
1. Михайлова В.А., Онохина Я.С., Сельков С.А., Соколов Д.И. Экспрессия адгезионных молекул и хе-мокиновых рецепторов NK-клетками периферической крвои при беременности // Иммунология, 2011. Т. 32, № 2. С. 78-81. [Mikhailova V.A., Onokhina Ya.S., Selkov S.A., Sokolov D.I. Expression of adhesion molecules and chemokine receptors by peripheral blood NK-cells in pregnancy. Immunologiya = Immunology, 2011, Vol. 32, no. 2, pp. 78-81. (In Russ.)]
2. Михайлова В.А., Сельков С.А., Соколов Д.И. Фенотипические и функциональные характеристики NK-клеток при беременности // Акушерство и гинекология, 2011. № 5. С.4-9. [Mikhailova V.A., Selkov S.A.,
Sokolov D.I. Phenotypical and functional characteristics of NK cells in pregnancy. Akusherstvo i ginekologiya = Obstetrics and Gynecology, 2011, no. 5, pp. 4-9. (In Russ.)]
3. Ярилин А.А. Иммунология. М.: ГЭОТАР-Медиа, 2010. 752 c. [Yarilin A.A. Immunology]. Moscow: GEOTAR-Media. 752 p.
4. Agarwal R., Loganath A., Roy A.C., Wong Y.C., Ng S.C. Expression profiles of interleukin-15 in early and late gestational human placenta and in pre-eclamptic placenta. Mol. Hum. Reprod., 2001, Vol. 7, no. 1, pp. 97-101.
5. Allan D.S., Rybalov B., Awong G., Zuniga-Pflucker J.C., Kopcow H.D., Carlyle J.R., Strominger J.L. TGF-beta affects development and differentiation of human natural killer cell subsets. Eur. J. Immunol., 2010, Vol. 40, no. 8, pp. 2289-2295.
6. Carrega P., Ferlazzo G. Natural killer cell distribution and trafficking in human tissues. Front. Immunol., 2012, Vol. 3, p. 347.
7. Chen Q., Ye W., Jian Tan W., Mei Yong K.S., Liu M., Qi Tan S., Loh E., Te Chang K., Chye Tan T., Preiser P.R., Chen J. Delineation of Natural Killer Cell Differentiation from Myeloid Progenitors in Human. Sci. Rep., 2015, Vol. 5, p. 15118.
8. Croxatto D., Vacca P., Canegallo F., Conte R., Venturini P.L., Moretta L., Mingari M.C. Stromal cells from human decidua exert a strong inhibitory effect on NK cell function and dendritic cell differentiation. PLoS One, 2014, Vol. 9, no. 2, p. e89006.
9. Fauriat C., Long E.O., Ljunggren H.G., Bryceson Y.T. Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood, 2010, Vol. 115, no. 11, pp. 2167-2176.
10. Freud A.G., Becknell B., Roychowdhury S., Mao H.C., Ferketich A.K., Nuovo G.J., Hughes T.L., Marburger T.B., Sung J., Baiocchi R.A., Guimond M., Caligiuri M.A. A human CD34(+) subset resides in lymph nodes and differentiates into CD56bright natural killer cells. Immunity, 2005, Vol. 22, no. 3, pp. 295-304.
11. Gomez-Lopez N., Guilbert L.J., Olson D.M. Invasion of the leukocytes into the fetal-maternal interface during pregnancy. J. Leukoc. Biol., 2010, Vol. 88, no. 4, pp. 625-633.
12. Hughes T., Becknell B., Freud A.G., McClory S., Briercheck E., Yu J., Mao C., Giovenzana C., Nuovo G., Wei L., Zhang X., Gavrilin M.A., Wewers M.D., Caligiuri M.A. Interleukin-1beta selectively expands and sustains interleukin-22+ immature human natural killer cells in secondary lymphoid tissue. Immunity, 2010, Vol. 32, no. 6, pp. 803-814.
13. Hughes T., Becknell B., McClory S., Briercheck E., Freud A.G., Zhang X., Mao H., Nuovo G., Yu J., Caligiuri M.A. Stage 3 immature human natural killer cells found in secondary lymphoid tissue constitutively and selectively express the TH 17 cytokine interleukin-22. Blood, 2009, Vol. 113, no. 17, pp. 4008-4010.
14. Ivarsson M.A., Loh L., Marquardt N., Kekalainen E., Berglin L., Bjorkstrom N.K., Westgren M., Nixon D.F., Michaelsson J. Differentiation and functional regulation of human fetal NK cells. J. Clin. Invest., 2013, Vol. 123, no. 9, pp. 3889-3901.
15. Jauniaux E., Watson A.L., Hempstock J., Bao Y.P., Skepper J.N., Burton G.J. Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure. Am. J. Pathol., 2000, Vol. 157, no. 6, pp. 2111-2122.
16. Kaufmann P., Black S., Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol. Reprod., 2003, Vol. 69, no. 1, pp. 1-7.
17. Keskin D.B., Allan D.S., Rybalov B., Andzelm M.M., Stern J.N., Kopcow H.D., Koopman L.A., Strominger J.L. TGFbeta promotes conversion of CD16+ peripheral blood NK cells into CD16- NK cells with similarities to decidual NK cells. Proc. Natl. Acad. Sci. USA, 2007, Vol. 104, no. 9, pp. 3378-3383.
18. Lehmann D., Spanholtz J., Sturtzel C., Tordoir M., Schlechta B., Groenewegen D., Hofer E. IL-12 directs further maturation of ex vivo differentiated NK cells with improved therapeutic potential. PLoS One, 2014, Vol. 9, no. 1, p. e87131.
19. Luevano M., Daryouzeh M., Alnabhan R., Querol S., Khakoo S., Madrigal A., Saudemont A. The unique profile of cord blood natural killer cells balances incomplete maturation and effective killing function upon activation. Hum. Immunol., 2012, Vol. 73, no. 3, pp. 248-257.
20. Lysakova-Devine T., O'Farrelly C. Tissue-specific NK cell populations and their origin. J. Leukoc. Biol., 2014, Vol. 96, no. 6, pp. 981-990.
21. Male V., Hughes T., McClory S., Colucci F., Caligiuri M.A., Moffett A. Immature NK cells, capable of producing IL-22, are present in human uterine mucosa. J. Immunol., 2010, Vol. 185, no. 7, pp. 3913-3918.
22. Male V., Sharkey A., Masters L., Kennedy P.R., Farrell L.E., Moffett A. The effect of pregnancy on the uterine NK cell KIR repertoire. Eur. J. Immunol, 2011, Vol. 41, no. 10, pp. 3017-3027.
23. Manaster I., Mizrahi S., Goldman-Wohl D., Sela H.Y., Stern-Ginossar N., Lankry D., Gruda R., Hurwitz A., Bdolah Y., Haimov-Kochman R., Yagel S., Mandelboim O. Endometrial NK cells are special immature cells that await pregnancy. J. Immunol., 2008, Vol. 181, no. 3, pp. 1869-1876.
24. Min-Oo G., Kamimura Y., Hendricks D.W., Nabekura T., Lanier L.L. Natural killer cells: walking three paths down memory lane. Trends Immunol., 2013, Vol. 34, no. 6, pp. 251-258.
25. Oboshi W., Watanabe T., Matsuyama Y., Kobara A., Yukimasa N., Ueno I., Aki K., Tada T., Hosoi E. The influence of NK cell-mediated ADCC: Structure and expression of the CD16 molecule differ among FcgammaRIIIa-V158F genotypes in healthy Japanese subjects. Hum. Immunol., 2016, Vol. 77, no. 2, pp. 165-171.
26. Peng H., Jiang X., Chen Y., Sojka D.K., Wei H., Gao X., Sun R., Yokoyama W.M., Tian Z. Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J. Clin. Invest., 2013, Vol. 123, no. 4, pp. 1444-1456.
27. Piao H.L., Wang S.C., Tao Y., Fu Q., Du M.R., Li D.J. CXCL12/CXCR4 signal involved in the regulation of trophoblasts on peripheral NK cells leading to Th2 bias at the maternal-fetal interface. Eur. Rev. Med. Pharmacol. Sci., 2015, Vol. 19, no. 12, pp. 2153-2161.
28. Pinho M.J., Marques C.J., Carvalho F., Punzel M., Sousa M., Barros A. Genetic regulation on ex vivo differentiated natural killer cells from human umbilical cord blood CD34+ cells. J. Recept. Signal. Transduct. Res., 2012, Vol. 32, no. 5, pp. 238-249.
29. Rolle A., Brodin P. Immune adaptation to environmental influence: the case of NK cells and HCMV. Trends Immunol., 2016, Vol. 37, no. 3, pp. 233-243.
30. Romee R., Schneider S.E., Leong J.W., Chase J.M., Keppel C.R., Sullivan R.P., Cooper M.A., Fehniger T.A. Cytokine activation induces human memory-like NK cells. Blood, 2012, Vol. 120, no. 24, pp. 4751-4760.
31. Saito S., Nakashima A., Myojo-Higuma S., Shiozaki A. The balance between cytotoxic NK cells and regulatory NK cells in human pregnancy. J. Reprod. Immunol., 2008, Vol. 77, no. 1, pp. 14-22.
32. Srivastava S., Pelloso D., Feng H., Voiles L., Lewis D., Haskova Z., Whitacre M., Trulli S., Chen Y.J., Toso J., Jonak Z.L., Chang H.C., Robertson M.J. Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin. Cancer Immunol. Immunother., 2013, Vol. 62, no. 6, pp. 1073-1082.
33. Tao Y., Li Y.H., Piao H.L., Zhou W.J., Zhang D., Fu Q., Wang S.C., Li D.J., Du M.R. CD56(bright)CD25+ NK cells are preferentially recruited to the maternal/fetal interface in early human pregnancy. Cell Mol. Immunol., 2015, Vol. 12, no. 1, pp. 77-86.
34. Tilburgs T., Evans J.H., Crespo A.C., Strominger J.L. The HLA-G cycle provides for both NK tolerance and immunity at the maternal-fetal interface. Proc. Natl. Acad. Sci. USA, 2015, Vol. 112, no. 43, pp. 13312-13317.
35. Vivier E., Tomasello E., Baratin M., Walzer T., Ugolini S. Functions of natural killer cells. Nat. Immunol., 2008, Vol. 9, no. 5, pp. 503-510.
36. Wallace A.E., Goulwara S.S., Whitley G.S., Cartwright J.E. Oxygen modulates human decidual natural killer cell surface receptor expression and interactions with trophoblasts. Biol. Reprod., 2014, Vol. 91, no. 6, pp. 134.
37. Yu J., Freud A.G., Caligiuri M.A. Location and cellular stages of natural killer cell development. Trends Immunol., 2013, Vol. 34, no. 12, pp. 573-582.
38. Yun S., Lee S.H., Yoon S.R., Myung P.K., Choi I. Oxygen tension regulates NK cells differentiation from hematopoietic stem cells in vitro. Immunol. Lett., 2011, Vol. 137, no. 1-2, pp. 70-77.
Авторы:
Михайлова В.А. — к.б.н., научный сотрудник лаборатории межклеточных взаимодействий отдела иммунологии и межклеточных взаимодействий ФГБНУ «Научно-исследовательский институт акушерства, гинекологии ирепродуктологии имени Д.О. Отта»; ГБОУ ВПО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФ, кафедра иммунологии, Санкт-Петербург, Россия
Белякова К.Л. — лаборант-исследователь лаборатории межклеточных взаимодействий отдела иммунологии и межклеточных взаимодействий ФГБНУ «Научно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта», Санкт-Петербург, Россия
Сельков С.А. — д.м.н., профессор, заслуженный деятель науки, заведующий отделом иммунологии и межклеточных взаимодействий ФГБНУ «Научно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта», Санкт-Петербург, Россия
Соколов Д.И. — д.б.н., заведующий лабораторией межклеточных взаимодействий отдела иммунологии и межклеточных взаимодействий ФГБНУ «Научно-исследовательский институт акушерства, гинекологии и репродуктологии имени Д.О. Отта»; ГБОУ ВПО «Первый Санкт-Петербургский государственный медицинский университет имени академика И.П. Павлова» Министерства здравоохранения РФ, кафедра иммунологии; ведущий научный сотрудник отдела иммунологии ФГБНУ «Институт экспериментальной медицины», Санкт-Петербург, Россия
Authors:
Mikhailova V.A., PhD (Biology), Research Associate, Laboratory of Cell Interactions, Department of Immunology and Cell Interactions, D. Ott Research Institute of Obstetrics, Gynecology and Reproductology; Pavlov First St. Petersburg State Medical University, Department of Immunology, St. Petersburg, Russian Federation
Belyakova K.L., Laboratory Assistant, Laboratory of Cell Interactions, Department of Immunology and Cell Interactions, D. Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russian Federation
Selkov S.A., PhD, MD (Medicine), Professor, Honored Scientist, Head, Department of Immunology and Cell Interactions, D. Ott Research Institute of Obstetrics, Gynecology and Reproductology, St. Petersburg, Russian Federation
Sokolov D.I., PhD, MD (Biology), Head, Laboratory of Cell Interactions, Department of Immunology and Cell Interactions, D. Ott Research Institute of Obstetrics, Gynecology and Reproductology; Pavlov First St. Petersburg State Medical University, Department of Immunology; Leading Research Associate, Department of Immunology, Institute of Experimental Medicine, St. Petersburg, Russian Federation
Поступила 06.09.2016 Received 06.09.2016
Отправлена на доработку 07.09.2016 Revision received 07.09.2016
Принята к печати 22.09.2016 Accepted 22.09.2016
