Postepy Hig Med Dosw. (online), 2012; 66: 674-682
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Antigen presenting cells costimulatory signaling during pre-implantation pregnancy
Sygnały kostymulacyjne wysyłane przez komórki prezentujące antigen w przedimplantacyjnym okresie ciąży
Anna Sławek, Tomasz Maj, Anna Chełmonska-Soyta
Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Laboratory of Reproductive Immunology, Wrocław
Corresponding author
Prof. Anna Chełmonska-Soyta, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Laboratory of Reproductive Immunology, R. Weigla Str. 12, 53-114 Wrocław, Poland; e-mail: soyta@ iitd.pan.wroc.pl

Source of support
This work is supported by Polish Ministry of Science and Higher Education, grant nr 474/N-COST/2009/0 related to COST Action FA0702 "Maternal Interaction With Gametes and Embryo"

Received:  2012.04.19
Accepted:  2012.08.09
Published:  2012.09.14

Streszczenie
Prawidłowy rozwój ciąży zależy od wielu współdziałających ze sobą czynników. Jednym z naj­ważniejszych jest ustalenie stanu tolerancji immunologicznej wobec antygenów semiallogenicz­nego płodu. W przedimplantacyjnym okresie ciąży zmieniające się środowisko hormonalne zależ­ne od cyklu jajnikowego, obecność nasienia w układzie rozrodczym, obecność oocytu i w końcu zarodka bezpośrednio i pośrednio oddziałują na komórki układu odpornościowego uczestniczące w powstawaniu tolerancji. W fazie indukcji odpowiedzi tolerogennej najważniejszą rolę odgry­wają komórki (APC) prezentujące antygen limfocytom dziewiczym. Wśród nich komórki den­drytyczne stanowią populację o najskuteczniejszej prezentacji ze względu na silne odziaływania kostymulacyjne. Komórki te komunikując się bezpośrednio z limfocytami T (kontakt komórka­-komórka) wysyłają sygnały kostymulacyjne, dzięki obecności tzw. cząsteczek kostymulacyjnych. Skutkiem prezentacji antygenu przez komórki APC w sprzyjającym środowisku cytokinowym jest indukcja limfocytów T o charakterze regulatorowym. Takie limfocyty odgrywają dominują­cą rolę w nabywaniu tolerancji obwodowej towarzyszącej ciąży. W artykule przedstawiono uwa­runkowania zmiennego potencjału kostymulacyjnego komórek prezentujących antygen w okre­sie przedimplantacyjnego rozwoju ciąży.
Słowa kluczowe: cząsteczki kostymulacyjne •komórki prezentujące antygen •ciąża


Summary
Success of pregnancy depends on many factors. Three phenomena inducing immune tolerance aga­inst semi-allogeneic conceptus may play a crucial role in the pre-implantation period of pregnancy: influence of sex hormones in sex cycle, presence of oocyte or embryo and the presence of semen in the female reproductive tract. On the other hand dendritic cells are the most effective antigen­-presenting cells in regulation of immune phenomena and also are considered as potent partici­pants in inducing immune tolerance in the pregnancy. They communicate with T cells in cell con­tact-dependent manner or via cytokines. During cell-cell contacts, costimulatory molecules play a key role and their expression is often dependent on cytokines milieu. Both costimulatory mole­cules and cytokines influence generation of T regulatory cells. Interactions of these molecules are closely related. In this paper we would like to pay attention to the importance of antigen presenting cells costimulatory potency in immune regulation during a pre-implantation period of pregnancy.
Key words: costimulatory molecules • antigen presenting cells • preimplantation pregnancy




Abbreviations:
Ag - antigen; APC - antigen presenting cell; BMDCs - bone marrow derived dendritic cells; CFSE - carboxyfluorescein succinimidyl ester; CTLA-4 - cytotoxic T-lymphocyte antygen-4; DC - dendritic cells; ERα - receptor α; G-CSF - granulocyte - colony stimulating factor; GM-CSF - granulocyte- macrophage - colony stimulating factor; hCG -human chorionic gonadotropin; HLA - human leukocyte antigen; HSP - heat shock protein; ICOS-1 - inducible costimulatory molecule 1; IDO - indoleamine 2,3-dioxygenase (IDO; EC 1.13.11.42); ICAM - intracellular adhesion molecule; IFN - interferon; IL - interleukin; iNKT -invariant NKT cell; LFA-1 - lymphocyte functional antigen-1; LPS - lipopolisaccharide; LN - lymph node; MHC - major histocompatibility complex; PD-1 - programmed death-1 antigen; ROR - related orphan receptor; TGF-β - transforming growth factor beta; Th - T helper lymphocyte; Tregs - regulatory T lymphocytes; URSA - unexplained recurrent spontaneous abortion.
Pre-implantation period of pregnancy as possible time of priming lymphocytes to developof immune tolerance
Implantation, a key process in an establishment of intimate contact between mother and fetus is a kind of paradox from an immunological point of view. On the one hand we can see a maternal organism, which has to fight infectious diseases, both locally in an uterus and peripherally, in other tissues. A female immune system should recognize each non-self an­tigens, especially proteins, and such action is a key point of immune response. On the other hand, molecules characte­ristic for sperm, zygotes and embryos are foreign for mater­nal immune system, since they are allogenic or semialloge­nic in their antigenic constituency. In 1953 Peter Medawar asked the key question in reproductive immunology: why immune system does not reject fetal cells and which immu­ne mechanisms are active for induction of immune toleran­ce against fetal cells [72]? After nearly 60 years the question is still topical, while some answers are known.
Thus, the pregnancy is an example of natural dilemma how to favor tolerance in face of continuous foreign antigens thre­aten. A lot of local and systemic events accompanied the pro­cess of pregnancy development, however a preimplatation pe­riod of pregnancy is critical for its maintenance. Recent data explain some of these crucial phenomena such as: pregnan­cy recognition or molecular interactions between uterus epi­thelium and embryo. However, it seems that the pre-implan­tation period of pregnancy is also important for priming the mother's immune system to recognize the antigenically fore­ign conceptus and to development of immune tolerance me­chanisms indispensable for its acceptance. It is the period of coexistence of many phenomena at the same time, which to­gether can initiate fetal-specific maternal immune tolerance.
Hormonal environment
The first of such mentioned above phenomena is an estro­us cycle-dependent regulation of a mother immune system. In the female reproductive tract, estrogens and progestero­ne are the main hormones influencing immune cells func­tion. The number and distribution of immune cells vary in a tissue-specific manner with the stage of the estrous cyc­le [49]. In the mice during estrus and diestrus-I, when an estrogen level in the uterus is the highest, the abudance of uterine macrophages with the expression of F4/80+ antigen (one of the surface markers of rodent macrophages) is also the highest. In contrast, in diestrus-II, when the estrogen le­vel decreases and the progesterone level increases, mature, major histocompatibility complex II (MHC II)-positive ma­crophages are found in small numbers [25,41]. Female rat steroid hormones regulate antigen presentation in the thy­mus: at estrus and proestrus the presentation is more effi­cient than at diestrus, when estradiol level is low [90,118]. Production of pro-inflammatory molecules in uterine leu­kocytes is also regulated by sex hormones [42]. Moreover, estrogen enhanced the Foxp3 transcription factor expres­sion, the most important regulatory T cells marker [88]. Dalal et al. [22] showed that risk of infection in each pha­se of estrous cycle is different. Mice were more suscepti­ble to Neisseria gonorrhoeae infection in an estrus. It is worth noting that influence of estrous cycle does not only limit to the reproductive tract, where though there it is the strongest. Maximal changes both at the local and systemic level precede ovulation that leads conclusion that modula­tion of immune response in the estrous cycle can be prepa­ration of mother's organism for the acceptance of embryo.
Cytokine environment
If the estrous cycle runs properly, the most important effect is an ovulation. Thus, the second signal of forthcoming pre­gnancy is the presence of ovulated oocyte in the lumen of reproductive tract. An ovulation is connected with disen­gagement of follicular fluid, which just like semen, is rich source of bioactive factors, like cytokines and growth fac­tors: IL-2, IL-4, IL-7, IL-8, IL-10, IL-13, IL12/IL-23, IL-18, G-CSF, IFN-gamma [16,83,111]. Follicular fluid induces the expression of IL-10 gene in lymphocytes. Moreover, in su­pernatants of lymphocytes incubated with the culture me­dium of sperms + oocytes, the concentration of IL-10 was significantly higher than in the lymphocytes incubated with follicular fluid alone. This result indicates the possibility of Th1/Th2 balance regulation shortly after fertilization [52].
Influence of semen
Obviously, the stage of estrous cycle and the presence of oocyte do not determine the beginning of pregnancy. However, if a fertile semen is present in female reproducti­ve tract the pregnancy is expected in a few hours. Therefore, the third factor, which can indirectly signaling incoming pre­gnancy is presence of a semen in a female reproductive tract during peri-ovulatory period. Seminal plasma is a rich so­urce of cytokines [14,64,74,78], hormones [81] and another bioactive substances, like prostaglandins [14]. Besides this, the presence of the semen itself stimulates the uterine mu­cous membrane to produce cytokines, like IL-1, TGF-β or GM-CSF [79,92]. The bioactive factors present in a seminal plasma and their influence on the female reproductive tract tissues evoke multidirectional effects. Spermatozoa and se­minal plasma induce a number of immune phenomena, espe­cially the influx of macrophages, dendritic cells and granu­locytes into the uteri of ewes, pigs and mice [47,71,80,101]. The number of endometrial macrophages increases consi­derably by two- to threefold after mating [9,24]. Moreover seminal fluid regulates the cytokines secretion and antigen presentation [91]. The influence of a semen on female im­mune response is visible several hours after an insemination. For example, one-time intravaginal application of bioactive TGF-β 3 can enhance success of pregnancy in an established abortion prone CBA x DBA/2 mouse model. The result co­uld be explained by a local recruitment of CD4+8+Foxp3+ cells [18]. In our own experiments we observed an eleva­tion of ERα level shortly after mating in splenic, but not in uterine macrophages. This observation probably indicates also an early systemic response to paternal antigens [87].
Therefore, we can speculate, that the permissiveness for pa­ternal/fetal antigens in female immune system is created very early after or even before fertilization. It seems to be reaso­nable from evolutionary point of view: a successful pregnan­cy and birth of the offsprings are the key points in the way of species survival and cheating of maternal immune sys­tem can be worth of its price. We can assume, that (1) es­trous stage of sex cycle ensures, that an uterus has a proper morphology and physiological properties needed for embryo implantation; (2) estrous stage means the presence of oocy­te(s); (3) the presence of fertile semen in connection with two previous factors leads to pregnancy. Thus, simultaneous presence of these three factors can prepare maternal immu­ne system for forthcoming pregnancy, even before fertiliza­tion. In this place the question of Sir Paul Medawar is still up-to-date: which mechanisms take part in setting up ma­ternal-fetal immune tolerance? To answer this question we have to look closer at the biology of antigen presenting cells.
Antigen delivery, presentation and recognition: a key process leading to immune tolerance
Antigen presenting cells (APCs) are the functionally dif­ferent cell subsets, sharing one basic property: they can endocyte foreign antigens, from their environment, digest them to small fragments (a few aminoacids oligopeptides in a case of proteins) and expose these oligopeptides on the cell surface as a complex with major histocompatibili­ty complex (MHC) class II proteins. Dendritic cells (DC) are a heterogeneous group of APCs, which are located in different tissues of an individual and they are known as the most potent APCs. During homeostasis DCs are tissue-re­sident cells. They efficiently absorb antigens present in the­ir environment by pinocytosis or endocytosis and the way of antigen internalization influences the effect of antigen presentation [11,48]. Tissue dendritic cells after picking-up antigens migrate to local lymph nodes where they acquired the state of maturity and expressed an array of costimula­tory molecules. Mature dendritic cells are capable of ef­fective antigen presentation to lymphocytes. Interdigitating DCs are capable to prime naive T cells. Other subsets of APCs, like monocytes/macrophages or B cells substantial­ly are not capable to priming T cells [7].
"Danger model" and pregnancy
Danger model of Poly Matzinger assumes that effectively protective immune response is developed when the non-self signal is associated with danger signal. Classical view of "danger" signal was concentrated on the presence of mi­crobial (like lipopolysacharide (LPS), CpG-rich sequen­ces etc.), viral (like ssDNA) or fungal antigens (like zymo­san), however contemporary comprehension is extended. In some cases specific invaders proteins and other compo­unds are not immunogenic. Some parasites are immuno­logically similar to individual's own antigens and in such situations DCs can sense the danger through receptors for heat shock proteins (HSP) released from stressed host cells [28,29,121]. Moreover, mediators secreted by other (non­-immune) cells in the tissue after infection or tissue dama­ge are able to stimulate DCs as well [67,95]. Danger model of immune response seems to fit well to the pregnancy: on the one hand we can see non-self (paternal) antigens, cy­tokines and other bioactive substances present in seminal plasma, on the other hand implantation of growing tropho­blast harms uterine tissue. As a result of activation, DCs and other APCs express higher level of MHC class II and co-stimulatory molecules (see next section), then they mi­grate to the nearest lymph node (LN) or another periphe­ral lymphoid organ and stimulate lymphocytes recognizing the antigens internalized in the tissue at the time of danger signal appearance [7]. Indeed, uterine DCs migrate to lo­cal lymph nodes even in the steady-state conditions, since CD11c+CFSEbright cells appeared in LN after 28 hours after CFSE injection into uterine lumen.. These DCs are imma­ture (iDCs), with low expression of costimulatory molecu­les. Localized in peripheral tissues they may migrate con­stitutively to secondary lymphoid organs under steady-state conditions inducing anergic, apoptotic, or T reg cells [105]. However, in transgenic mouse model using OVA expres­sion in a uterus and OVA-specific T cells Erlebacher et al., [27] demonstrated, that migratory DCs were also capable to elicit immune response. Such mature DCs (mDCs) express high levels of MHC class II and costimulatory molecules, including CD40, CD80 (B7-1), CD83 and CD86 (B7-2), on their surface. Nonetheless, in comparison with the ute­rus, the CD11c+ population in the uterine draining nodes express higher levels of both MHC class II and CD80 [8].
Three interactive signals: DC-T cell interaction
Three general signals are involved in DC-T cell cross-talk: the first is MHC - TCR signal, the second signal is me­diated by costimulatory molecules (especially B7-family members with their ligands like CD28 and CTLA-4) and the third by cytokines [60]. It is worth noting, that Ag-specific CD4+ and CD8+ T cell activation can occur after coitus in response to male seminal fluid Ags, via Ag cross­-presentation in female APCs [73]. Pooley et al. [89] indi­cate, that the CD8+ DCs, but not CD8- DCs, are specia­lized for in vivo cross-presentation of exogenous soluble Ags via the class I MHC presentation pathway.
In fact, the effect of antigen presentation is dependent on the properties of APC and other cells bound to these cells. For example, it is well known, that low-level expression of costimulatory molecules is connected with tolerogenic pro­perties of DCs, while high expression of these molecules results in inflammatory response. On the other hand, cyto­kines in environment of APC can modify the properties of these cells. After exposition of DCs to IL-10 the cells gain the ability to induce Foxp3+ Tregs [40]. At any time eve­ry single APC is tied with several different immune cells. The cells communicate not only with APC, but with other cells in such complex as well and in this way they create a microenvironment determining the outcome of antigen presentation. For instance, iNKT cells have ability to trig­ger tolerogenic phenotype of DCs [13] and Tregs, after in­teraction with DCs can not only down-regulate the level of CD80 and CD86 on APC, but also out-compete naive T cells, blocking their maturation and differentation [82]. Therefore, the result of antigen presentation is dependent on different cell-dependent and cell independent signals and APCs are a central point, orchestrating all of these phenomena. In these interactions especially in context of pregnancy the role of cytokines is considerably well-stu­died, on the other hand the role of costimulatory molecu­les, is still enigmatic.
The participation of dendritic cells and costimulatory molecules in tolerance induction
In general expression of costimulatory molecules on APC may be constitutive or regulated by external factors like hormones [50,77] and cytokines [10,53,103]. For example, the expression of MHC II and CD40, stimulatory capaci­ty and intracellular levels of IL-6 and IL-10 is increased, while the expression of CD54 and IL-12, endocytosis and nuclear level of NF-kappaB P65 of murine spleen CD11c-positive dendritic cells decreased after progesterone treat­ment [120]. On the other hand, the progesterone treatment of mature bone marrow-derivied dendritic cells (BMDCs) in rat caused down-regulation of costimulatory molecules CD80 and MHC II expression [12]. Another data consi­dering the influence of sex hormones on the maturation and function of human dendritic cells indicate, that unli­ke human chorionic gonadotropin (hCG), which inhibited HLA-DR expression, progesterone and estradiol (E2) did not prevent the upregulation of surface markers characte­ristic for mature DCs, such as CD40, CD83, and CD86. Moreover, hCG and E2 inhibit the T-cell stimulatory ca­pacity of DCs, which may help in preventing an allogenic T-cell response against the embryo [102].
CD40 and CD40L (CD154) belong to the TNF family ligands and receptors, that also includes OX40L, OX40 (CD134), 4-1BBL, 4-1BB (CD137), TRANCE (RANK), TRANCE (RANK-L), CD27, CD27L (CD70), CD30L (CD153), CD30 [65]. Originally B lymphocytes were described as a source of CD40. However, subsequent data indicated, that many cells also could express CD40, for example: monocytes/macropha­ges, dendritic (Langerhans) cells, epithelial cells and fibrobla­sts. Similarly, CD40L previously described on the activated CD4+ T lymphocytes, occurs also on monocytes/macropha­ges, dendritic cells, epithelial cells, mast cells, natural kil­ler (NK) cells and platelets [36,98]. At the amino acid level, human and murine CD40 share 62% overall sequence simi­larity [6]. Expression of CD40 and CD40L depends on the presence of cytokines. Shurin et al. [103] show, that IL-10 in­hibits CD40 expression on DCs and DC precursors and sup­press their maturation and function. On the other hand, IL-1, IL-12, TNF-α, GM-CSF, IFN-γ enhance the expression of CD40 and its ligand. The CD40-CD154 interactions can in­fluence T cell priming, T cell-mediated effector functions; they can also upregulate costimulatory molecules and acti­vate macrophages, NK cells and endothelia [36,98,99]. The CD40 activation improves the antigen presentation capaci­ty by B cells [63]. Darmochwal-Kolarz et al. [23] showed, that in pregnancy the expression of the CD40L on periphe­ral CD4+ T lymphocytes and the concentration of soluble CD40L were significantly lower than in non-pregnant women.
B7 family members play a critical role in maintaining fetal tolerance [86]. This family contains the most important mo­lecules for APCs-T cells interactions i.e.: CD80 (B7-1)/CD86 (B7-2) on APCs cooperating with CD28 or CTLA-4 on naive and activated T cells respectively, which together can induce tolerance or immunity [21]. These molecules play a critical role in the initiation of T-cell response. The CD28 and CD86 are constitutively expressed molecules, whereas CD80 and CTLA-4 are inducible upon activation. On murine activa­ted DCs, the surface expression of CD86 is 10 times greater than that of CD80. Engagement of CD28 on naive T cells by either CD80 or CD86 ligands on APCs provides a potent co­stimulatory signal for T cells activated through their T cell receptor, which results in an induction of IL-2 transcription and a CD25 expression [1,15,44]. Kelleher and Knight [53] showed, that IL-12 increased CD80 expression in bone mar­row-derived dendritic cells. On the other hand, recombinant IL-10 decreased CD86 expression at the human DCs purified from peripheral blood of healthy volunteers [10]. The lack of CD80 expression at the maternal-fetal interface in human was found by Petroff et al. [85]. However, this authors indi­cate, that CD86 is expressed by both maternal and some fe­tal macrophages. Restricted expression of CD80 and CD86 could inhibit maternal rejection of fetuses in abortion-pro­ne model of mice. The blocking antibodies administration caused an increase of T regulatory cells frequency and ske­wing toward a Th2 response. Bachy et al. [5] also show, that dendritic cell system in pregnancy favors Th2 response. On the other hand it is well known that blocking CD80/CD86 costimulation inhibits autoimmune disease progression in a variety of animal models [30,55,59,62].
Both CD80 and CD86 are able to bind CD28 and CTLA-4 molecules. Very often their function as molecules deli­vering the second signal to naive lymphocytes is join­tly considered.
However, despite their homology they differ in structure, mode of interaction with ligands and in effector function of a transmission of activating and inhibitory signals in co­stimulated lymphocytes. CTLA-4 binds with a higher af­finity to CD80 and CD86 than CD28 and downregulates the immune response [113]. CTLA-4 displays an important role in indoleamine-pyrole 2,3-dioxygenase (IDO) synthe­sis, an enzyme which promotes tolerance in murine pre­gnancy [37,75]. Moreover, recent data show, that regula­tory T cells contribute to peripheral tolerance by keeping the DCs in an immature state and CTLA-4 is necessary for control of DCs by regulatory T cells [97].
Another B7 family members: PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC) bind to the programmed cell death 1 (PD-1, CD-279) receptor on T cells and strongly inhibit CD4 T cells activation, thus they may also contribute to the ma­intenance of peripheral immune tolerance [100]. PD-L1 is constitutively expressed on mouse APCs (DCs, macropha­ges and B cells) and T cells. The expression of PD-L1 on cells surface was demonstrated on some endothelial cells as well as in tissues of placenta, testes and eye [26,51]. Tamura and colleagues [108] indicate, that this costimula­tory molecule is capable of enhancing T cell proliferation and IFN-γ, IL-10 and GM-CSF production. On the other hand, another studies show that interaction of PD-L1 or PD-L2 with PD-1 inhibits T cell proliferation and cytoki­ne production by phosphorylation of immunoreceptor ty­rosine-based switch motifs and blockade of T cell receptor signalling [21,31,33]. PD-L1 is highly expressed in human placenta [85] and its expression increases after IFN-γ or EGF treatment [84]. Cytokines IL-2, IL-7, IL-15, IL-21 up-regulate both PD-1 and its ligands both in vitro and in vivo, whereas proinflammatory (IL-1β, TNF-α, IL-6, IL-8), immunosuppressive (TGF-β, IL-10), and immuno­regulatory (IL-4, IFN-γ, IL-18) cytokines had no signifi­cant effect [57]. Polanczyk et al. [88] demonstrate, that both estrogen and pregnancy, enhanced PD-1 expression in several types of APCs.
Another member of B7 family - inducible costimulator ligand (ICOS-L) (also known as B7h, B7-RP1, GL50, LICOS, B7-H2) is expressed on most types of APC, subset of T cells, and also on endothelial cells [19,54]. Stimulation of ICOS on human T cells preferentially promotes IL-10 production, although production of IL-4, IL-5, IFN-γ, TNF-α, GM-CSF is also increased [43]. ICOS can sti­mulate both Th1 and Th2 cytokine production, but may have a preferential role in the generation of Th2 cells [70].
Suciu-Foca et al. [106] using cDNA microarray showed that expression of costimulatory molecules: CD40, CD80, CD86, OX40L, CD54 (ICAM-1 -intracellular adhesion molecule-1) and CD58 is down-regulated on tolerogenic DC. Interactions of ICAM-1 and ICAM-2 with LFA-1 (CD11a/CD18) are important for Th1/Th2 balance. Thus, blocking these interactions shifted Th1 immune response to a Th2 response (15- to 40-fold increase of Th2 cytoki­nes production) [96]. Moreover, IL-10 decreases ICAM-1 expression on monocytes [116]. Maturation state of DCs might be a control point for the induction of tolerance thro­ugh modifications of the activation state of T cells. iDCs are prone to induce regulatory T cells and promote toleran­ce, whereas mDCs stimulate effector T cells. Tolerogenic DCs are characterized by low MHC II, CD80 and CD86 expression. They also produce reduced level of IL-12. Molecules: IL-10, PD-L1 and IDO, which are expressed by DCs, may by connected signals to generate regulatory Tregs [68,93,100]. Immunosuppression, which is induced by iDCs, is mediated by both TGF-β- and IL-10-positive CD4+ regulatory T cells [20].
Interactions of costimulatory molecules and cytokines in Treg generation
In context of pregnancy, it was belived that during gestation a polarization of immune response towards Th2-mediated phenomena was critical for fetal tolerance [115]. However, this opinion is currently under discussion [17]. The impor­tance of Th1/Th2 balance is diminished after accurate de­scription of further Th cells subpopulations: Treg cells and Th17 cells. Tregs have a unique ability to antigen-specific and non-specific dampening of immune response and are characterized by expression of CD25 molecule, Foxp3 trans­cription factor, and secretion of immunoregulatory cytoki­nes TGF-β and IL-10 [32,114,117]. The presence of Tregs during gestation is one of the key points to acquire acti­ve tolerogenic immune response against fetal alloantigens [3,110]. Th17 cells are defined as CD4+ T cells expressing ROR-γt transcription factor and producing IL-17 [45]. Th17 cells seems to be harmful to the maintenance of pregnan­cy, at least in humans. Liu et al. [66] showed, that the pro­portion of Th17 cells and IL-17A concentration was both significantly higher in patients with unexplained recurrent spontaneous abortion (URSA) than in normal early pre­gnancy and non-pregnant patients. Moreover, the ratio of Th17 to Treg was also significantly higher in URSA group than in the other two. There are evidences, that develop­ment of Th17 and induced Treg cells during immune re­sponse is mutually exclusive [58] and Th17/Treg system is similar to the Th1/Th2 balance. All above mentioned T cell subset can convert into another subset. Conversion betwe­en Th1/Th2 cells is well documented. Treg cells in inflam­matory environment or converted to a population showing mixed properties of Th1 and Treg cells [122].
The induction and maintenance of tolerance is regulated by CD3+CD4+CD25+Foxp3+ regulatory T (Treg) cells, Th3 cells, Tr1 cells, regulatory NK cells and a trypto­phan-catabolizing enzyme IDO [4,94,109]. Th3 cells are characterized as cells, which produce immunosuppres­sive cytokine TGF-β, whereas Tr1 cells produce IL-10. Recently, it has been clarified that there are also a regula­tory NK cells: NK3 producing TGF-β, NKr1 producing IL-10 and NKreg also producing TGF-β [94]. However, recent reports suggest, that Treg cells play essential roles in alloantigen tolerance [2]. There are three mechanisms, by which this cells induce tolerance. In the first mecha­nism, cell-to-cell interaction-dependent membrane-bound TGF-β1 [76], Lag-3 [39] and galectin-1 [35] are involved. These cell-to-cell interactions inhibit T cells proliferation and NK cells activity. The second mechanism is when the cytokines such as TGF-β and IL-10 are produced by CD4+CD25+ Treg cells and inhibit T cell activation. The third mechanism depends on interactions CTLA-4 expres­sed on Treg cells with B7 complex on DCs and macropha­ges. These interactions induce interferon (IFN)-γ produc­tion and this cytokine, in turn, enhances the IDO expression on DCs or macrophages [37]. Thus, by catabolizing tryp­tophan, T cell activity is suppressed [75].The generating of Treg depends on costimulatory molecules expression. Wakkach et al. [112] demonstrate, that CD2-CD58 inte­raction induces the differentiation of regulatory T cells se­creting high level of IL-10 (Tr1 cells). CD28/CTLA-4 in­teractions with their B7-ligands are also very important. The blocking of CD80 and CD86 causes increasing Treg function [46]. The expression of costimulatory molecules is regulated by cytokines, for example IL-10 down-regu­lates CD80 [116] and CD86 [104] on APCs. The changes of costimulatory molecules expression are completed by changes in cytokines secretion, especially these regulating Th1/Th2 balance and Treg generation. The main cytoki­ne, which is responsible for Treg generation, is TGF-β. A subset of DCs, CD11c+CD205+, is specialized to indu­ce Treg in a TGF-β-dependent manner [119]. This cyto­kine, also present in semen, causes increase the level of two important Treg markers: Foxp3 [34] and CD25 [56].
Moreover, another cytokines play important roles in Treg generation and Th1/Th2 balance regulation, for example IL-10 [5,112] or IL-4, which determines the shape of im­mune response [38]. The effect of cytokines have a pleio­tropic character, since these proteins can both directly in­fluence the lymphocytes activity and can regulate APCs function, for example by regulation of costimulatory mo­lecules expression presented higher up.
Conclusions
In early pregnancy maternal immune system faces to fo­reign paternal antigens. Still there is not confirmed where and how their recognition is achieved, however costimu­lation potency of antigen presenting cells is changed un­der the influence of sex hormone, cytokines and mating act (Fig. 1). Therefore it may by assumed that proper co­stimulation of naive T cells may participate in favorable state of immune tolerance during pregnancy.
Figure 1. Costimulatory environment of T lymphocytes during pregnancy. Antigen presenting cells are present both in local and peripheral compartment. They have putative contact with paternal antigens and are aware of trophoblast antigens. They deliver the second-costimulatory signal to naive lymphocytes. The strength and duration on it is dependent on hormonal and cytokine environment. However, precise mechanisms of costimulation regulation remain still not well recognized

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The authors have no potential conflicts of interest to declare.
The work was corrected on Feb. 28, 2013