I. V. Nekrasova

Role of Melatonin in the Regulation of Differentiation of T Cells Producing Interleukin-17 (Th17)

We studied the ability of melatonin in physiological and pharmacological concentrations to induce and/or regulate differentiation of T cells producing IL-17 (Th17). This hormone produced the opposite effect on CD4+T cells, which depended on their activation status. Melatonin induced the synthesis of IL-17A by intact T cells, but had little effect on activated cells. Melatonin in high (pharmacological) concentration decreased the intracellular expression of this cytokine under conditions of polyclonal activation. Melatonin had a dose-depended effect. Taking into the fact that Th17 cells play an important role in the immune defense, it can be suggested that the regulation of their activity by melatonin contributes to this process.

The role of pregnancy-associated hormones in regulation of expression of molecules responsible for NK cell functional activity

261 The phenomenon of tolerance of the immune syss tem of the mother to the genetically alien fetus is an urgent problem of reproductive immunology, in the framework of which analysis of the role of hormones in the immunity regulation is the most important line of research. It is known that, in the period of early pregg nancy, natural killers (NK cells) are the dominant population among lymphoid cells localized in the decidual membrane [1]. NK cells with the CD16 + CD56 dim phenotype account for over 90% of peripheral NK cells and exhibit high cytoxicity comm pared to CD16 – CD56 bright [2]. It is suggested that decidd ual NK cells mature from peripheral CD16 – CD56 bright lymphocytes migrating to the uterus [3]. During pregnancy, the cytotoxic potential of the NKKcell population decreases due to a decrease in the percentage of CD16 + CD56 dim lymphocytes. At the same time, the increased concentration of CD16 + 56 dim NK cells in the peripheral blood of women is associated with habitual miscarriage of pregg nancy [4], which is related to their ability to lyse cells of trophoblast [2]. In turn, CD16 – CD56 bright NK cells express inhibitory receptors, such as NKG2A and LILRB, due to which they fulfill an immunotrophic function instead of the cytolytic one [2]. For instance, CD16 – CD56 bright cells directly participate in implann tation, neoangiogenesis, and support of pregnancy [3]. In addition, NK cells potentiate the induction of TT regulatory lymphocytes, which leads to formation of immunologic tolerance in the period of pregnancy [5]. Along with CD16 molecule, the activation recepp tors NKG2D and NKp46 are responsible for the cytoo toxic function of NK cells, the latter is constitutionally expressed over the entire population of NK cells and serves as the main marker for their identification [6]. It is known that hormones can determine the funcc tional activity of the immune system cells [7]. The most physiologically important, from this point of view, are hormones that appear in the woman body only during pregnancy—chorionic gonadotropin (CG) and estriol (Е 3). Apart from this, the immunoo regulation function is exercised by hormones whose level considerably increases during pregnancy due to placental synthesis. These are, first of all, leptin, ghree lin, and kisspeptin. Their important role in reproducc tion regulation is well known [8–10]; however, the modulating activity with respect to NK cells at conn …

Hormonal regulation of thymic-stage differentiation of IL-17-producing and T-regulatory lymphocytes.

65 The immune system is exposed to a significant influence of the endocrine system. The thymic stage of T lymphocyte differentiation, when the main T cell populations are formed, is a potential target of the hormonal regulatory effect. Natural T regulatory lymphocytes (nTreg) that inhibit the effector cell pro liferation and IL 17 producing T lymphocytes (Th17) involved in initiating the inflammatory and autoim mune responses are the most important among T cell populations [1]. The immune response direction and formation of immune tolerance (during pregnancy or tumor growth) depend on the balance of regulatory T lymphocyte subtypes (Th17/Treg) [1].

Semaforin Sema4D in the immune system in multiple sclerosis.

The expression of class IV semaforin Sema4D and its CD72 receptor on lymphocytes was studied in patients with multiple sclerosis. The disease was associated with an increase in Sema4D level on intact T lymphocytes and with its more intense shedding from the membrane of activated cell. Multiple sclerosis was also associated with a decrease of CD72 receptor expression by B lymphocytes. Possible contribution of Sema4D to the disease development via the direct effects in the CNS and the immunomodulatory effect, specifi cally, B cell activity regulation, was discussed.

Hormonal regulation of the thymic stage of differentiation of invariant NKT cells.

331 Natural killer T cells (NKT cells) are effectors of innate immunity characterized by cytotoxic and immunoregulatory activities [1]. NKT cell differentii ation occurs in the thymus from doubleepositive (СD4 + СD8 +) thymocytes [1]. In humans, the NKT cell population is mainly presented by invariant (i) NKT cells expressing TTcellular receptor (TCR) with only one variant of the VVdomain of the αchain (Vα244JαQ) complexed with Vβ11, in contrast to nonninvariant lymphocytes (minor subpopulation) [1]. The TCR of iNKT cells has the ability to distinguish glycolipids presented by CD1d similar to the molee cules of the major histocompatibility complex [1]. The quantity of iNKTTcells in peripheral blood was shown to decrease in the case of normal pregnancy, while an increase in their quantity was reported to be associated with spontaneous miscarriage and preeclampsia [2]. Despite the small amount of iNKT cells in the periphh eral blood (less than 1.2% of the total quantity of T cells), they possess the ability for the rapid and massive cytokines production, which determines their role in the regulation of immune reactions [1]. Previously, we demonstrated that reproduction hormones, such as chorionic gonadotropin (hGC) and estriol (E 3), as well as leptin and ghrelin produced by placenta, were involved in the regulation of express sion of NKT cell surface markers in the peripheral blood [3] and were characterized by their own differr entiating and growth effects on intact thymocytes. Leptin is known to prevent steroiddinduced thymocyte apoptosis through stimulating СD4 + СD8 + thymocyte proliferation [4], while ghrelin is involved in prevenn tion of ageerelated thymus involution [5]. Accordd ingly, the problem of hormonal regulation of the thyy mic stage of iNKT cell differentiation is urgent in the context of fetomaternal immune interactions. The aim of the present study was to investigate the ability of hCG, Е 3 , leptin and ghrelin to regulate the growth and differentiation of iNKT cells at the level of intrathymic TTcell precursors. It has been established that hCG, Е 3 , and ghrelin decrease the quantity of iNKT cells in the cultured 72h lymphocytes at concentrations similar to the levv els of these hormones during pregnancy trimesters II and III. In contrast, leptin was observed to increase significantly the number of iNKT cells at a concentration similar to its level during pregnancy trimesters II and III. All the hormones studied did not significantly affected the quantity of iNKT cells …

Role of Endogenous Melatonin in the Regulation of Th17/Treg Balance during Pregnancy

We studied the role of endogenous melatonin in the development and functioning of T cells that produce IL-17 (Th17) and regulatory T cells (Treg) during pregnancy. The study was performed ex vivo and in vitro with auto-serum as the source of endogenous melatonin under conditions of blockade of melatonin-dependent signaling. Participation of the hormone in the regulation of differentiation of both CD4+RORγt+ and CD4+FoxP3+T cells and their key products IL-17A and TGF-β was demonstrated. It is known that the normal gestational process is accompanied by a decrease in Th17/Treg ratio due to hormonal changes. The sensitivity of the studied subpopulations to melatonin during pregnancy can affect its outcome.

Involvement of Semaphorin (Sema4D) in T-Dependent Activation of B Cells

The involvement of endogenous semaphorin (Sema4D) into the key stage of T-dependent differentiation of B cells, formation of plasmoblasts, was demonstrated in vitro in T/B cell co-culture under conditions of polyclonal activation of T cells. The effect of semaphorin was not associated with activation of high-affinity Sema4D receptor plexin B1, but involves lowaffinity receptor CD72. These data indicate that Sema4D-dependent signal regulates not only the initial stage of B-cell activation, proliferative response to the antigen, but also further differentiation of B cells into plasma cells.

The influence of chorionic gonadotropin and estriol on NK cell phenotype and functional activity

The influence of chorionic gonadotropin (CG) and estriol (Е3) at the concentrations typical of pregnancy on the expression of phenotypic markers and cytokine production by separated NK cells has been studied. It has been found that these hormones increase the percentage of CD56bright L-selectin+ NK cells, but also stimulate the expression of the inhibitory molecule NKG2A in the lymphocytes. In addition, Е3 and CG stimulate the production of TGF-β, inhibiting the secretion of all other cytokines by separated NK cells. In general, these hormones contribute to the formation of the phenotype and cytokine spectrum characteristic of the regulatory NK3 subpopulation of NK cells during pregnancy.

Roles of leptin and ghrelin in the regulation of the phenotype and cytokine production by NK cells from peripheral blood

Both leptin and ghrelin used separately at the concentrations corresponding to trimesters II–III of pregnancy increase the number of CD56bright NK cells in mononuclear cell suspension; their combination also enhances the L-selectin expression on the surface of these cells in the culture. These hormones do not affect the production of TGF-β1, IL-17А, or IFN-γ by NK cells, and they inhibit the production of IL-10. Leptin decreses the IL-4 production by NKp46+ cells, but the presence of ghrelin abrogates this effect.

Hormonal Regulation of Dendritic Cell Differentiation in the Thymus

We studied the effect of hormones estriol, ghrelin, kisspeptin, and chorionic gonadotropin in concentrations corresponding to their content in the peripheral blood in each trimester of pregnancy on the expression of membrane molecules on myeloid and plasmacytoid dendritic cells of the thymus. It was found that thymic myeloid dendritic cells are sensitive to the action of estriol and kisspeptin. Estriol in a concentration of the first trimester of pregnancy reduces the number of myeloid dendritic cells expressing receptor for thymic stromal lymphopoietin (CD11c+TSLP-R+) and inhibitory molecule B7-H3 (CD11c+CD276+). In contrast to estriol, kisspeptin regulates the processes of differentiation of thymic myeloid dendritic cells in concentrations typical of the second-third trimesters and reduced their total number (CD11c+) and the number of cells expressing TSLP-R (CD11c+TSLP-R+). Estriol and kisspeptin do not affect the total number of plasmacytoid dendritic cells (CD303+) and expression of TSLP-R and CD276 by these cells. Ghrelin and chorionic gonadotropin in the studied concentrations had no significant effect on the total number of thymic myeloid and plasmacytoid dendritic cells and on the expression of membrane molecules of TSLP-R and CD276.