Molecular Mechanisms of Control of Differentiation of Regulatory T-Lymphocytes by Exogenous Melatonin.

We investigated the role of epiphyseal hormone melatonin in the differentiation of naive CD4+ T cells into regulatory T cells (Treg). The hormone at physiological and pharmacological concentrations inhibited Treg differentiation, decreasing both the proportion of CD4+FOXP3+ cells in the culture and the level of TGF-ß, the key cytokine for this T cell subpopulation. The inhibitory effect of exogenous melatonin was due to its interaction with the membrane receptors MT1 and MT2. At the same time, the signals realized through RORα-the nuclear receptor for melatonin-stimulated Treg formation; however, they were considerably weaker than the signals from the membrane receptors and were overlapped by the latter. Since the Treg subpopulation plays an important role in physiological and pathological processes in the body, the revealed effects of melatonin should be taken into account in its therapeutic use.

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-ß 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.

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.

[Extrathymic Differentiation of αßT Lymphocytes].

Extrathymic differentiation is an alternative way of αßT lymphocyte development. In normal conditions it is expressed slightly and limited mainly to the liver and intestinal mucous. However, it increases significantly with age, as well as in certain physiological and pathological conditions, buying more widespread. In the review, the phenotypical and functional features of extrathymic T lymphocytes have been considered in detail depending on their localization and a way of the process activation. The mechanisms of such differentiation induction have been analyzed. Special attention is paid to the biological significance of extrathymic αßT cell development.

[Extrathymic differentiation and antigen response of alphabetaT lymphocytes in pregnancy].

We studied reactivity of alphabetaT lymphocytes in CBA pregnant females toward male antigens and the presence of gene rearrangement in T-cells antigen receptor in peripheral lymphoid organs of mice in the case of three breeding variants: CBA x BALB/c (normal allogenic pregnancy), CBA x CBA (syngenetic pregnancy), and CBA x DBA/2 (prone to abortion combination). It was shown that proliferative response of alphabetaT lymphocytes in pregnant CBA females to male spleen cells was the most marked at normal allogenic pregnancy, the least marked at syngenic pregnancy, and was not observed at the combination CBA x DBA/2. In addition, cells ofparaaortic lymphatic nodes (draining uterus) respond to male antigen reliably more effectively than lymphocytes in mesenterial and axillary lymphatic nodes. Simultaneous estimation of recombinase RAG-1, the key enzyme in rearrangement of T-receptor genes, revealed similar principles: predominant activity of recombinase in T lymphocytes in paraaortal lymphatic nodes of CBA pregnant females. This points to the relationship between extrathymic rearrangement of antigen receptor genes and change in the antigen-detecting repertoire of these cells. The possible biological significance of the discovered phenomenon is discussed.