E. M. Kuklina

Molecular mechanisms of T-cell anergy

Anergy is a long-term stable state of T-lymphocyte unresponsiveness to antigenic stimulation associated with the blockade of IL-2 production and proliferation. Anergy is a pathway of peripheral tolerance formation. In this review, mechanisms underlying T-cell tolerization are considered in a classical in vitro model of clonal anergy, and these mechanisms are compared with different pathways of anergy induction in vivo. Special attention is given to regulatory T-lymphocytes because, on one hand, anergy is a specific feature of these cells, and on the other hand anergy is also a mechanism of their action on target cells — effector T-lymphocytes. The role of this phenomenon in the differentiation of regulatory T-cells and also in the development of activation-induced apoptosis in effector T-lymphocytes is discussed.

Role of Transcription Factor NFAT in the Immune Response

Molecular mechanisms of activation of nuclear factor NFAT in cells of the lympho-myeloid complex are considered. Members of the NFAT family regulate transcription of genes encoding proteins involved in the induction and/or regulation of the immune response. It is possible that altered transcription activity of NFAT under conditions of its deficit or blockade of expression may account for changes in the immune status of an organism.

Role of Reproductive Hormones in Control of Apoptosis of T-Lymphocytes

Effects of chorionic gonadotropin (CG), estradiol, progesterone, and their physiological combinations on apoptosis of human peripheral blood T-lymphocytes were studied. Neither the hormones separately nor their combinations affected the spontaneous apoptosis of T-cells. On stimulation with mitogens, a high dose of CG (100 IU/ml) significantly increased apoptosis of T-lymphocytes, but its combination with steroid hormones specific for trimester I of pregnancy decreased this parameter. Apoptosis of T-lymphocytes induced by neutrophils in mixed culture was also inhibited by the hormone combination corresponding to trimester I. In greater detail, this hormonal combination was shown to display differential effects on different T-cell subpopulations: it stimulated apoptosis of CD8+-lymphocytes (which seemed to be provided by CG) and inhibited apoptosis of CD4+-cells. Apoptosis of T-lymphocytes induced by anti-CD95 was suppressed by a high dose of progesterone (100 ng/ml) and also by its combination with CG and estradiol specific for trimester III of pregnancy. Thus, the reproductive hormones studied effectively regulated apoptosis of peripheral blood T-lymphocytes. The effect of the hormones depended on the cell type and their activation and seemed to be an important mechanism of hormonal control of immune reactions in pregnancy.

Revision of the antigen receptor of T-lymphocytes

This review considers a crucially new mechanism of T-cell antigen-recognizing repertoire formation. It includes the revision of T-cell antigen receptor (TCR), which implies the secondary rearrangement of TCR genes in peripheral T-lymphocytes and surface expression of a new antigen receptor with altered specificity. Factors and mechanisms involved in the induction of this process have been analyzed. Certain attention is paid to a possible role of TCR revision in the formation of peripheral tolerance in the processes of “avidity maturation” of T-lymphocytes during immune response and also negative consequences related to appearance of potentially autoreactive clones in the periphery.

Extrathymic rearrangement of αβT-lymphocyte antigen receptor genes during pregnancy

The existence of αβT-lymphocyte differentiation processes have been demonstrated in mouse peripheral lymphoid organs during pregnancy. Study of pregnant Swiss mice has shown that the development of the second half of gestation is accompanied by expression of RAG-1 recombinase mRNA and unrearranged TCR α-chain (pre-TCRα) preferentially in T-lymphocytes of lymph nodes involved in uterine drainage (para-aortal lymph nodes), and to a lesser extent in other lymph nodes (mainly from axillary lymph nodes). The data suggest that during pregnancy the differentiation of αβT lymphocytes may occur not only in central (thymus) but also in peripheral lymphoid organs.

Reproductive hormones in the regulation of apoptosis of neutrophils.

The ability of main reproductive hormones such as chorionic gonadotropin (CG), estradiol, and progesterone to regulate apoptosis of human neutrophils was studied. The hormones were studied separately and in physiological combinations specific for different trimesters of pregnancy. A low dose of CG (10 IU/ml) increased the spontaneous apoptosis of neutrophils, whereas its combination with estradiol and progesterone corresponding to that of trimester III of pregnancy significantly decreased this parameter. The stimulating effect of CG was prevented by an inhibitor of protein kinase A, whereas the hormone-induced suppression of apoptosis depended on the activity of Ca2+-channels. The antiapoptotic effect of the hormonal combination corresponding to that of trimester III was also manifested in the presence of autologous T-lymphocytes and on stimulation of neutrophils by bacterial lipopolysaccharide. The apoptosis induced with monoclonal antibodies to CD95 was significantly suppressed by the hormones studied and their combinations. Thus, apoptosis of neutrophils is effectively regulated by reproductive hormones; this seems to be an important control mechanism of activation of these cells in pregnancy.

Role of cAMP and neutrophil cyclooxygenase in gonadotropin-dependent regulation of T lymphocyte proliferation.

The effect of the main pregnancy hormone, chorionic gonadotropin (CG), on proliferation of peripheral blood mononuclear cells (PBMC) was studied in the presence of autologous neutrophils; also, hormone-dependent regulation of the cAMP levels in T lymphocytes and neutrophils was evaluated. PBMC proliferation in response to a mitogen is suppressed by physiological doses of CG (10, 50, and 100 IU/ml). Autologous neutrophils enhance the suppression induced by the low dose of CG (10 IU/ml), but when cyclooxygenase was inhibited this effect was not observed; this suggests that the anti-proliferative effects of the low dose of CG can be mediated by the products generated by neutrophil cyclooxygenase. The effect of CG was associated with increased cAMP levels in T lymphocytes and neutrophils. Comparison of functional and cAMP-related effects of CG in both cell populations indicates that cAMP is involved in the anti-proliferative effects of CG.

Extrathymic αβT cells differentiation

Extrathymic differentiation is an alternative pathway of αßT lymphocyte development. In the normal state, it is expressed slightly and limited mainly by the liver and intestinal mucosa, but it significantly increases with age, as well as under certain physiological and pathological conditions, and acquires more widespread distribution. In the review, phenotypic and functional properties of T lymphocytes of extrathymic origin are examined in detail depending on their localization and activation conditions. Mechanisms of induction of such differentiation are analyzed. Particular attention is paid to the biological significance of extrathymic αßT cell development.

Extrathymic differentiation and antigen response of αβT lymphocytes in pregnancy

We studied reactivity of αβT-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 × BALB/c (normal allogenic pregnancy), CBA × CBA (syngenetic pregnancy), and CBA × DBA/2 (prone to abortion combination). It was shown that proliferative response of αβT-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 × DBA/2. In addition, cells of paraaortic 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.

Effects of Chorionic Gonadotropin on Differentiation of Thymocytes in the Presence of Epithelial Thymus Cells

We studied the effects of the main placental hormone, chorionic gonadotropin, on differentiation of human thymocytes in vitro in the presence of thymic epithelial cells. It was shown that the hormone at a high dose (100 IU/ml) enhanced the epithelium-induced phenotypic maturation of thymocytes, which is registered by an increased expression of the membrane marker CD3 and transition of CD4+8+ thymocytes in the cells with CD4+8– and CD4–8+ phenotypes. In addition, gonadotropin enhanced the proliferative response of thymocytes to the mitogen during their cultivation with the epithelium. The stimulating effect of the hormone on the epithelium-induced differentiation of thymocytes is mediated by the humoral factors of epithelial cells. In addition, gonadotropin at this dose exerts its own differentiating activity with respect to thymocytes and stimulates their phenotypic and functional maturation in a monoculture.