engleski

Cytokine and hormone networks in the regulation of cytotoxicity at the interface

Human feto-placental unit (FPU) has a unique position of a true allograft residing for nine months in immunologically fully competent maternal organism. At the materno-fetal interface the FPU tissues, primarily various subsets of trophoblast cells, come into direct contact with a maternal decidua which is heavily infiltrated with maternal immunocompetent cells. Besides macrophages and classical T lymphocytes (CD3+ cells) decidual large granulated lymphocytes (dLGL) with an unusual phenotype (CD56bright+CD16-) and negative for T cell markers are the major leukocyte population present in the decidua. Therefore, cytolytic lymphocytes capable of both antigen specific and MHC restricted killing and antigen-nonspecific and MHC nonrestricted killing are present in the vicinity of fetoplacental allograft. Cytotoxic lymphocytes, both CTL and NK cells contain in their granules a pore forming protein - perforin (P), a cytolytic molecule which is a mediator in cell-mediated cytotoxicity reactions. Our recent investigations showed abundant P expression in decidual lymphocytes. The percentage of P+ cells was two times higher in the suspension of first trimester pregnancy decidual lymphocytes (55%) then in the PBL of the same women (27%). We have found that decidual macrophages are the source of stimuli holding P expression in decidual lymphocytes (DL) at extremely high levels. Decidual LGL are during pregnancy constantly targeted by Progesterone in high concentrations. Progesterone contributes to immunoregulation through the production of progesterone induced blocking factor (PIBF), which directly and indirectly affects P expression in cytolytic cells. Progesterone in a concentrations close to physiologic concentrations at the interface is suppressing cytolytic activity of decidual NK cells. PIBF also suppressed cytolytic activity of DL against NK sensitive line K-562. Maternal-fetal interface is also exposed to maternally acquired infectious agents and pathological processes, but as a rule there are no signs that immune functions are compromised. Very complex cytokine network is operating at the interface and can influence DL reactivity against infectious agents and fetoplacental allograft. Pregnancy generally favors the development of TH2 cytokines over TH1 type cytokines at the interface, and there is almost complete absence of IL-2. Recently, attention has been focused on the role of IL-15 in reproduction, which has many similarities but differences as well, with IL-2. IL-15 in a dose which is efficient in stimulating PBL activity, upregulates the cytolytic machinery (perforin expression) of DL, but not the functional cytolytic potential of these cells against the NK sensitive line K-562. Cytolytic potential is enhanced by stimulation of NK cells with IL-2, IL-12 and IL-12+IL-15 ; all of which are TH1 type cytokines that may prevail during infections and pathological pregnancies. Decidual macrophages influence P expression and cytolytic activity of DL, probably in a paracrine manner. Immunocytochemistry showed that decidual macrophages are IL-15 + cells. IL-18 induce gene expression and synthesis of TNF, IL-1, Fas ligand, and several chemokines. Activated macrophages were first shown to express high levels of IL-18. IL-18 plays an important role in the Th1 response, primarily by its ability to induce IFN production in T cells and NK cells. IL-18 shows a variety of biologic actions, including the stimulation of the proliferation of activated T cells, enhancement of the lytic activity of NK cells, induction of IFN and GM-CSF production. IL-18 alone, or in the combination with IL-10, IL-12 and IL-15 added overnight in the suspension of peripheral blood leukocytes or decidual cells, upregulates cytotoxic activity against NK sensitive cell line K562 in 2 hours cytotoxicity assay. By flow cytometry and immunocytochemistry we found IL-18 positive cell in the suspension of decidual adherent cells. IL-18 positive cells are giant cells that show the same distribution as GZ CT4 positive cells (marker for trophoblastic cells).

cytokines; interleukin-15; interleukin-18; pregnancy; decidual lymphocytes; perforin

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