engleski

Lymphocyte mediated cytotoxicity at the interface

Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are the two main types of immune cytotoxic cells that have an important role in eliminating virus-infected cells, tumor surveillance as well as in regulating and terminating the immune response. The cytotoxic mechanisms used by NK cells or CTL at the molecular level are generally very similar and use either perforin and granzymes or death ligands and death receptors. Perforin and granzymes are both stored exclusively in the cytoplasmic granules of the cytotoxic cells. Upon the granule release, these molecules, complexed with the proteoglycan serglycin, enter the target cell and then become able to induce apoptosis by cleaving a selected set of cellular proteins. The second pathway is a death receptor pathway mediated by the ligation of cell death ligands and receptors on target cells, such as the members of the tumor necrosis factor (TNF)-receptor family, Fas and Fas ligand (FasL) (type I and type II transmembrane proteins, respectively). During pregnancy, the maternal-fetal interface is a zone of close contact and immunological interrelations between maternal tissues and fetal semiallogeneic trophoblast cells. It represents an active interplay between different immunocompetent cell types. Normal human early pregnancy decidua is infiltrated by a substantially high proportion of leukocytes, predominantly lymphocytes and macrophages. Uterine NK (uNK) cells (CD3-CD16-CD56 bright) constitute approximately 70-80% of resident lymphocytes in the first trimester pregnancy decidua while they comprise only 10% of peripheral blood NK cells. These cells proliferate, enlarge and acquire numerous granules filled with cytolytic mediators (perforin, granzymes and TNF-a). Perforin content in decidua is higher than in any other tissue under physiological or pathological conditions since more than 95% of all decidual CD56bright+ cells expressed perforin. It seems paradoxical that these cells accumulate in decidua during normal pregnancy, when the cytotoxicity should be overridden in favor of maternal tolerance. Besides perforin, many studies reported the presence of FasL molecule in murine and human pregnant and non-pregnant uterus. FasL expression was localized to sites of direct contact between placental tissue and the maternal immune system. Generally, FasL is stored in intracellular granules of T and NK cells and can be exocytosed upon non-specific activation of these cells. Such secretion of FasL is associated with apoptosis of Fas+ targets, although the cell-cell contact is avoided. Our recent investigation (in preparation for publication), revealed that uterine CD56bright cells, obtained after 18 hour-culture in the suspension of decidual mononuclear cells efficiently killed P815 mouse mastocytoma cell line, which can be attacked by LAK cells only. Trophoblast cells, besides FasL, also express Fas molecule, and trophoblast is protected of the killing by activated maternal lymphocytes during normal pregnancy. Although both cytolytic mediators, perforin and FasL, were thoroughly investigated at the maternal-fetal interface, relatively little is known about the nature of the mechanisms or the factors that regulate their expression. Cytokines at the maternal-fetal interface are primary candidates for these functions. A lot of studies in the past have failed to detect IL-2 protein in the first trimester pregnancy deciduas. IL-15, a stromal cell and macrophage-derived cytokine, is critical for NK differentiation in human and murine lymphoid tissue and NK cell development in decidualizing uterus. Similarly to IL-2 and IL-12, IL-15 enhances peripheral blood NK cell cytotoxicity mediated by perforin, granzymes and IFN-g. The precise role of both perforin and Fas/FasL mechanisms during pregnancy remains hypothetical. The high cytolytic potential of uNK cells most probably ensures protection of the mother and fetus against microbial attack, but still does not explain the need for such significant cytotoxic armamentarium during pregnancy. Knockout mice represent the excellent models for studying perforin and/or FasL deficiency allowing us to characterize the biology of these cytolytic mediators during pregnancy. It seems that the essential function of these two rapidly acting cytolytic effector pathways would be in regulating the homeostasis of uNK cells. Granule exocytosis pathway (perforin) and Fas/FasL system clearly represent two major rapid cytolytic pathways through which locally acting cytokines and hormones may influence the activation status of uNK cells and participate in the immune modulation at the maternal-fetal interface.

Cytotoxic T lymphocytes (CTL); Natural killer (NK) cells; Tumor necrosis factor; Perforin; Pregnancy

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