David Kägi

Lymphocyte-mediated Cytotoxicity in vitro and in vivo: Mechanisms and Significance

Two classes of lymphocytes are able to exert contact-dependent cytotoxicity: cytotoxic T cells (CTL) react specifically against target cells presenting processed antigenic peptides on self MHC molecules whereas NK cells lyse a variety of target cells without classical restriction by MHC molecules. Although these two effector populations differ in specificity and lineage, the characteristics of their cytotoxic activity and some of their morphological aspects are remarkably similar (Henkart 1985). Because cytotoxicity is thought to be involved in a wide range of immune processes, the mechanisms accounting for lymphocyte-mediated cytotoxicity were studied intensively ever since cell-mediated cytolysis was first described (Govaertz 1960, Brunner et al. 1970). Important steps in the characterisation of cytolytic effector mechanisms were microscopic and microcinematographic studies showing that cytotoxic T cells form reversible conjugates with their target cells and secrete the content of their cytoplasmic granules during this process (Bykovskaja et al. 1978a,b, Matter 1979, Sanderson & Glauert 1979, Granger & Kolb 1968, Thiernesse et al. 1977, Zagury 1982), the isolation of perforin from granules of cytolytic lymphocytes and the demonstration that isolated perforin possess cytolytic activity in vitro (Podack et al. 1985. Young et al. I986a.b.c)., the observation of circular lesions on target cells lysed by lymphocytes (Dourmashkin et al. 1980, Dennert & Podack 1983) and the subsequent cloning of perforin (Shinkai et al. 1988, Lichtenheld et al. 1988) and other granule-associated proteins (Gershenfeld & Weissman 1986, Bleackley et al. 1988, Masson and

Pregnancy and perforin: What could be the role of a ‘natural killer’ in the decidua?

Summary Perforin is a cytotoxic molecule which is found in high concentration at the fetomaternal interface. In this location, perforin is contained in a specialized subset of natural killer cells, called uterine NK cells. By the use of perforin-deficient mice, we studied the function of perforin in the pregnant uterus. Perforin-deficient mice, we studied the function of perforin in the pregnant uterus. Perforin-deficient mice were found to reproduce as efficiently as wild type controls; however, they differed from normal in that the frequency of uterine NK cells was significantly higher and these cells were found to proliferate during more advanced stages of pregnancy. Lipopolysaccharide, which caused a massive increase of fetal resorptions in C57BL/6 control mice when given intraperitoneally on day 6.5 of pregnancy, had the same effect in the perforin-deficient counterpart. This argues against uterine NK cells being effector cells in infection-mediated abortion. Furthermore, no differences in fertility were observed under restricted mating conditions and with severe social stress. However, when embryo transfer was performed, the implantation of blastocysts was achieved in unprepared endometrium of perforin-deficient mice, which was not possible in wild type controls of the same genetic background. This could argue for a role of perforin in the defense of the mother against undue pregnancies.