Natural immunity最新文献

In an attempt to understand the basis of lowered natural killer (NK) and T cell functions in unaffected members from cancer families, we investigated cytotoxic T lymphocyte function (CD3-directed lysis) and the ability of the lymphocytes to respond to cytokines such as IL-2, IFN-alpha and IL-12. We observed lower CD3-mediated cytotoxic activity in these individuals supported by significantly lower numbers of circulating CD3+ lymphocytes. The cytokine treatment studies revealed impaired response to IFN-alpha and IL-12 in unaffected members and breast cancer patients. The observations presented herein not only reinforce our earlier finding that lower NK and T lymphocyte function may be a feature of cancer families, but also suggest that such impaired responses may be one of the factors contributing to lower cytotoxic potential of the circulating lymphocytes.

Mice expressing genetic alterations have been extremely valuable in providing insights into both the lineage relationships and functions of lymphohematopoietic cells. This approach has been applied to granulated lymphocytes that localize to implantation sites in the rodent uterus during pregnancy. Histological analyses of implantation sites collected from various mutant and transgenic mice over the course of gestation strongly support the conclusions that these granulated lymphocytes, previously named granulated metrial gland (GMG) cells, are natural killer (NK) cells and that they are essential for normal development of the placenta. Pregnancy-associated uterine NK (uNK) cells have limited lytic activity suggesting that their secretory products, particularly cytokines and matrix proteins, may be critical for normal placental maturation. This review will highlight information collected from pregnancies in mutant and transgenic mice that have contributed to the current understanding of functions of uNK cells during gestation.

In numerous investigations it has been found that natural killer (NK) cells are among the cells arriving early at the site of defense. To reach the tissue sites of defense, the circulating NK cells have to penetrate through the capillary wall and actively migrate along the matrix proteins towards the tumor or infected target cells. For this process NK cells need adhesion receptors which do not anchor them but allow reversible binding. The migration capacity of NK cells is found to be higher than that of other lymphocytes. NK cells also have the ability to increase rapidly the migratory response. IL-2 and a peptide derived from ICAM-2 are potential inducers of NK cell migration. ICAM-2 is expressed on endothelium, a site where lymphocytes start migration. Also, a matrix protein, fibronectin, increases NK cell migration. This review focuses on the migratory capacity of NK cells and on the receptors which NK cells use when they migrate on different substrata.

Murine lymphokine-activated natural killer (A-NK) cells are able to migrate to and accumulate in tumor metastases. However, the exact migratory pattern is as yet unknown. In the present study, we have investigated the migration from the vasculature towards malignant tissues of various effector cells. Our results indicate that murine A-NK cells seem to be arrested for an extended period of time in the microvasculature and also, although infrequently, to adhere to the endothelial lining of larger vessels close to tumor tissues before extravasation. While murine T lymphokine-activated killer and rat A-NK cells accumulate significantly in the subendothelial areas of larger venules in normal tissues, no such accumulation is observed with respect to murine A-NK cells. Electron microscopy reveals that the murine A-NK cells undergo an extreme deformation during extravasation and tumor infiltration. Furthermore, the cells are shown to be in an activated stage probably facilitating their migration, and hence, the elimination of tumor cells.

The human uterine mucosa is infiltrated by large numbers of CD56+ natural killer (NK) cells which are particularly abundant around the time of implantation and during early pregnancy. These NK cells have the phenotype CD56bright CD16-mCD3- and the characteristic morphology of large granular lymphocytes. The NK cells are in close association with the trophoblast cells which invade into the uterus. The expression of HLA class I antigens, HLA-G and HLA-C, by these trophoblast cells raises the possibility that maternal NK cells can recognise and respond to the fetal trophoblast cells. Thus, the maternal-fetal interaction, and hence reproductive success, may depend on an NK allorecognition system.

Despite the importance of natural killer (NK) cells in the immune response, the regulation of human NK cell growth has not been well characterized. We have hypothesized that, similar to the proliferation of T and B lymphocytes, optimal proliferation of NK cells requires costimulatory signals as well as a primary mitogenic stimulus. Evidence for costimulation by both soluble cytokines and cell contact-dependent factors is presented. Soluble IL-1 and TNF were found to augment NK cell proliferation in response to primary mitogenic cytokines, including IL-2, IL-4, IL-7, and IL-12. The costimulatory effect of IL-1 and TNF is strongly enhanced by the calcium ionophore ionomycin. Coculture of NK cells with irradiated K562 cells can largely substitute for the costimulatory signal provided by ionomycin. Costimulation by K562 requires intimate cell contact and is not reconstituted by cell-free supernatants. Activated T lymphocytes can also mediate contact-dependent costimulation of NK cells; resting PBMC, several NK-sensitive cell lines, and all NK-resistant cell lines tested were not found to be costimulatory. Engagement of CD16 did not augment NK cell proliferation. Thus, triggering of natural killing or antibody-dependent cell-mediated cytotoxicity (ADCC) does not consistently provide a costimulatory signal for NK cell proliferation. Cell contact-dependent costimulation of NK cells does not appear to involve known receptors that can costimulate T cells, including CD2, CD27, CD28, CD29, or LFA-1. The molecular nature of the putative NK cell costimulatory receptor remains to be elucidated. Nevertheless, human NK cells could be expanded in vitro using leukocyte-conditioned medium (LCM) as a source of IL-2 and accessory cytokines and ionomycin to bypass the putative receptor for cell contact-dependent costimulation. NK cells expanded in LCM and ionomycin express typical NK cell antigens and mediate natural killing and ADCC. Further characterization of the costimulatory signals for NK cell proliferation may elucidate the physiologic regulation of NK cell growth and may ultimately allow more effective manipulation of these lymphocytes in the immunotherapy of human diseases.

Mannan binding protein (MBP) may be important for host defence particularly in infancy. MBP concentration was measured in 237 umbilical cord blood samples from singleton pregnancies and compared to those of 352 blood donors. Both data sets yielded a bimodal frequency distribution, consisting of a log-normal peak and a long tail of lower values. The range (0-23 U/ml) and median (7.2 U/ml) of cord blood values were significantly lower than those of blood donors (range 0-43 U/ml; median 8.3 U/ml). MBP was also measured in the cord blood samples of 8 pairs of twin siblings. Discordant values in two pairs of twins suggest that cord blood MBP is derived from the fetoplacental unit and not from the maternal circulation by transplacental passage.

The epitheliochorial placenta represents the least intimate association between maternal and fetal tissues. The best known examples of this form of placentation are the domestic livestock species. Current information on the nature and proposed functions of uterine lymphocyte populations in ruminants (sheep and cattle), horses and pigs is presented. In ruminants unusual gamma delta T cells may play a role in mid to late gestation. During normal horse pregnancy, fetally derived endometrial cup cells invade the uterine stroma and are destroyed by maternal leukocytes midway through gestation. Natural killer (NK) cells or lymphokine-activated killer cells may be involved in this process, but the presence of these cell types in the equine uterus has yet to be established. The pig is similar to the human and rodent in that NK-like cells are present in the uterine stroma and seem to play a role in pregnancy. These cells are activated during early placental development and may be important in early interactions between the conceptus and the maternal immune system. The contribution of pregnancy-associated uterine lymphocytes to successful gestation has not been established. However, a common theme among these species is that the presence of the genetically foreign conceptus seems to activate uterine lymphocytes and to redirect their activities towards the promotion of fetal survival.

A galactoside-specific plant lectin, Viscum album agglutinin-I (VAA-I) with protein synthesis-inhibiting properties, has been shown to be cytotoxic in various eukaryotic cells, in vitro above a 10 ng/ml concentration. Noncytotoxic concentrations of VAA-I induced mRNA expression and enhanced secretion of proinflammatory cytokines in cultures of human peripheral blood mononuclear cells. In an animal model VAA-I has been shown to stimulate natural killer cells and granulocytes. In this study, human peripheral blood lymphocytes (PBL), human peripheral blood monocytes (PBM), murine thymocytes and human monocytic THP-1 cells were incubated for 24 h in the presence of various concentrations of VAA-I. The apoptotic effect of VAA-I was analyzed by flow cytometry following staining of the apoptotic nuclei in the cells with PI in hypotonic buffer and quantitative detection of DNA breaks were analyzed by the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) assay. In cultures of all types of investigated cells, a dose-dependent VAA-I concentrations above 10 ng/ml in PBL and at 1 ng/ml VAA-I concentration in PBM, thymocytes and THP-1 cells, a lectin-induced increase of the apoptotic nuclei was observed. In 24-hour cultures of PBL and thymocytes, the ratios between apoptotic and nonapoptotic cells were enhanced 10 times and 8 times, respectively, by 100 ng/ml VAA-I compared to the negative control. The concentration of 100 micrograms/ml VAA-I only caused necrosis. The isolated A chain of the VAA-I induced apoptosis in PBL and thymocytes. In the culture of PBL the isolated B chain of the VAA-I was not effective indicating that cytokine induction by VAA-I is probably not involved in its apoptotic effect. On CD4+8+ thymocytes, VAA-I resulted in a reduced expression of CD8+ molecules that could be related to a loss of volume and increase of density, both characteristic features of apoptosis.