Biomolecule-polymer hybrid compartments: combining the best of both worlds.

Compartmentalization is a fundamental principle in biology that is needed for the temporal and spatial separation of chemically incompatible reactions and biomolecules. Nano- or micro-sized compartments made of synthetic polymers are used to mimick this principle. The self-assembly of these polymers into vesicular objects is highly compatible with the integration of biomolecules, either into the lumen, the membrane or onto the surface of the vesicles. Thus, a great variety of biohybrid nano- and microscaled compartments has been developed exploiting the specific function and properties of targeting peptides, antibodies, enzymes, nucleic acids or lipids. Such biohybrid compartments have moved from simple systems encapsulating e.g. a model protein into complex multicompartmentalized structures that are able to combine the activity of different biomolecular cargos getting closer to the realization of artifical organelles or cells. Encapsulation of medically relevant cargos combined with careful design of the polymeric scaffold and specific surface functionalization have led to a significant progress in therapeutical applications such as targeted drug delivery or enzyme replacement therapy.

Expression of the inhibitory receptor NKG2A correlates with increased liver and splenic NK cell response to activating receptor engagement.

INTRODUCTION: Natural killer (NK) cells play a critical role in the innate immune response to viruses and tumors, and comprise a large proportion of the hepatic lymphocyte population. They must remain tolerant to non-pathogenic antigens while protecting the host from harmful agents. Herein, we investigate how the NK cell response to activation receptor engagement is altered in the liver. METHODS: In this study, we assess IFN-γ production and degranulation of splenic NK cells and selected subsets of liver NK cells. Flow cytometry (FCM) was used to asses IFN-γ production and degranulation following stimulation of the NK cells with plate bound antibodies to activating receptors. RESULTS: We show that smaller percentages of hepatic NK cells produce interferon (IFN)-γ and/or degranulate than do splenic NK cells upon stimulation through activating receptors. We also found that smaller percentages of the circulating NK (cNK) cells in the liver produce IFN-γ and/or degranulate, compared to the liver tissue resident NK (trNK) cells. In addition, IFN-γ production by liver cNK cells is not increased in IL-10 deficient mice, suggesting that their hyporesponsiveness is not mediated by the presence of this anti-inflammatory cytokine in the hepatic microenvironment. On the other hand, liver trNK cells express higher levels of the inhibitory receptor NKG2A than do cNK cells, correlating with their increased IFN-γ production and degranulation. CONCLUSIONS: Liver cNK cells' hyporesponsiveness to stimulation through activating receptors is independent of IL-10, but correlates with decreased NKG2A expression compared to trNK cells. In addition, we demonstrate that liver NK cells become further hyporesponsive upon continuous engagement of an activating receptor on their cell surface.

Acquisition of activation receptor ligand by trogocytosis renders NK cells hyporesponsive.

Because NK cells secrete cytotoxic granules and cytokines that can destroy surrounding cells and help shape the subsequent immune response, they must be kept under tight control. Several mechanisms, at different levels, are in place to control NK cell function. In this study, we describe a novel mechanism regulating NK cell function in which NK cells acquire ligands for activating receptors from target cells by trogocytosis, rendering the NK cells hyporesponsive. In this model, murine NK cells acquire m157, the murine CMV-encoded ligand for the Ly49H-activating receptor, from target cells both in vitro and in vivo. Although acquisition of m157 requires cell-to-cell contact, it does not require the expression of the Ly49H receptor by the NK cell. Acquired m157 protein is expressed on the NK cell surface with a glycosylphosphatidylinisotol linkage and interacts with the Ly49H receptor expressed on the NK cell. This interaction results in blocking the Ly49H receptor that prevents the NK cells from recognizing m157-expressing targets and continuous engagement of the Ly49H-activating receptor, which results in the hyporesponsiveness of the Ly49H(+) NK cell to stimulation through other activating receptors. Thus, NK cell acquisition of a ligand for an activation receptor by trogocytosis renders them hyporesponsive. This mechanism, by which mature NK cell function can be altered, has important implications in regard to how NK cells respond to tumors in specific microenvironments as well as the use of expanded NK cells in treating various malignancies.