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1.  NK Cell Lytic Granules are Highly Motile at the Immunological Synapse and Require F-Actin for Post-degranulation Persistence1 
The formation of a dynamic, actin-rich immunological synapse (IS)3 and the polarization of cytolytic granules towards target cells are essential to the cytotoxic function of NK cells. Following polarization, lytic granules navigate through the pervasive actin network at the IS in order to degranulate and secrete their toxic contents onto target cells. We examined lytic granule motility and persistence at the cell cortex of activated human NK cells using high resolution total internal reflection microscopy (TIRFm) and highly quantitative analysis techniques. We illustrate that lytic granules are dynamic and observe substantial motility at the plane of the cell cortex prior to, but not after degranulation. We also show that there is no significant change in granule motility in the presence of Latrunculin A (which induces actin depolymerization), when added after granule polarization, but that there is a significant decrease in lytic granule persistence subsequent to degranulation. Thus, we show that lytic granules are highly dynamic at the cytolytic human NK cell IS prior to degranulation and that the persistence of granules at the cortex following exocytosis requires the integrity of the synaptic actin network.
PMCID: PMC3558996  PMID: 23066148
2.  Beta cell antigens in type 1 diabetes: triggers in pathogenesis and therapeutic targets 
Recognition of pancreatic beta cell antigens by autoreactive T lymphocytes plays a central role in the pathogenesis of insulin-dependent type 1 diabetes. Recent results suggest that non-conventional antigenic epitope processing and presentation may contribute to triggering and maintaining autoreactive responses. Moreover, promising results raise hope that autoantigens may become safe and specific therapeutics for type 1 diabetes in the future.
PMCID: PMC2981181  PMID: 21173836
3.  Regulation of translation is required for dendritic cell function and survival during activation 
The Journal of Cell Biology  2007;179(7):1427-1439.
In response to inflammatory stimulation, dendritic cells (DCs) have a remarkable pattern of differentiation (maturation) that exhibits specific mechanisms to control antigen processing and presentation. Here, we show that in response to lipopolysaccharides, protein synthesis is rapidly enhanced in DCs. This enhancement occurs via a PI3K-dependent signaling pathway and is key for DC activation. In addition, we show that later on, in a manner similar to viral or apoptotic stress, DC activation leads to the phosphorylation and proteolysis of important translation initiation factors, thus inhibiting cap-dependent translation. This inhibition correlates with major changes in the origin of the peptides presented by MHC class I and the ability of mature DCs to prevent cell death. Our observations have important implications in linking translation regulation with DC function and survival during the immune response.
PMCID: PMC2373495  PMID: 18166652
4.  Cell biological steps and checkpoints in accessing NK cell cytotoxicity 
Immunology and Cell Biology  2014;92(3):245-255.
Natural killer (NK) cell-mediated cytotoxicity is governed by the formation of a lytic immune synapse in discrete regulated steps, which give rise to an extensive array of cellular checkpoints in accessing NK cell-mediated cytolytic defense. Appropriate progression through these cell biological steps is critical for the directed secretion of specialized secretory lysosomes and subsequent target cell death. Here we highlight recent discoveries in the formation of the NK cell cytolytic synapse as well as the molecular steps and cell biological checkpoints required for this essential host defense process.
PMCID: PMC3960583  PMID: 24445602
cytotoxicity; innate immunity; natural killer cell
5.  No Major Role for Insulin-Degrading Enzyme in Antigen Presentation by MHC Molecules 
PLoS ONE  2014;9(2):e88365.
Antigen presentation by MHC class I molecules requires degradation of epitope source proteins in the cytosol. Although the preeminent role of the proteasome is clearly established, evidence suggesting a significant role for proteasome-independent generation of class I ligands has been reported repeatedly. However, an enzyme responsible for such a role has not been identified. Recently insulin-degrading enzyme (IDE) was shown to produce an antigenic peptide derived from the tumor antigen MAGE-A3 in an entirely proteasome-independent manner, raising the question of the global impact of IDE in MHC class I antigen processing. Here we report that IDE knockdown in human cell lines, or knockout in two different mouse strains, has no effect on cell surface expression of various MHC class I molecules, including allomorphs such as HLA-A3 and HLA-B27 suggested to be loaded in an at least a partly proteasome-independent manner. Moreover, reduced or absent IDE expression does not affect presentation of five epitopes including epitopes derived from beta amyloid and proinsulin, two preferred IDE substrates. Thus, IDE does not play a major role in MHC class I antigen processing, confirming the dominant and almost exclusive role of the proteasome in cytosolic production of MHC class I ligands.
PMCID: PMC3917890  PMID: 24516642

Results 1-5 (5)