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1.  Distinct Integrin-Dependent Signals Define Requirements for Lytic Granule Convergence and Polarization in Natural Killer Cells 
Science signaling  2014;7(346):pe24.
Lytic granules in natural killer (NK) cells represent a dangerous cargo that is targeted for secretion to destroy diseased cells. The appropriate management of these organelles enables the mounting of a precise and valuable host defense. The process of NK cell adhesion to a target cell through engagement of the integrin LFA-1 (lymphocyte function–associated antigen 1) promotes lytic granule organization through complex cellular mechanics and a signaling pathway characterized by Zhang et al. in this issue of Science Signaling. A limited, partially overlapping set of signaling molecules can be distinguished for their ability to promote the convergence of NK cell lytic granules on the microtubule organizing center and their polarization as they progress en masse toward the interface with a target cell.
PMCID: PMC4369380  PMID: 25292212
2.  PTEN Is a Negative Regulator of NK Cell Cytolytic Function 
Human NK cells are characterized by their ability to initiate an immediate and direct cytolytic response to virally infected or malignantly transformed cells. Within human peripheral blood, the more mature CD56dim NK cell efficiently kills malignant targets at rest, whereas the less mature CD56bright NK cells cannot. In this study, we show that resting CD56bright NK cells express significantly more phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein when compared with CD56dim NK cells. Consistent with this, forced overexpression of PTEN in NK cells resulted in decreased cytolytic activity, and loss of PTEN in CD56bright NK cells resulted in elevated cytolytic activity. Comparable studies in mice showed PTEN overexpression did not alter NK cell development or NK cell–activating and inhibitory receptor expression yet, as in humans, did decrease expression of downstream NK activation targets MAPK and AKT during early cytolysis of tumor target cells. Confocal microscopy revealed that PTEN overexpression disrupts the NK cell’s ability to organize immunological synapse components including decreases in actin accumulation, polarization of the microtubule organizing center, and the convergence of cytolytic granules. In summary, our data suggest that PTEN normally works to limit the NK cell’s PI3K/AKT and MAPK pathway activation and the consequent mobilization of cytolytic mediators toward the target cell and suggest that PTEN is among the active regulatory components prior to human NK cells transitioning from the noncytolytic CD56bright NK cell to the cytolytic CD56dim NK cells.
PMCID: PMC4319309  PMID: 25595786
3.  Follicular Helper T Cells Promote Liver Pathology in Mice during Schistosoma japonicum Infection 
PLoS Pathogens  2014;10(5):e1004097.
Following Schistosoma japonicum (S. japonicum) infection, granulomatous responses are induced by parasite eggs trapped in host organs, particular in the liver, during the acute stage of disease. While excessive liver granulomatous responses can lead to more severe fibrosis and circulatory impairment in chronically infected host. However, the exact mechanism of hepatic granuloma formation has remained obscure. In this study, we for the first time showed that follicular helper T (Tfh) cells are recruited to the liver to upregulate hepatic granuloma formation and liver injury in S. japonicum-infected mice, and identified a novel function of macrophages in Tfh cell induction. In addition, our results showed that the generation of Tfh cells driven by macrophages is dependent on cell–cell contact and the level of inducible costimulator ligand (ICOSL) on macrophages which is regulated by CD40–CD40L signaling. Our findings uncovered a previously unappreciated role for Tfh cells in liver pathology caused by S. japonicum infection in mice.
Author Summary
Schistosomiasis is a chronic helminthic disease that affects approximately 200 million people. After S. japonicum infection, parasite eggs are trapped in host liver and granulomas are induced to form around eggs. Severe granuloma subsequently results in serious liver fibrosis and circulatory impairment chronically. It is important to fully elucidate the mechanism of the granuloma formation. Here, we show that Tfh cells play a novel role of promoting the hepatic granuloma formation and liver injury, and identified a novel function of macrophages in Tfh cells induction in S. japonicum-infected mouse model. In addition, we show that the generation of Tfh cells driven by macrophages is cell–cell contact dependent and regulated by CD40-CD40L signaling. Our findings revealed a novel role and mechanism of macrophages in Tfh cell generation and the liver pathogenesis in S. japonicum-infected mouse model.
PMCID: PMC4006917  PMID: 24788758
4.  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
5.  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
6.  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
7.  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
8.  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

Results 1-8 (8)