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1.  The draft genome of Primula veris yields insights into the molecular basis of heterostyly 
Genome Biology  2015;16(1):12.
Background
The flowering plant Primula veris is a common spring blooming perennial that is widely cultivated throughout Europe. This species is an established model system in the study of the genetics, evolution, and ecology of heterostylous floral polymorphisms. Despite the long history of research focused on this and related species, the continued development of this system has been restricted due the absence of genomic and transcriptomic resources.
Results
We present here a de novo draft genome assembly of P. veris covering 301.8 Mb, or approximately 63% of the estimated 479.22 Mb genome, with an N50 contig size of 9.5 Kb, an N50 scaffold size of 164 Kb, and containing an estimated 19,507 genes. The results of a RADseq bulk segregant analysis allow for the confident identification of four genome scaffolds that are linked to the P. veris S-locus. RNAseq data from both P. veris and the closely related species P. vulgaris allow for the characterization of 113 candidate heterostyly genes that show significant floral morph-specific differential expression. One candidate gene of particular interest is a duplicated GLOBOSA homolog that may be unique to Primula (PveGLO2), and is completely silenced in L-morph flowers.
Conclusions
The P. veris genome represents the first genome assembled from a heterostylous species, and thus provides an immensely important resource for future studies focused on the evolution and genetic dissection of heterostyly. As the first genome assembled from the Primulaceae, the P. veris genome will also facilitate the expanded application of phylogenomic methods in this diverse family and the eudicots as a whole.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0567-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-014-0567-z
PMCID: PMC4305239  PMID: 25651398
2.  Activation of Invariant Natural Killer T-cells in Periodontitis Lesions 
Periodontitis is one of the most prevalent human inflammatory diseases. The major clinical phenotypes of this polymicrobial, biofilm-mediated disease are chronic and aggressive periodontitis, the latter being characterized by a rapid course of destruction that is generally attributed to an altered immune-inflammatory response against periodontal pathogens. Still, the biological basis for the pathophysiological distinction of the two disease categories has not been well documented yet.
Type I natural killer T (NKT) cells are a lymphocyte subset with important roles in regulating immune responses to either tolerance or immunity, including immune responses against bacterial pathogens. Here, we delineate the mechanisms of NKT cell activation in periodontal infections.
We show an infiltration of type I NKT cells in aggressive, but not chronic periodontitis lesions in vivo. Murine DCs infected with aggressive periodontitis-associated Aggregatibacter actinomycetemcomitans triggered a type I interferon response followed by type I NKT cell activation. In contrast, infection with Porphyromonas gingivalis, a principal pathogen in chronic periodontitis, did not induce NKT cell activation. This difference could be explained by the absence of a type I interferon response to P. gingivalis infection. We found these interferons to be critical for NKT cell activation.
Our study provides a conceivable biological distinction between the two periodontitis subforms and identifies factors required for the activation of the immune system in response to periodontal bacteria.
doi:10.4049/jimmunol.1201215
PMCID: PMC3620697  PMID: 23365081
natural killer T cells; immune evasion; bacterial pathogenesis; Porphyromonas gingivalis; Aggregatibacter actinomycetemcomitans
3.  Staurosporine and Extracellular Matrix Proteins Mediate the Conversion of Small Cell Lung Carcinoma Cells into a Neuron-Like Phenotype 
PLoS ONE  2014;9(2):e86910.
Small cell lung carcinomas (SCLCs) represent highly aggressive tumors with an overall five-year survival rate in the range of 5 to 10%. Here, we show that four out of five SCLC cell lines reversibly develop a neuron-like phenotype on extracellular matrix constituents such as fibronectin, laminin or thrombospondin upon staurosporine treatment in an RGD/integrin-mediated manner. Neurite-like processes extend rapidly with an average speed of 10 µm per hour. Depending on the cell line, staurosporine treatment affects either cell cycle arrest in G2/M phase or induction of polyploidy. Neuron-like conversion, although not accompanied by alterations in the expression pattern of a panel of neuroendocrine genes, leads to changes in protein expression as determined by two-dimensional gel electrophoresis. It is likely that SCLC cells already harbour the complete molecular repertoire to convert into a neuron-like phenotype. More extensive studies are needed to evaluate whether the conversion potential of SCLC cells is suitable for therapeutic interventions.
doi:10.1371/journal.pone.0086910
PMCID: PMC3938400  PMID: 24586258
4.  Development of 12 polymorphic microsatellite loci in the high alpine perennial Primula halleri (Primulaceae)1 
Applications in Plant Sciences  2013;1(12):apps.1300052.
• Premise of the study: Primula halleri is a high alpine endemic species with a patchy distribution in Central and Eastern European mountains. Little is known about the structure of genetic variation and mating system in populations of this species.
• Methods and Results: We report on the development of 12 novel, polymorphic microsatellite loci for P. halleri. Tests for amplification and polymorphism were performed on 45 individuals sampled from three populations in the Swiss Alps. Interspecific amplification of the loci was evaluated using samples of the closely related species P. farinosa, P. frondosa, and P. scotica.
• Conclusions: The results show that the new microsatellite loci will be useful to study the structure of genetic diversity and mating system of P. halleri, and possibly its closely related species.
doi:10.3732/apps.1300052
PMCID: PMC4103119  PMID: 25202506
genetic diversity; microsatellite; Primula halleri; Primula sect. Aleuritia
5.  Role of the NK Cell-Activating Receptor CRACC in Periodontitis 
Infection and Immunity  2013;81(3):690-696.
Periodontitis is a highly prevalent, biofilm-mediated chronic inflammatory disease that results in the loss of the tooth-supporting tissues. It features two major clinical entities: chronic periodontitis, which is more common, and aggressive periodontitis, which usually has an early onset and a rapid progression. Natural killer (NK) cells are a distinct subgroup of lymphocytes that play a major role in the ability of the innate immune system to steer immune responses. NK cells are abundant in periodontitis lesions, and NK cell activation has been causally linked to periodontal tissue destruction. However, the exact mechanisms of their activation and their role in the pathophysiology of periodontitis are elusive. Here, we show that the predominant NK cell-activating molecule in periodontitis is CD2-like receptor activating cytotoxic cells (CRACC). We show that CRACC induction was significantly more pronounced in aggressive than chronic periodontitis and correlated positively with periodontal disease severity, subgingival levels of specific periodontal pathogens, and NK cell activation in vivo. We delineate how Aggregatibacter actinomycetemcomitans, an oral pathogen that is causally associated with aggressive periodontitis, indirectly induces CRACC on NK cells via activation of dendritic cells and subsequent interleukin 12 (IL-12) signaling. In contrast, we demonstrate that fimbriae from Porphyromonas gingivalis, a principal pathogen in chronic periodontitis, actively attenuate CRACC induction on NK cells. Our data suggest an involvement of CRACC-mediated NK cell activation in periodontal tissue destruction and point to a plausible distinction in the pathobiology of aggressive and chronic periodontitis that may help explain the accelerated tissue destruction in aggressive periodontitis.
doi:10.1128/IAI.00895-12
PMCID: PMC3584889  PMID: 23250953
6.  A Simple Method for Estimating Informative Node Age Priors for the Fossil Calibration of Molecular Divergence Time Analyses 
PLoS ONE  2013;8(6):e66245.
Molecular divergence time analyses often rely on the age of fossil lineages to calibrate node age estimates. Most divergence time analyses are now performed in a Bayesian framework, where fossil calibrations are incorporated as parametric prior probabilities on node ages. It is widely accepted that an ideal parameterization of such node age prior probabilities should be based on a comprehensive analysis of the fossil record of the clade of interest, but there is currently no generally applicable approach for calculating such informative priors. We provide here a simple and easily implemented method that employs fossil data to estimate the likely amount of missing history prior to the oldest fossil occurrence of a clade, which can be used to fit an informative parametric prior probability distribution on a node age. Specifically, our method uses the extant diversity and the stratigraphic distribution of fossil lineages confidently assigned to a clade to fit a branching model of lineage diversification. Conditioning this on a simple model of fossil preservation, we estimate the likely amount of missing history prior to the oldest fossil occurrence of a clade. The likelihood surface of missing history can then be translated into a parametric prior probability distribution on the age of the clade of interest. We show that the method performs well with simulated fossil distribution data, but that the likelihood surface of missing history can at times be too complex for the distribution-fitting algorithm employed by our software tool. An empirical example of the application of our method is performed to estimate echinoid node ages. A simulation-based sensitivity analysis using the echinoid data set shows that node age prior distributions estimated under poor preservation rates are significantly less informative than those estimated under high preservation rates.
doi:10.1371/journal.pone.0066245
PMCID: PMC3673923  PMID: 23755303
7.  Development of 13 microsatellite markers in the endangered Sinai primrose (Primula boveana, Primulaceae)1 
Applications in Plant Sciences  2013;1(6):apps.1200515.
• Premise of the study: We developed microsatellite markers for the endangered plant Primula boveana, the Sinai primrose, and assessed the cross-transferability of these markers to six related taxa.
• Methods and Results: DNA sequences containing microsatellites were isolated from a microsatellite-enriched library. We obtained successful amplification of 13 microsatellite primer pairs, seven of which were polymorphic in P. boveana. Eleven of these primers successfully cross-amplified to related taxa.
• Conclusions: The markers reported herein will be useful to characterize the genetic diversity of the endangered P. boveana and to evaluate its mating system, and have the potential to be useful for similar studies in close relatives.
doi:10.3732/apps.1200515
PMCID: PMC4105029  PMID: 25202556
cross-amplification; Dionysia; microsatellites; Primula boveana; Sinai; sect. Sphondylia.
8.  Historical Biogeography and Diversification of Truffles in the Tuberaceae and Their Newly Identified Southern Hemisphere Sister Lineage 
PLoS ONE  2013;8(1):e52765.
Truffles have evolved from epigeous (aboveground) ancestors in nearly every major lineage of fleshy fungi. Because accelerated rates of morphological evolution accompany the transition to the truffle form, closely related epigeous ancestors remain unknown for most truffle lineages. This is the case for the quintessential truffle genus Tuber, which includes species with socio-economic importance and esteemed culinary attributes. Ecologically, Tuber spp. form obligate mycorrhizal symbioses with diverse species of plant hosts including pines, oaks, poplars, orchids, and commercially important trees such as hazelnut and pecan. Unfortunately, limited geographic sampling and inconclusive phylogenetic relationships have obscured our understanding of their origin, biogeography, and diversification. To address this problem, we present a global sampling of Tuberaceae based on DNA sequence data from four loci for phylogenetic inference and molecular dating. Our well-resolved Tuberaceae phylogeny shows high levels of regional and continental endemism. We also identify a previously unknown epigeous member of the Tuberaceae – the South American cup-fungus Nothojafnea thaxteri (E.K. Cash) Gamundí. Phylogenetic resolution was further improved through the inclusion of a previously unrecognized Southern hemisphere sister group of the Tuberaceae. This morphologically diverse assemblage of species includes truffle (e.g. Gymnohydnotrya spp.) and non-truffle forms that are endemic to Australia and South America. Southern hemisphere taxa appear to have diverged more recently than the Northern hemisphere lineages. Our analysis of the Tuberaceae suggests that Tuber evolved from an epigeous ancestor. Molecular dating estimates Tuberaceae divergence in the late Jurassic (∼156 million years ago), with subsequent radiations in the Cretaceous and Paleogene. Intra-continental diversification, limited long-distance dispersal, and ecological adaptations help to explain patterns of truffle evolution and biodiversity.
doi:10.1371/journal.pone.0052765
PMCID: PMC3534693  PMID: 23300990
9.  Developing Understanding of the Roles of CD1d-restricted T cell Subsets in Cancer: Reversing Tumor-induced Defects 
Clinical immunology (Orlando, Fla.)  2011;140(2):184-195.
Summary
Invariant natural killer T-cells (‘iNKT’) are the best-known CD1d-restricted T-cells, with recently-defined roles in controlling adaptive immunity. CD1d-restricted T-cells can rapidly produce large amounts of Th1 and/or Th2//Treg/Th17-type cytokines, thereby regulating immunity. iNKT can stimulate potent anti-tumor immune responses via production of Th1 cytokines, direct cytotoxicity, and activation of effectors. However, Th2//Treg-type iNKT can inhibit anti-tumor activity. Furthermore, iNKT are decreased and/or reversibly functionally impaired in many advanced cancers. In some cases, CD1d-restricted T-cell cancer defects can be traced to CD1d+ tumor interactions, since hematopoietic, prostate, and some other tumors can express CD1d. Ligand and IL-12 can reverse iNKT defects and therapeutic opportunities exist in correcting such defects alone and in combination. Early stage clinical trials have shown potential for reconstitution of iNKT IFN-gamma responses and evidence of activity in a subset of patients, with rational new approaches to capitalize on this progress ongoing, as will be discussed here.
doi:10.1016/j.clim.2011.04.017
PMCID: PMC3143311  PMID: 21646050
cytokines; tumor immunity; CD1; CD1d-reactive T cells; iNKT; NKT
10.  Essential role for the prolyl isomerase Pin1 in Toll-like receptor signaling and type I interferon-mediated immunity 
Nature Immunology  2011;12(8):733-741.
Toll-like receptors (TLRs) shape innate and adaptive immunity to microorganisms. The enzyme IRAK1 transduces signals from TLRs, but its activation and regulation mechanisms remain unknown. We show that TLR7 and TLR9 activated the isomerase Pin1, which then bound to IRAK1, resulting in IRAK1 activation and facilitating its release from the receptor complex to activate the transcription factor IRF7 and induce type I interferons. Consequently, Pin1-null cells and mice failed to mount TLR-mediated, interferon-dependent innate and adaptive immune responses. Given the critical role of aberrant IRAK1 activation and type I interferons in various immune diseases, controlling IRAK1 activation via Pin1 inhibition may represent a useful therapeutic approach.
doi:10.1038/ni.2069
PMCID: PMC3298750  PMID: 21743479
11.  Natural Killer T Cells Subsets in Cancer, Functional Defects in Prostate Cancer and Implications for Immunotherapy 
Cancers  2011;3(3):3661-3675.
Natural killer T cells are T lymphocytes with unique activation and effector properties. The majority of NKT cells, termed type-I or iNKT cells, recognize lipid antigens presented on MHC-like CD1d molecules. Type-I NKT cells have the capacity to rapidly secrete various cytokines upon activation, thereby regulate immune responses exerts dominant anti-tumor and anti-microbial effector functions. Specific activation of type-I NKT cells in mouse models boosts immunity and prevents metastasis, which has led to a number of phase I-II clinical trials. Since the discovery of NKT cells other subsets with different specificities and effector functions have been described. This article briefly reviews the physiological functions of NKT cell subsets, their implications in cancer and the attempts that have been made to employ NKT cells for immune therapy of cancer.
doi:10.3390/cancers3033661
PMCID: PMC3759215  PMID: 24212972
NKT cell; prostate cancer; immunotherapy
12.  Expression and Trans-Specific Polymorphism of Self-Incompatibility RNases in Coffea (Rubiaceae) 
PLoS ONE  2011;6(6):e21019.
Self-incompatibility (SI) is widespread in the angiosperms, but identifying the biochemical components of SI mechanisms has proven to be difficult in most lineages. Coffea (coffee; Rubiaceae) is a genus of old-world tropical understory trees in which the vast majority of diploid species utilize a mechanism of gametophytic self-incompatibility (GSI). The S-RNase GSI system was one of the first SI mechanisms to be biochemically characterized, and likely represents the ancestral Eudicot condition as evidenced by its functional characterization in both asterid (Solanaceae, Plantaginaceae) and rosid (Rosaceae) lineages. The S-RNase GSI mechanism employs the activity of class III RNase T2 proteins to terminate the growth of “self” pollen tubes. Here, we investigate the mechanism of Coffea GSI and specifically examine the potential for homology to S-RNase GSI by sequencing class III RNase T2 genes in populations of 14 African and Madagascan Coffea species and the closely related self-compatible species Psilanthus ebracteolatus. Phylogenetic analyses of these sequences aligned to a diverse sample of plant RNase T2 genes show that the Coffea genome contains at least three class III RNase T2 genes. Patterns of tissue-specific gene expression identify one of these RNase T2 genes as the putative Coffea S-RNase gene. We show that populations of SI Coffea are remarkably polymorphic for putative S-RNase alleles, and exhibit a persistent pattern of trans-specific polymorphism characteristic of all S-RNase genes previously isolated from GSI Eudicot lineages. We thus conclude that Coffea GSI is most likely homologous to the classic Eudicot S-RNase system, which was retained since the divergence of the Rubiaceae lineage from an ancient SI Eudicot ancestor, nearly 90 million years ago.
doi:10.1371/journal.pone.0021019
PMCID: PMC3120821  PMID: 21731641
13.  Increased population sampling confirms low genetic divergence among Pteropus (Chiroptera: Pteropodidae) fruit bats of Madagascar and other western Indian Ocean islands 
PLoS Currents  2011;3:RRN1226.
Fruit bats of the genus Pteropus occur throughout the Austral-Asian region west to islands off the eastern coast of Africa. Recent phylogenetic analyses of Pteropus from the western Indian Ocean found low sequence divergence and poor phylogenetic resolution among several morphologically defined species. We reexamine the phylogenetic relationships of these taxa by using multiple individuals per species. In addition, we estimate population genetic structure in two well-sampled taxa occurring on Madagascar and the Comoro Islands (P. rufus and P. seychellensis comorensis). Despite finding a similar pattern of low sequence divergence among species, increased sampling provides insight into the phylogeographic history of western Indian Ocean Pteropus, uncovering high levels of gene flow within species.
doi:10.1371/currents.RRN1226
PMCID: PMC3064450  PMID: 21479256
14.  The A2aR adenosine receptor controls cytokine production in iNKT cells 
European journal of immunology  2010;40(3):682-687.
The purine nucleoside adenosine is an important anti-inflammatory molecule, inhibiting a variety of immune cells by adenosine receptor-mediated mechanisms. Invariant natural killer T (iNKT) cells recognize glycolipids presented on CD1d molecules and produce vigorous amounts of cytokines upon activation, hence regulating immune reactions. The mechanisms polarizing their cytokine pattern are elusive. Previous studies demonstrated that adenosine can suppress IFN-γ production by iNKT cells.
We describe the expression of all four known adenosine receptors A1R, A2aR, A2bR, and A3R, on mouse iNKT cells. We show that IL-4 production in primary mouse iNKT cells and a human iNKT line is efficiently inhibited by A2aR blockade with an inverse relation to IL-4. These data are supported by A2aR-deficient mice, which exhibit largely decreased levels of IL-4, IL-10 and TGF-β concomitantly with an increase of IFN-γ upon α-GalCer administration in vivo. While A2aR inhibits other lymphocyte populations, A2aR is required for the secretion of IL-4 and IL-10 by iNKT cells. These data suggest adenosine:A2aR-mediated mechanisms can control the cytokine secretion pattern of iNKT cells.
doi:10.1002/eji.200939897
PMCID: PMC2967447  PMID: 20039304
NKT cells; Cellular activation; Immune regulation
15.  DIRECT CD1d-MEDIATED STIMULATION OF APC IL-12 PRODUCTION AND PROTECTIVE IMMUNE RESPONSE TO VIRUS INFECTION In Vivo 
CD1d-restricted ‘NKT’ rapidly stimulate innate and adaptive immunity through production of Th1 and/or Th2 cytokines and induction of CD1d+ antigen-presenting cell (APC) maturation. However, therapeutic exploitation of NKT has been hampered by their paucity and defects in human disease. NKT:APC interactions can be modeled by direct stimulation of human APC through CD1d in vitro. We have now found that direct ligation with multiple CD1d mAbs also stimulated bioactive IL-12 release from CD1d+ but not CD1d KO murine splenocytes in vitro. Moreover, all CD1d mAbs tested also induced IL-12 as well as both IFN-γ and IFN-α in vivo from CD1d+ but not CD1d-deficient recipients. Unlike IFN-γ, CD1d-induced IFN-α was at least partially dependent on invariant NKT. Optimal resistance to infection with picornavirus encephalomyocarditis virus (EMCV) is known to require CD1d-dependent APC IL-12-induced IFN-γ as well as IFN-α. CD1d ligation in vivo enhanced systemic IL-12, IFN-γ, and IFN-α, and was protective against infection by EMCV, suggesting an alternative interpretation for previous results involving CD1d ‘blocking’ in other systems. Such protective responses, including elevations in Th1 cytokines, were also seen with CD1d FAb’2s in vivo, while an IgM mAb (with presumably minimal tissue penetration) was comparably effective at protection in vivo as well as cytokine induction both in vivo and in vitro. Although presumably acting immediately ‘downstream’, CD1d mAbs were protective later during infection than iNKT agonist α-galactosylceramide. These data indicate that NKT can be bypassed with CD1d-mediated induction of robust Th1 immunity, which may have therapeutic potential both directly and as adjuvant.
doi:10.4049/jimmunol.0800924
PMCID: PMC2967442  PMID: 19949077
antibodies; cell activation; cytokines; NKT cells; viral infection
16.  Engagement and Retention: Measuring Breadth and Depth of Participant Use of an Online Intervention 
Background
The Internet provides us with tools (user metrics or paradata) to evaluate how users interact with online interventions. Analysis of these paradata can lead to design improvements.
Objective
The objective was to explore the qualities of online participant engagement in an online intervention. We analyzed the paradata in a randomized controlled trial of alternative versions of an online intervention designed to promote consumption of fruit and vegetables.
Methods
Volunteers were randomized to 1 of 3 study arms involving several online sessions. We created 2 indirect measures of breadth and depth to measure different dimensions and dynamics of program engagement based on factor analysis of paradata measures of Web pages visited and time spent online with the intervention materials. Multiple regression was used to assess influence of engagement on retention and change in dietary intake.
Results
Baseline surveys were completed by 2513 enrolled participants. Of these, 86.3% (n = 2168) completed the follow-up surveys at 3 months, 79.6% (n = 2027) at 6 months, and 79.4% (n = 1995) at 12 months. The 2 tailored intervention arms exhibited significantly more engagement than the untailored arm (P < .01). Breadth and depth measures of engagement were significantly associated with completion of follow-up surveys (odds ratios [OR] = 4.11 and 2.12, respectively, both P values < .001). The breadth measure of engagement was also significantly positively associated with a key study outcome, the mean increase in fruit and vegetable consumption (P < .001).
Conclusions
By exploring participants’ exposures to online interventions, paradata are valuable in explaining the effects of tailoring in increasing participant engagement in the intervention. Controlling for intervention arm, greater engagement is also associated with retention of participants and positive change in a key outcome of the intervention, dietary change. This paper demonstrates the utility of paradata capture and analysis for evaluating online health interventions.
Trial Registration
NCT00169312; http://clinicaltrials.gov/ct2/show/NCT00169312 (Archived by WebCite at http://www.webcitation.org/5u8sSr0Ty)
doi:10.2196/jmir.1430
PMCID: PMC3056524  PMID: 21087922
Methodological studies; Internet; process metrics; tailored intervention
17.  Natural Killer T Cell Dysfunction in CD39-Null Mice Protects Against Concanavalin A–Induced Hepatitis 
Hepatology (Baltimore, Md.)  2008;48(3):841-852.
Concanavalin A (Con A)–induced injury is an established natural killer T (NKT) cell–mediated model of inflammation that has been used in studies of immune liver disease. Extracellular nucleotides, such as adenosine triphosphate, are released by Con A–stimulated cells and bind to specific purinergic type 2 receptors to modulate immune activation responses. Levels of extracellular nucleotides are in turn closely regulated by ectonucleotidases, such as CD39/NTPDase1. Effects of extracellular nucleotides and CD39 on NKT cell activation and upon hepatic inflammation have been largely unexplored to date. Here, we show that NKT cells express both CD39 and CD73/ecto-5’-nucleotidase and can therefore generate adenosine from extracellular nucleotides, whereas natural killer cells do not express CD73. In vivo, mice null for CD39 are protected from Con A–induced liver injury and show substantively lower serum levels of interleukin-4 and interferon-γ when compared with matched wild-type mice. Numbers of hepatic NKT cells are significantly decreased in CD39 null mice after Con A administration. Hepatic NKT cells express most P2X and P2Y receptors; exceptions include P2X3 and P2Y11. Heightened levels of apoptosis of CD39 null NKT cells in vivo and in vitro appear to be driven by unimpeded activation of the P2X7 receptor.
Conclusion
CD39 and CD73 are novel phenotypic markers of NKT cells. Deletion of CD39 modulates nucleotide-mediated cytokine production by, and limits apoptosis of, hepatic NKT cells providing protection against Con A–induced hepatitis. This study illustrates a further role for purinergic signaling in NKT-mediated mechanisms that result in liver immune injury.
doi:10.1002/hep.22401
PMCID: PMC2929828  PMID: 18752325
18.  Defective NKT Cell Activation by CD1d+ TRAMP Prostate Tumor Cells Is Corrected by Interleukin-12 with alpha-Galactosylceramide 
PLoS ONE  2010;5(6):e11311.
Numerical and functional defects of invariant natural killer T cells (iNKT) have been documented in human and mouse cancers, resulting in a defect in IFN production in several malignancies. iNKT cells recognize glycolipids presented on CD1d molecules by dendritic and related cells, leading to their activation and thereby regulating immune reactions. Activated iNKT cells cytokine secretion and cytotoxicity can inhibit existing and spontaneous tumor growth, progression, and metastasis. We have identified functional iNKT cell defects in the murine TRAMP prostate cancer model. We found that iNKT cells show the ability to migrate into TRAMP prostate tumors. This infiltration was mediated through CCL2: CCR5 chemokine: receptor interaction. Prostate tumor cells expressing CD1d partially activated iNKT cells, as appreciated by up-regulation of CD25, PD-1 and the IL-12R. However, despite inducing up-regulation of these activation markers and, hence, delivering positive signals, prostate tumor cells inhibited the IL-12-induced STAT4 phosphorylation in a cell-cell contact dependent but CD1d-independent manner. Consequently, tumor cells did not induce secretion of IFNγ by iNKT cells. Blocking the inhibitory Ly49 receptor on iNKT cells in the presence of α-GalCer restored their IFNγ production in vivo and in vitro. However, Ly49 blockade alone was not sufficient. Importantly, this defect could be also be reversed into vigorous secretion of IFNγ by the addition of both IL-12 and the exogenous CD1d ligand alpha-galactosylceramide, but not by IL-12 alone, both in vivo and in vitro. These data underscore the potential to optimize iNKT-based therapeutic approaches.
doi:10.1371/journal.pone.0011311
PMCID: PMC2892484  PMID: 20593019

Results 1-18 (18)