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1.  GigaDB: promoting data dissemination and reproducibility 
Often papers are published where the underlying data supporting the research are not made available because of the limitations of making such large data sets publicly and permanently accessible. Even if the raw data are deposited in public archives, the essential analysis intermediaries, scripts or software are frequently not made available, meaning the science is not reproducible. The GigaScience journal is attempting to address this issue with the associated data storage and dissemination portal, the GigaScience database (GigaDB). Here we present the current version of GigaDB and reveal plans for the next generation of improvements. However, most importantly, we are soliciting responses from you, the users, to ensure that future developments are focused on the data storage and dissemination issues that still need resolving.
Database URL: http://www.gigadb.org
doi:10.1093/database/bau018
PMCID: PMC3950661  PMID: 24622612
2.  Differential Induction of TLR3-Dependent Innate Immune Signaling by Closely Related Parasite Species 
PLoS ONE  2014;9(2):e88398.
The closely related protozoan parasites Toxoplasma gondii and Neospora caninum display similar life cycles, subcellular ultrastructure, invasion mechanisms, metabolic pathways, and genome organization, but differ in their host range and disease pathogenesis. Type II (γ) interferon has long been known to be the major mediator of innate and adaptive immunity to Toxoplasma infection, but genome-wide expression profiling of infected host cells indicates that Neospora is a potent activator of the type I (α/β) interferon pathways typically associated with antiviral responses. Infection of macrophages from mice with targeted deletions in various innate sensing genes demonstrates that host responses to Neospora are dependent on the toll-like receptor Tlr3 and the adapter protein Trif. Consistent with this observation, RNA from Neospora elicits TLR3-dependent type I interferon responses when targeted to the host endo-lysosomal system. Although live Toxoplasma fail to induce type I interferon, heat-killed parasites do trigger this response, albeit much weaker than Neospora, and co-infection studies reveal that T. gondii actively suppresses the production of type I interferon. These findings reveal that eukaryotic pathogens can be potent inducers of type I interferon and that related parasite species interact with this pathway in distinct ways.
doi:10.1371/journal.pone.0088398
PMCID: PMC3914978  PMID: 24505488
3.  Disruption of TgPHIL1 Alters Specific Parameters of Toxoplasma gondii Motility Measured in a Quantitative, Three-Dimensional Live Motility Assay 
PLoS ONE  2014;9(1):e85763.
T. gondii uses substrate-dependent gliding motility to invade cells of its hosts, egress from these cells at the end of its lytic cycle and disseminate through the host organism during infection. The ability of the parasite to move is therefore critical for its virulence. T. gondii engages in three distinct types of gliding motility on coated two-dimensional surfaces: twirling, circular gliding and helical gliding. We show here that motility in a three-dimensional Matrigel-based environment is strikingly different, in that all parasites move in irregular corkscrew-like trajectories. Methods developed for quantitative analysis of motility parameters along the smoothed trajectories demonstrate a complex but periodic pattern of motility with mean and maximum velocities of 0.58±0.07 µm/s and 2.01±0.17 µm/s, respectively. To test how a change in the parasite's crescent shape might affect trajectory parameters, we compared the motility of Δphil1 parasites, which are shorter and wider than wild type, to the corresponding parental and complemented lines. Although comparable percentages of parasites were moving for all three lines, the Δphil1 mutant exhibited significantly decreased trajectory lengths and mean and maximum velocities compared to the parental parasite line. These effects were either partially or fully restored upon complementation of the Δphil1 mutant. These results show that alterations in morphology may have a significant impact on T. gondii motility in an extracellular matrix-like environment, provide a possible explanation for the decreased fitness of Δphil1 parasites in vivo, and demonstrate the utility of the quantitative three-dimensional assay for studying parasite motility.
doi:10.1371/journal.pone.0085763
PMCID: PMC3906025  PMID: 24489670
4.  A Host GPCR Signaling Network Required for the Cytolysis of Infected Cells Facilitates Release of Apicomplexan Parasites 
Cell host & microbe  2013;13(1):15-28.
Summary
Following intracellular replication, the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii cause host cell cytolysis to facilitate parasite release and disease progression. Parasite exit from infected cells requires the interplay of parasite-derived proteins and host actin cytoskeletal changes; however, the host proteins underlying these changes remain obscure. We report the identification of a Gαq-coupled host-signaling cascade required for the egress of both P. falciparum and T. gondii. Gαq-coupled signaling results in protein kinase C (PKC)-mediated loss of the host cytoskeletal protein adducin and weakening of the cellular cytoskeleton. This cytoskeletal compromise induces catastrophic Ca2+ influx mediated by the mechanosensitive cation channel TRPC6, which activates host calpain that proteolyzes the host cytoskeleton allowing parasite release. Reinforcing the feasibility of targeting host proteins as an antiparasitic strategy, mammalian PKC inhibitors demonstrated activity in murine models of malaria and toxoplasmosis. Importantly, an orally bioavailable PKC inhibitor prolonged survival in an experimental cerebral malaria model.
doi:10.1016/j.chom.2012.12.001
PMCID: PMC3638031  PMID: 23332153
5.  IL-27 receptor signalling regulates CD4+ T cell chemotactic responses during infection 
Journal of immunology (Baltimore, Md. : 1950)  2013;190(9):10.4049/jimmunol.1202916.
IL-27 exerts pleiotropic suppressive effects on naïve and effector T cell populations during infection and inflammation. Surprisingly, however, the role of IL-27 in restricting or shaping effector CD4+ T cell chemotactic responses, as a mechanism to reduce T cell-dependent tissue inflammation, is unknown. In this study, using Plasmodium berghei NK65 as a model of a systemic, pro-inflammatory infection, we demonstrate that IL-27R signalling represses chemotaxis of infection-derived splenic CD4+ T cells in response to the CCR5 ligands, CCL4 and CCL5. Consistent with these observations, CCR5 was expressed on significantly higher frequencies of splenic CD4+ T cells from malaria-infected, IL-27R deficient (WSX-1−/−) mice than from infected wild type (WT) mice. We find that IL-27 signalling suppresses splenic CD4+ T cell CCR5-dependent chemotactic responses during infection by restricting CCR5 expression on CD4+ T cell sub-types, including Th1 cells, and also by controlling the overall composition of the CD4+ T cell compartment. Diminution of the Th1 response in infected WSX-1−/− mice in vivo by neutralisation of IL-12p40 attenuated CCR5 expression by infection-derived CD4+ T cells and also reduced splenic CD4+ T cell chemotaxis towards CCL4 and CCL5. These data reveal a previously unappreciated role for IL-27 in modulating CD4+ T cell chemotactic pathways during infection, which is related to its capacity to repress Th1 effector cell development. Thus, IL-27 appears to be a key cytokine that limits the CCR5-CCL4/CCL5 axis during inflammatory settings.
doi:10.4049/jimmunol.1202916
PMCID: PMC3886378  PMID: 23536628
6.  Toxoplasma gondii Rhoptry 16 Kinase Promotes Host Resistance to Oral Infection and Intestinal Inflammation Only in the Context of the Dense Granule Protein GRA15 
Infection and Immunity  2013;81(6):2156-2167.
Toxoplasma gondii transmission between intermediate hosts is dependent on the ingestion of walled cysts formed during the chronic phase of infection. Immediately following consumption, the parasite must ensure survival of the host by preventing adverse inflammatory responses and/or by limiting its own replication. Since the Toxoplasma secreted effectors rhoptry 16 kinase (ROP16) and dense granule 15 (GRA15) activate the JAK-STAT3/6 and NF-κB signaling pathways, respectively, we explored whether a particular combination of these effectors impacted intestinal inflammation and parasite survival in vivo. Here we report that expression of the STAT-activating version of ROP16 in the type II strain (strain II+ROP16I) promotes host resistance to oral infection only in the context of endogenous GRA15 expression. Protection was characterized by a lower intestinal parasite burden and dampened inflammation. Host resistance to the II+ROP16I strain occurred independently of STAT6 and the T cell coinhibitory receptors B7-DC and B7-H1, two receptors that are upregulated by ROP16. In addition, coexpression of ROP16 and GRA15 enhanced parasite susceptibility within tumor necrosis factor alpha/gamma interferon-stimulated macrophages in a STAT3/6-independent manner. Transcriptional profiling of infected STAT3- and STAT6-deficient macrophages and parasitized Peyer's patches from mice orally challenged with strain II+ROP16I suggested that ROP16 activated STAT5 to modulate host gene expression. Consistent with this supposition, the ROP16 kinase induced the sustained phosphorylation and nuclear localization of STAT5 in Toxoplasma-infected cells. In summary, only the combined expression of both GRA15 and ROP16 promoted host resistance to acute oral infection, and Toxoplasma may possibly target the STAT5 signaling pathway to generate protective immunity in the gut.
doi:10.1128/IAI.01185-12
PMCID: PMC3676013  PMID: 23545295
7.  Immune response and immunopathology during toxoplasmosis1 
Seminars in immunopathology  2012;34(6):793-813.
Toxoplasma gondii is a protozoan parasite of medical and veterinary significance that is able to infect any warm-blooded vertebrate host. In addition to its importance to public health, several inherent features of the biology of T. gondii have made it an important model organism to study host-pathogen interactions. One factor is the genetic tractability of the parasite, which allows studies on the microbial factors that affect virulence and allows the development of tools that facilitate immune studies. Additionally, mice are natural hosts for T. gondii, and the availability of numerous reagents to study the murine immune system makes this an ideal experimental system to understand the functions of cytokines and effector mechanisms involved in immunity to intracellular microorganisms. In this article, we will review current knowledge of the innate and adaptive immune responses required for resistance to toxoplasmosis, the events that lead to the development of immunopathology, and the natural regulatory mechanisms that limit excessive inflammation during this infection.
doi:10.1007/s00281-012-0339-3
PMCID: PMC3498595  PMID: 22955326
Toxoplasma gondii; T. gondii; immune response; immunopathology; pathology; infection; parasite
8.  Replication and Distribution of Toxoplasma gondii in the Small Intestine after Oral Infection with Tissue Cysts 
Infection and Immunity  2013;81(5):1635-1643.
Natural infection by Toxoplasma gondii occurs via oral ingestion of tissue cysts that rupture in the small intestine, releasing zoites that infect locally before disseminating throughout the host. The studies presented here used fluorescent parasites combined with flow cytometry and multiphoton microscopy techniques to understand the events associated with parasite replication in the mucosa. At 3 days postinfection with tissue cysts, parasites were localized in small foci and flow cytometry revealed parasites present in macrophages, neutrophils, and monocytes in the lamina propria. By day 6 postinfection, there were large foci of replicating parasites; however, foci unexpectedly varied in the number of villi involved and were associated with the presence of viable tachyzoites within the intestinal lumen. Consistent with the flow cytometry data, neutrophils and monocytes in the lamina propria were preferentially associated with parasite plaques. In contrast, dendritic cells comprised a small fraction of the infected immune cell population and were localized at the periphery of parasite plaques. Together, these findings reveal the formation of localized sites of parasite replication and inflammation early during infection and suggest that sustained replication of T. gondii in the gut may be a function of pathogen luminal spread.
doi:10.1128/IAI.01126-12
PMCID: PMC3647985  PMID: 23460516
9.  Modulation of innate immunity by Toxoplasma gondii virulence effectors 
Nature reviews. Microbiology  2012;10(11):766-778.
Preface
Toxoplasma gondii is a common parasite of animals and humans that can cause serious opportunistic infections. However, the majority of infections are asymptomatic possibly because the organism has co-evolved with its many vertebrate hosts and has developed multiple strategies to persist asymptomatically for the lifetime of the host. Over the past two decades, infection studies in the mouse, combined with forward genetic approaches aimed at unraveling the molecular basis of infection, have revealed that T. gondii virulence is mediated, in part, by secretion of effector proteins into the host cell during invasion. Here, we review recent advances that illustrate how these virulence factors disarm innate immunity and promote survival of the parasite.
doi:10.1038/nrmicro2858
PMCID: PMC3689224  PMID: 23070557
10.  Eupolybothrus cavernicolus Komerički & Stoev sp. n. (Chilopoda: Lithobiomorpha: Lithobiidae): the first eukaryotic species description combining transcriptomic, DNA barcoding and micro-CT imaging data 
We demonstrate how a classical taxonomic description of a new species can be enhanced by applying new generation molecular methods, and novel computing and imaging technologies. A cave-dwelling centipede, Eupolybothrus cavernicolus Komerički & Stoev sp. n. (Chilopoda: Lithobiomorpha: Lithobiidae), found in a remote karst region in Knin, Croatia, is the first eukaryotic species for which, in addition to the traditional morphological description, we provide a fully sequenced transcriptome, a DNA barcode, detailed anatomical X-ray microtomography (micro-CT) scans, and a movie of the living specimen to document important traits of its ex-situ behaviour. By employing micro-CT scanning in a new species for the first time, we create a high-resolution morphological and anatomical dataset that allows virtual reconstructions of the specimen and subsequent interactive manipulation to test the recently introduced ‘cybertype’ notion. In addition, the transcriptome was recorded with a total of 67,785 scaffolds, having an average length of 812 bp and N50 of 1,448 bp (see GigaDB). Subsequent annotation of 22,866 scaffolds was conducted by tracing homologs against current available databases, including Nr, SwissProt and COG. This pilot project illustrates a workflow of producing, storing, publishing and disseminating large data sets associated with a description of a new taxon. All data have been deposited in publicly accessible repositories, such as GigaScience GigaDB, NCBI, BOLD, Morphbank and Morphosource, and the respective open licenses used ensure their accessibility and re-usability.
doi:10.3897/BDJ.1.e1013
PMCID: PMC3964625  PMID: 24723752
Cybertaxonomy; gene sequence data; micro-CT; data integration; molecular systematics; caves; Croatia; biospeleology
11.  EBI metagenomics—a new resource for the analysis and archiving of metagenomic data 
Nucleic Acids Research  2013;42(D1):D600-D606.
Metagenomics is a relatively recently established but rapidly expanding field that uses high-throughput next-generation sequencing technologies to characterize the microbial communities inhabiting different ecosystems (including oceans, lakes, soil, tundra, plants and body sites). Metagenomics brings with it a number of challenges, including the management, analysis, storage and sharing of data. In response to these challenges, we have developed a new metagenomics resource (http://www.ebi.ac.uk/metagenomics/) that allows users to easily submit raw nucleotide reads for functional and taxonomic analysis by a state-of-the-art pipeline, and have them automatically stored (together with descriptive, standards-compliant metadata) in the European Nucleotide Archive.
doi:10.1093/nar/gkt961
PMCID: PMC3965009  PMID: 24165880
12.  Interleukin-27 priming of T cells controls Interleukin-17-production in trans via induction of the ligand PD-L1 
Immunity  2012;36(6):1017-1030.
SUMMARY
Interleukin (IL)-27 is a key immunosuppressive cytokine that counters T helper 17 (Th17) cell-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in T cells rapidly induced by IL-27. We found that IL-27 priming of naïve T cells upregulated expression of programmed death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)1-dependent manner. When co-cultured with naïve CD4+ T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans through a PD-1-PD-L1 interaction. In vivo, co-administration of naïve TCR transgenic T cells (2D2 T cells) with IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Thus, these data identify a suppressive activity of IL-27, by which CD4+ T cells can restrict differentiation of Th17 cells in trans.
doi:10.1016/j.immuni.2012.03.024
PMCID: PMC3785111  PMID: 22726954
13.  The cytokines Interleukin 27 and Interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology 
Immunity  2012;37(3):511-523.
SUMMARY
Interferon-γ (IFN-γ) promotes a population of T-bet+ CXCR3+ regulatory T (Treg) cells that limit T helper 1 (Th1) cell-mediated pathology. Our studies demonstrate that interleukin-27 (IL-27) also promoted expression of T-bet and CXCR3 in Treg cells. During infection with Toxoplasma gondii a similar population emerged which limited T cell responses and were dependent on IFN-γ in the periphery but IL-27 at mucosal sites. Transfer of Treg cells ameliorated the infection-induced pathology observed in Il27−/− mice and this was dependent on their ability to produce IL-10. Microarray analysis revealed that Treg cells exposed to either IFN-γ or IL-27 have distinct transcriptional profiles. Thus, IFN-γ and IL-27 have different roles in Treg cell biology and IL-27 is a key cytokine that promotes the development of Treg cells specialized to control Th1 cell-mediated immunity at local sites of inflammation.
doi:10.1016/j.immuni.2012.06.014
PMCID: PMC3477519  PMID: 22981537
14.  Suppression of GM-CSF expression in murine and human T cells by IL-27 
GM-CSF is a potent pro-inflammatory cytokine that plays a pathogenic role in the CNS inflammatory disease, EAE. As IL-27 ameliorates EAE, we hypothesised that IL-27 suppresses GM-CSF expression by T cells. We found that IL-27 suppressed GM-CSF expression in CD4+ and CD8+ T cells in splenocyte and purified T cell cultures. IL-27 suppressed GM-CSF in Th1, but not Th17 cells. IL-27 also suppressed GM-CSF expression by human T cells in non-polarised and Th1 but not Th17 polarised PBMC cultures. In vivo, IL-27p28 deficiency resulted in increased GM-CSF expression by CNS infiltrating T cells during Toxoplasma gondii infection. While in vitro suppression of GM-CSF by IL-27 was independent of IL-2 suppression, IL-10 up-regulation or SOCS3 signalling, we observed that IL-27-driven suppression of GM-CSF was STAT1 dependent. Our findings demonstrate that IL-27 is a robust negative regulator of GM-CSF expression in T cells which likely inhibits T cell pathogenicity in CNS inflammation.
doi:10.4049/jimmunol.1200131
PMCID: PMC3424384  PMID: 22837488
15.  IL-6 promotes NK cell production of IL-17 during toxoplasmosis1 
Previous studies have implicated T cell production of IL-17 in resistance to T. gondii as well as the development of immune mediated pathology during this infection. Analysis of C57BL/6 and C57BL/6 RAG-/- mice challenged with T. gondii identified NK cells as a major innate source of IL-17. The ability of soluble toxoplasma antigen to stimulate NK cells to produce IL-17 was dependent on the presence of accessory cells and the production of IL-6, IL-23 and TGF-β. In contrast, these events were inhibited by IL-2, IL-15 and IL-27. Given that IL-6 was one of the most potent enhancers of NK cell production of IL-17, further studies revealed that only a subset of NK cells expressed both chains of the IL-6R, IL-6 upregulated expression of the Th17 associated transcription factor RORγt, and IL-6-/- mice challenged with T. gondii had a major defect in NK cell production of IL-17. Together, these data indicate that many of the same cytokines that regulate Th17 cells are part of a conserved pathway that also control innate production of IL-17 and identify a major role for IL-6 in the regulation of NK cell responses.
doi:10.4049/jimmunol.0901843
PMCID: PMC3757499  PMID: 20083665
IL-6; IL-17; Natural Killer cells and Toxoplasma gondii
16.  Neutrophil Depletion Diminishes Monocyte Infiltration and Improves Functional Outcome After Experimental Intracerebral Hemorrhage 
Inflammation contributes to secondary injury and neuronal loss after intracerebral hemorrhage, but the role of individual immune populations in these processes is unclear. In a mouse model, the injection of autologous blood into the striatum was associated with an intense inflammatory cell infiltrate composed of neutrophils, monocytes, and dendritic cells. Selective depletion of neutrophils resulted in decreased infiltration of monocytes and improved functional outcomes at day 3 post-hemorrhage. These findings indicate that neutrophil infiltration into the site of hemorrhage contributes to brain injury either by direct cellular damage or the recruitment of monocytes.
doi:10.1007/978-3-7091-0693-8_29
PMCID: PMC3702167  PMID: 21725751
Intracerebral hemorrhage; Inflammation; Neutrophils; Monocytes
17.  Toll-like Receptor 4 Contributes to Poor Outcome after Intracerebral Hemorrhage 
Annals of neurology  2011;70(4):646-656.
Objective
Intracerebral hemorrhage (ICH) is a devastating stroke subtype in which perihematomal inflammation contributes to neuronal injury and functional disability. Histologically, the region becomes infiltrated with neutrophils and activated microglia followed by neuronal loss but little is known about the immune signals that coordinate these events. This study aimed to determine the role of Toll-like receptor 4 (TLR4) in the innate immune response after ICH and its impact on neurobehavioral outcome.
Methods
Transgenic mice incapable of TLR4 signaling and wild-type controls were subjected to striatal blood injection to model ICH. The perihematomal inflammatory response was then quantified by immunohistochemistry, whole brain flow cytometry, and PCR. The critical location of TLR4 signaling was determined by blood transfer experiments between genotypes. Functional outcomes were quantified in all cohorts using the cylinder and open field tests.
Results
TLR4-deficient mice had markedly decreased perihematomal inflammation, associated with reduced recruitment of neutrophils and monocytes, fewer microglia, and improved functional outcome by day 3 after ICH. Moreover, blood transfer experiments revealed that TLR4 on leukocytes or platelets within the hemorrhage contributes to perihematomal leukocyte infiltration and the neurological deficit.
Interpretation
Together, these data identify a critical role for TLR4 signaling in perihematomal inflammation and injury and indicate this pathway may be a target for therapeutic intervention.
doi:10.1002/ana.22528
PMCID: PMC3671585  PMID: 22028224
18.  IL-21 Is Required for Optimal Antibody Production and T Cell Responses during Chronic Toxoplasma gondii Infection 
PLoS ONE  2013;8(5):e62889.
Previous studies have indicated that Il21r−/− mice chronically infected with Toxoplasma gondii display a defect in serum IgG; however, the basis for this antibody defect was not defined and questions remain about the role of IL-21 in promoting the production of IL-10, which is required to limit infection-induced pathology during toxoplasmosis. Therefore, Il21−/− mice were challenged with T. gondii to determine whether IL-21 impacts the parasite-specific CD8+ T cell response, its contribution to thymus-dependent antibody production after infection, and balance between protective and pathogenic responses. Whereas IL-21 has been implicated in the differentiation of IL-10 producing CD4+ T cells no immune-mediated pathology was evident in Il21−/− mice during the acute response, nor was there a defect in the development of this population in chronically infected Il21−/− mice. However, Il21−/− mice displayed a defect in IgG production after infection that correlated with a decrease in GC B cell numbers, the CD4+ and CD8+ T cell numbers in the brain were reduced over the course of the chronic infection leading to a decrease in total IFN-γ production and an increase in parasite numbers associated with susceptibility to toxoplasmic encephalitis. Together, these results identify a key role for IL-21 in shaping the humoral and cellular response to T. gondii, but indicate that IL-21 has a limited role in regulating immunopathology.
doi:10.1371/journal.pone.0062889
PMCID: PMC3647013  PMID: 23667536
19.  IL-27 Receptor Signalling Restricts the Formation of Pathogenic, Terminally Differentiated Th1 Cells during Malaria Infection by Repressing IL-12 Dependent Signals 
PLoS Pathogens  2013;9(4):e1003293.
The IL-27R, WSX-1, is required to limit IFN-γ production by effector CD4+ T cells in a number of different inflammatory conditions but the molecular basis of WSX-1-mediated regulation of Th1 responses in vivo during infection has not been investigated in detail. In this study we demonstrate that WSX-1 signalling suppresses the development of pathogenic, terminally differentiated (KLRG-1+) Th1 cells during malaria infection and establishes a restrictive threshold to constrain the emergent Th1 response. Importantly, we show that WSX-1 regulates cell-intrinsic responsiveness to IL-12 and IL-2, but the fate of the effector CD4+ T cell pool during malaria infection is controlled primarily through IL-12 dependent signals. Finally, we show that WSX-1 regulates Th1 cell terminal differentiation during malaria infection through IL-10 and Foxp3 independent mechanisms; the kinetics and magnitude of the Th1 response, and the degree of Th1 cell terminal differentiation, were comparable in WT, IL-10R1−/− and IL-10−/− mice and the numbers and phenotype of Foxp3+ cells were largely unaltered in WSX-1−/− mice during infection. As expected, depletion of Foxp3+ cells did not enhance Th1 cell polarisation or terminal differentiation during malaria infection. Our results significantly expand our understanding of how IL-27 regulates Th1 responses in vivo during inflammatory conditions and establishes WSX-1 as a critical and non-redundant regulator of the emergent Th1 effector response during malaria infection.
Author Summary
The cytokine interleukin 27 (IL-27), a member of the IL-12 family, is produced by cells of the innate immune system and has been shown to exert mainly suppressive effects during a wide range of inflammatory conditions, including malaria infection, where it suppresses the development of CD4+ T cell-dependent immunopathology. In this study we show that IL-27 suppresses the production of IFN-gamma by CD4+ T cells during blood stage malaria infection by preventing the development of terminally differentiated Th1 cells. We investigated the molecular mechanisms by which IL-27 inhibits the formation of terminally differentiated Th1 cells and found that it does so specifically by restricting IL-12 signals. Importantly, we demonstrate that IL-27 mediates its regulatory effects on the Th1 response through IL-10 and Foxp3+ regulatory T cell independent mechanisms. Thus, we have identified a new pathway though which IL-27 signalling regulates the size and quality of the Th1 response during malaria infection, which we believe will have relevance to many other pro-inflammatory conditions. Manipulation of the IL-27 pathway may therefore represent an amenable therapeutic approach during chronic inflammatory disorders.
doi:10.1371/journal.ppat.1003293
PMCID: PMC3623720  PMID: 23593003
20.  Infection with Toxoplasma gondii Alters Lymphotoxin Expression Associated with Changes in Splenic Architecture 
Infection and Immunity  2012;80(10):3602-3610.
B cell responses are required for resistance to Toxoplasma gondii; however, the events that lead to production of class-switched antibodies during T. gondii infection have not been defined. Indeed, mice challenged with the parasite exhibited an expansion of T follicular helper cells and germinal center B cells in the spleen. Unexpectedly, this was not associated with germinal center formation and was instead accompanied by profound changes in splenic organization. This phenomenon was transient and was correlated with a decrease in expression of effector proteins that contribute to splenic organization, including lymphotoxins α and β. The importance of lymphotoxin was confirmed, as the use of a lymphotoxin β receptor agonist results in partial restoration of splenic structure. Splenectomized mice were used to test the splenic contribution to the antibody response during T. gondii infection. Analysis of splenectomized mice revealed delayed kinetics in the production of parasite-specific antibody, but the mice did eventually develop normal levels of parasite-specific antibody. Together, these studies provide a better understanding of how infection with T. gondii impacts the customized structures required for the optimal humoral responses to the parasite and the role of lymphotoxin in these events.
doi:10.1128/IAI.00333-12
PMCID: PMC3457551  PMID: 22851754
21.  The composition and signaling of the IL-35 receptor are unconventional 
Nature immunology  2012;13(3):290-299.
Interleukin-35 (IL-35) belongs to the IL-12 family of heterodimeric cytokines but has a distinct functional profile. IL-35 suppresses T cell proliferation and converts naïve T cells into IL-35-producing iTr35. Here we show that IL-35 signals through a unique IL-12Rβ2:gp130 heterodimer or via homodimers. Conventional T cells are sensitive to IL-35-mediated suppression in the absence of one but not both receptor chains, whereas signaling through both chains is required for IL-35 expression and iTr35 conversion. IL35R signaling requires the transcription factors STAT1 and STAT4, which form a unique heterodimer that binds to distinct sites within the Il12a and Ebi3 promoters. This unconventional mode of signaling, which is distinct from other members of the IL-12 family, may broaden the spectrum and specificity of IL-35-mediated suppression.
doi:10.1038/ni.2227
PMCID: PMC3529151  PMID: 22306691
22.  New directions in the basic and translational biology of IL-27 
Trends in Immunology  2011;33(2):91-97.
Interleukin(IL)-27 is a member of the IL-6 and IL-12 family composed of the IL-27p28 and Epstein Barr-induced virus 1 subunits. While IL-27 was originally identified as a pro-inflammatory factor, subsequent studies have revealed the pleotropic nature of this cytokine. This review discusses recent work that explores the effect of IL-27 on CD4+ T cell subsets, including T regulatory type 1 cells, T follicular helper cells, and Foxp3+ T regulatory cells. Additionally, we highlight studies that identify a role for the IL-27p28 subunit as a cytokine receptor antagonist. Much of the recent work on IL-27 has been relevant to human disease states characterized by inappropriate or excessive inflammation, and this review will discuss potential opportunities to use IL-27 as a therapeutic.
doi:10.1016/j.it.2011.11.003
PMCID: PMC3273610  PMID: 22177689
23.  Particle-mediated delivery of cytokines for immunotherapy 
Immunotherapy  2012;4(4):425-441.
The ability of cytokines to direct the immune response to vaccination, infection and tumors has motivated their use in therapy to augment or shape immunity. To avoid toxic side effects associated with systemic cytokine administration, several approaches have been developed using particle-encapsulated cytokines to deliver this cargo to specific cell types and tissues. Initial work used cytokine-loaded particles to deliver proinflammatory cytokines to phagocytes to enhance antimicrobial and antitumor responses. These particles have also been used to create a cytokine depot at a local site to supplement prophylactic or antitumor vaccines or injected directly into solid tumors to activate immune cells to eliminate established tumors. Finally, recent advances have revealed that paracrine delivery of cytokines directly to T cells has the potential to enhance T-cell mediated therapies. The studies reviewed here highlight the progress in the last 30 years that has established the potential of particle-mediated cytokine immunotherapy.
doi:10.2217/imt.12.26
PMCID: PMC3395888  PMID: 22512636
cancer; cytokine; immunotherapy; influenza; liposome; nanoparticle; PLGA; polymer; vaccine
24.  IFN-γ producing CD4+ T cells promote experimental cerebral malaria by modulating CD8+ T cell accumulation within the brain 
It is well established that IFN-γ is required for the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. To date, however, the temporal and tissue-specific cellular sources of IFN-γ during P. berghei ANKA infection have not been investigated and it is not known if IFN-γ production by a single cell type in isolation can induce cerebral pathology. In this study, using IFN-γ reporter mice, we show that NK cells dominate the IFN-γ response during the early stages of infection in the brain, but not in the spleen, before being replaced by CD4+ and CD8+ T cells. Importantly, we demonstrate that IFN-γ producing CD4+ T cells, but not innate or CD8+ T cells, can promote the development of ECM in normally resistant IFN-γ−/− mice infected with P. berghei ANKA. Adoptively transferred wild-type (WT) CD4+ T cells accumulate within the spleen, lung and brain of IFN-γ−/− mice and induce ECM through active IFN-γ secretion, which increases accumulation of endogenous IFN-γ−/− CD8+ T cells within the brain. Depletion of endogenous IFN-γ−/− CD8+ T cells abrogated the ability of WT CD4+ T cells to promote ECM. Finally we show that IFN-γ production specifically by CD4+ T cells is sufficient to induce expression of CXCL9 and CXCL10 within the brain, providing a mechanistic basis for the enhanced CD8+ T cell accumulation. These observations demonstrate, for the first time, the importance of and pathways by which IFN-γ-producing CD4+ T cells promote the development of ECM during P. berghei ANKA infection.
doi:10.4049/jimmunol.1200688
PMCID: PMC3393641  PMID: 22723523
25.  A mouse model of vitiligo with focused epidermal depigmentation requires IFN-γ for autoreactive CD8+ T cell accumulation in the skin 
Vitiligo is an autoimmune disease of the skin causing disfiguring patchy depigmentation of the epidermis and, less commonly, hair. Therapeutic options for vitiligo are limited, reflecting in part limited knowledge of disease pathogenesis. Existing mouse models of vitiligo consist of hair depigmentation but lack prominent epidermal involvement, which is the hallmark of human disease. They are thus unable to provide a platform to fully investigate disease mechanisms and treatment. CD8+ T cells have been implicated in the pathogenesis of vitiligo and expression of interferon-gamma (IFN-γ) is increased in the lesional skin of patients, however it is currently unknown what role IFN-γ plays in disease. Here, we have developed an adoptive transfer mouse model of vitiligo using melanocyte-specific CD8+ T cells, which recapitulates the human condition by inducing epidermal depigmentation while sparing the hair. Like active lesions in human vitiligo, histology of depigmenting skin reveals a patchy mononuclear infiltrate and single-cell infiltration of the epidermis. Depigmentation is accompanied by accumulation of autoreactive CD8+ T cells in the skin, quantifiable loss of tyrosinase transcript, and local IFN-γ production. Neutralization of IFN-γ with antibody prevents CD8+ T cell accumulation and depigmentation, suggesting a therapeutic potential for this approach.
doi:10.1038/jid.2011.463
PMCID: PMC3343174  PMID: 22297636

Results 1-25 (89)