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normal development and function but impaired memory phenotype of cd8⁺ t cells in transgenic mice expressing hiv-1 nef in its natural target cells.we studied the impact of hiv nef on cd8(+) t cells in a mouse model of aids, the cd4c/hiv(nef) transgenic (tg) mice. we found that negative and positive thymic selections of cd8(+) t cells proceeded normally in nef tg mice bred respectively with hy or ot-1 tcr tg mice. tg peripheral cd8(+) t cells showed an activated phenotype and enhanced cell division in vivo and proliferated efficiently when stimulated in vitro with antigenic peptide. when challenged with lcmv(armstrong), nef tg mice develope ...201323433958
anti-ifn-γ and peptide-tolerization therapies inhibit acute lung injury induced by cross-reactive influenza a-specific memory t cells.viral infections have variable outcomes, with severe disease occurring in only few individuals. we hypothesized that this variable outcome could correlate with the nature of responses made to previous microbes. to test this, mice were infected initially with influenza a virus (iav) and in memory phase challenged with lymphocytic choriomeningitis virus (lcmv), which we show in this study to have relatively minor cross-reactivity with iav. the outcome in genetically identical mice varied from mild ...201323408839
the risk of hemophagocytic lymphohistiocytosis in hermansky-pudlak syndrome type 2.genetic disorders of lymphocyte cytotoxicity predispose patients to hemophagocytic lymphohistiocytosis (hlh). reduced lymphocyte cytotoxicity has been demonstrated in hermansky-pudlak syndrome type 2 (hps2), but only a single patient was reported who developed hlh. because that patient also carried a potentially contributing heterozygous rab27a mutation, the risk for hlh in hps2 remains unclear. we analyzed susceptibility to hlh in the pearl mouse model of hps2. after infection with lymphocytic ...201323403622
assessment of cd4(+) and cd8 (+) t cell responses using mhc class i and ii tetramers.the low frequency of t cells specific for given antigens makes the study of antigen-specific t cell responses difficult. the development of mhc class i and ii tetramer staining techniques allows precise quantification and tracking of antigen-specific cd8(+) and cd4(+) t cell responses. here, we describe a protocol for mhc class i and ii tetramer staining of mouse t cells isolated from various tissues of mice infected with lymphocytic choriomeningitis virus (lcmv) or with murine cytomegalovirus ( ...201323397390
blockade but not overexpression of the junctional adhesion molecule c influences virus-induced type 1 diabetes in mice.type 1 diabetes (t1d) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. recruitment of inflammatory cells is prerequisite to beta-cell-injury. the junctional adhesion molecule (jam) family proteins jam-b and jam-c are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. blocking of jam-c efficiently attenuated cerulean-induced pancreati ...201323372751
arenavirus reverse genetics for vaccine development.arenaviruses are important human pathogens with no food and drug administration (fda)-licensed vaccines available and current antiviral therapy being limited to an off-label use of the nucleoside analogue ribavirin of limited prophylactic efficacy. the development of reverse genetics systems represented a major breakthrough in arenavirus research. however, rescue of recombinant arenaviruses using current reverse genetics systems has been restricted to rodent cells. in this study, we describe the ...201323364194
reversal of chronic to resolved infection by il-10 blockade is lcmv strain dependent.chronic viral infections lead to cd8(+) t-cell exhaustion, characterized by impaired cytokine secretion. the immune-regulatory cytokine il-10 promotes chronicity of infection with lymphocytic choriomeningitis virus (lcmv) clone 13, as absence of il-10 or blocking of il-10r during early lcmv clone 13 infection results in viral clearance. thus, treatment of humans suffering from chronic viral infections with il-10 neutralizing or il-10r blocking antibodies was proposed to boost virus-specific t-ce ...201323348876
lessons learned and concepts formed from study of the pathogenesis of the two negative-strand viruses lymphocytic choriomeningitis and influenza.viruses have unique lifestyles. to describe the pathogenesis and significance of viral infection in terms of host responses, resultant injury, and therapy, we focused on two rna viruses: lymphocytic choriomeningitis (lcmv) and influenza (flu). many of the currently established concepts and consequences about viruses and immunologic tolerance, virus-induced immunosuppression, virus-induced autoimmunity, immune complex disease, and virus-lymphocyte and virus-dendritic cell interactions evolved thr ...201323341590
reactive oxygen species delay control of lymphocytic choriomeningitis virus.cluster of differentiation (cd)8(+) t cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. elevated levels of reactive oxygen species (ros) have been reported during virus infections. however, the role of ros in t-cell-mediated immunopathology remains unclear. here we used the murine lymphocytic choriomeningitis virus to explore the role of ros during the processes of virus elimination ...201323328631
is the tam receptor axl a receptor for lymphocytic choriomeningitis virus?a recent publication indicated that overexpression of axl, a cellular receptor that negatively regulates toll-like receptor signaling, enhanced the entry of viruses pseudotyped with the glycoprotein of lymphocytic choriomeningitis virus (lcmv) in vitro. in testing the biological relevance of these observations, we found differences in neither viral kinetics between lcmv infections of axl(-/-) and wild-type mice nor t-cell responses prior to spontaneous viral clearance. thus, axl is not required ...201323325690
lcmv glycosylation modulates viral fitness and cell tropism.the glycoprotein (gp) of arenaviruses is glycosylated at 11 conserved n-glycosylation sites. we constructed recombinant lymphocytic choriomeningitis virus (rlcmv) featuring either additions or deletions of these n-glycans to investigate their role in the viral life cycle. n-glycosylation at two sites, t87 and s97, were found to be necessary to rescue rlcmv. three of nine successfully rescued mutants, s116a, t234a, and s373a, under selective pressures in either epithelial, neuronal, or macrophage ...201323308183
lymphocytic choriomeningitis virus infection in fvb mouse produces hemorrhagic disease.the viral family arenaviridae includes a number of viruses that can cause hemorrhagic fever in humans. arenavirus infection often involves multiple organs and can lead to capillary instability, impaired hemostasis, and death. preclinical testing for development of antiviral or therapeutics is in part hampered due to a lack of an immunologically well-defined rodent model that exhibits similar acute hemorrhagic illness or sequelae compared to the human disease. we have identified the fvb mouse str ...201223300439
micro-rna 155 is required for optimal cd8+ t cell responses to acute viral and intracellular bacterial challenges.recent studies have begun to define the role of micro-rnas in regulating the immune response. micro-rna155 (mir-155) has been shown to play a role in germinal center formation, t cell inflammation, and regulatory t cell development. in this study, we evaluated the role of mir-155 in cytotoxic t cell function. we report in this study that mice lacking mir-155 have impaired cd8(+) t cell responses to infections with lymphocytic choriomeningitis virus and the intracellular bacteria listeria monocyt ...201223275599
cd70 deficiency impairs effector cd8 t cell generation and viral clearance but is dispensable for the recall response to lymphocytic choriomeningitis virus.cd27 interactions with its ligand, cd70, are thought to be necessary for optimal primary and memory adaptive immune responses to a variety of pathogens. thus far, all studies addressing the function of the cd27-cd70 axis have been performed in mice lacking cd27, in those overexpressing cd70, or in those in which these molecules were blocked or mimicked by abs or recombinant soluble cd70. because these methods have in some cases led to divergent results, we generated cd70-deficient mice to direct ...201223269247
targeting virulence mechanisms for the prevention and therapy of arenaviral hemorrhagic fever.a number of arenaviruses are pathogenic for humans, but they differ significantly in virulence. lassa virus, found in west africa, causes severe hemorrhagic fever (hf), while the other principal old world arenavirus, lymphocytic choriomeningitis virus, causes mild illness in persons with normal immune function, and poses a threat only to immunocompromised individuals. the new world agents, including junin, machupo and sabia virus, are highly pathogenic for humans. arenaviral hf is characterized ...201323261843
antioxidant treatment regulates the humoral immune response during acute viral infection.generation of reactive oxygen intermediates (roi) following antigen receptor ligation is critical to promote cellular responses. however, the effect of antioxidant treatment on humoral immunity during a viral infection was unknown. mice were infected with lymphocytic choriomeningitis virus (lcmv) and treated with mn(iii)tetrakis(4-benzoic acid)porphyrin chloride (mntbap), a superoxide dismutase mimetic, from days 0 to 8 postinfection. on day 8, at the peak of the splenic response in vehicle-trea ...201323255789
the depletion of nk cells prevents t cell exhaustion to efficiently control disseminating virus infection.nk cells have well-established functions in immune defense against virus infections and cancer through their cytolytic activity and production of cytokines. in this study, we examined the frequency of nk cells and their influence on t cell responses in mice given variants of lymphocytic choriomeningitis virus that cause acute or persisting infection. we found increased frequencies of circulating nk cells during disseminating infection compared with uninfected or acutely infected mice. consistent ...201323241878
viral infections of the central nervous system in spain: a prospective study.the aim of the study was to determine the incidence of viruses causing aseptic meningitis, meningoencephalitis, and encephalitis in spain. this was a prospective study, in collaboration with 17 spanish hospitals, including 581 cases (csf from all and sera from 280): meningitis (340), meningoencephalitis (91), encephalitis (76), febrile syndrome (7), other neurological disorders (32), and 35 cases without clinical information. csf were assayed by pcr for enterovirus (ev), herpesvirus (herpes simp ...201323239485
the initial draining lymph node primes the bulk of the cd8 t cell response and influences memory t cell trafficking after a systemic viral infection.lymphocytic choriomeningitis virus (lcmv) causes a systemic infection in mice with virus replication occurring in both peripheral tissues and secondary lymphoid organs. because of the rapid systemic dissemination of the virus, the secondary lymphoid organs responsible for the induction of the lcmv-specific cd8 t cell response are poorly defined. we show that the mediastinal lymph node (medln) serves as the primary draining lymph node following lcmv infection. in addition, we demonstrate that the ...201223236277
programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice.the inhibitory programmed death 1 (pd-1)-programmed death ligand 1 (pd-l1) pathway contributes to the functional down-regulation of t cell responses during persistent systemic and local virus infections. the blockade of pd-1-pd-l1-mediated inhibition is considered as a therapeutic approach to reinvigorate antiviral t cell responses. yet previous studies reported that pd-l1-deficient mice develop fatal pathology during early systemic lymphocytic choriomeningitis virus (lcmv) infection, suggesting ...201223230000
nlrp1 inflammasome activation induces pyroptosis of hematopoietic progenitor cells.cytopenias are key prognostic indicators of life-threatening infection, contributing to immunosuppression and mortality. here we define a role for caspase-1-dependent death, known as pyroptosis, in infection-induced cytopenias by studying inflammasome activation in hematopoietic progenitor cells. the nlrp1a inflammasome is expressed in hematopoietic progenitor cells and its activation triggers their pyroptotic death. active nlrp1a induced a lethal systemic inflammatory disease that was driven by ...201223219391
the role of proteolytic processing and the stable signal peptide in expression of the old world arenavirus envelope glycoprotein ectodomain.maturation of the arenavirus gp precursor (gpc) involves proteolytic processing by cellular signal peptidase and the proprotein convertase subtilisin kexin isozyme 1 (ski-1)/site 1 protease (s1p), yielding a tripartite complex comprised of a stable signal peptide (ssp), the receptor-binding gp1, and the fusion-active transmembrane gp2. here we investigated the roles of ski-1/s1p processing and ssp in the biosynthesis of the recombinant gp ectodomains of lymphocytic choriomeningitis virus (lcmv) ...201323218200
antigen incorporated in virus-like particles is delivered to specific dendritic cell subsets that induce an effective antitumor immune response in vivo.virus-like particles (vlp) from rabbit hemorrhagic disease virus (rhdv) can be used as a scaffold to facilitate the delivery of antigens to induce cell-mediated immune responses. in this study, we investigated the immune response to lymphocytic choriomeningitis virus-derived peptide antigen (gp33) delivered by rhdv vlp. the gp33 peptides were incorporated into the vlp in 2 different forms, either recombinantly expressed inside the vlp (vlp-gp33r) or chemically coupled to the surface of the vlp ( ...201323211625
molecular anatomy and number of antigen specific cd8 t cells required to cause type 1 diabetes.we quantified cd8 t cells needed to cause type 1 diabetes and studied the anatomy of the cd8 t cell/beta (β) cell interaction at the immunologic synapse. we used a transgenic model, in situ tetramer staining to distinguish antigen specific cd8 t cells from total t cells infiltrating islets and a variety of viral mutants selected for functional deletion(s) of various cd8 t cell epitopes. twenty percent of cd8 t cells in the spleen were specific for all immunodominant and subdominant viral glycopr ...201223209415
arenaviruses and lethal mutagenesis. prospects for new ribavirin-based interventions.lymphocytic choriomeningitis virus (lcmv) has contributed to unveil some of the molecular mechanisms of lethal mutagenesis, or loss of virus infectivity due to increased mutation rates. here we review these developments, and provide additional evidence that ribavirin displays a dual mutagenic and inhibitory activity on lcmv that can be relevant to treatment designs. using 5-fluorouracil as mutagenic agent and ribavirin either as inhibitor or mutagen, we document an advantage of a sequential inhi ...201223202505
role of lymphocytic choriomeningitis virus (lcmv) in understanding viral immunology: past, present and future.lymphocytic choriomeningitis virus (lcmv) is a common infection of rodents first identified over eighty years ago in st. louis, mo, u.s.a. it is best known for its application in immunological studies. the history of lcmv closely correlates with the development of modern immunology. with the use of lcmv as a model pathogen several key concepts have emerged: major histocompatibility complex (mhc) restriction, t cell memory, persistent infections, t cell exhaustion and the key role of immune patho ...201223202498
d471g mutation in lcmv-np affects its ability to self-associate and results in a dominant negative effect in viral rna synthesis.arenaviruses merit significant interest because several family members are etiological agents of severe hemorrhagic fevers, representing a major burden to public health. currently, there are no fda-licensed vaccines against arenaviruses and the only available antiviral therapy is limited to the use of ribavirin that is partially effective. arenavirus nucleoprotein (np) is found associated with the genomic rna forming the viral ribonucleoproteins (vrnps) that together with the polymerase (l) dire ...201223202457
hemophagocytic lymphohistiocytosis in syntaxin-11-deficient mice: t-cell exhaustion limits fatal disease.syntaxin-11 (stx11), an atypical member of the snare protein family, is part of the cytolytic machinery of t and nk cells and involved in the fusion of lytic granules with the plasmamembrane. functional loss of syntaxin-11 in humans causes defective degranulation and impaired cytolytic activity of t and nk cells. furthermore, patients with stx11 deficiency develop familial hemophagocytic lymphohistiocytosis type 4 (fhl4), a life-threatening disease of severe hyperinflammation. we established stx ...201323190531
distinct severity of hlh in both human and murine mutants with complete loss of cytotoxic effector prf1, rab27a, and stx11.inherited defects of granule-dependent cytotoxicity led to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (hlh), characterized by uncontrolled cd8 t-cell and macrophage activation. in a cohort of hlh patients with genetic abnormalities expected to result in the complete absence of perforin, rab27a, or syntaxin-11, we found that disease severity as determined by age at hlh onset differed significantly, with a severity gradient from perforin (early onset) > rab27a > syntax ...201323160464
coupling to the surface of liposomes alters the immunogenicity of hepatitis c virus-derived peptides and confers sterile immunity.we have previously demonstrated that antigens chemically coupled to the surface of liposomes consisting of unsaturated fatty acids were cross-presented by antigen presenting cells to cytotoxic t lymphocytes (ctls). liposomal form of immunodominant ctl epitope peptides derived from lymphocytic choriomeningitis virus exhibited highly efficient antiviral ctl responses in immunized mice. in this study, we coupled 15 highly conserved immunodominant ctl epitope peptides derived from hepatitis c virus ...201323159619
alternative serotype adenovirus vaccine vectors elicit memory t cells with enhanced anamnestic capacity compared to ad5 vectors.the failure of the adenovirus serotype 5 (ad5) vector-based human immunodeficiency virus type 1 (hiv-1) vaccine in the step study has led to the development of adenovirus vectors derived from alternative serotypes, such as ad26, ad35, and ad48. we have recently demonstrated that vaccines using alternative-serotype ad vectors confer partial protection against stringent simian immunodeficiency virus (siv) challenges in rhesus monkeys. however, phenotypic differences between the t cell responses el ...201323152535
reduced type i interferon production by dendritic cells and weakened antiviral immunity in patients with wiskott-aldrich syndrome protein deficiency.wiskott-aldrich syndrome (was) is a rare x-linked primary immunodeficiency caused by absence of wiskott-aldrich syndrome protein (wasp) expression, resulting in defective function of many immune cell lineages and susceptibility to severe bacterial, viral, and fungal infections. despite a significant proportion of patients with was having recurrent viral infections, surprisingly little is known about the effects of wasp deficiency on antiviral immunity.201323141740
mouse liver-specific cd8(+) t-cells encounter their cognate antigen and acquire capacity to destroy target hepatocytes.cd8(+) t-cell immune response to liver antigens is often functionally diminished or absent. this may occur via deletion of these autoaggressive t-cells, through the acquisition of an anergic phenotype, or via active suppression mediated by other cell populations. we generated a double transgenic model in which mice express cd8(+) t-cells specific for the lymphocytic choriomeningitis virus nucleoprotein (lcmv-np) and lcmv-np as a hepatic neo-autoantigen, to study the immunological response of pot ...201323137675
cd8+ t cell-derived ifn-γ prevents infection by a second heterologous virus.persistent viral infection is often associated with dysfunctional immune responses against unrelated pathogens. lymphocytic choriomeningitis virus (lcmv) can establish acute or chronic infections in mice and is widely used as a model for persistent virus infections in humans. mice infected with lcmv develop a transient defect in ag-specific immunity against heterologous viral infection. although it has been proposed that lcmv infection induces an immunosuppressed state within the host, our data ...201223136204
characterization of cd8+ t cell function and immunodominance generated with an h2o2-inactivated whole-virus vaccine.cd8(+) t cells play an important role in protection against both acute and persistent viral infections, and new vaccines that induce cd8(+) t cell immunity are currently needed. here, we show that lymphocytic choriomeningitis virus (lcmv)-specific cd8(+) t cells can be generated in response to a nonreplicating h(2)o(2)-inactivated whole-virus vaccine (h(2)o(2)-lcmv). vaccine-induced cd8(+) t cell responses exhibited an increased ability to produce multiple cytokines at early time points followin ...201223055558
ox40 facilitates control of a persistent virus infection.during acute viral infections, clearance of the pathogen is followed by the contraction of the anti-viral t cell compartment. in contrast, t cell responses need to be maintained over a longer period of time during chronic viral infections in order to control viral replication and to avoid viral spreading. much is known about inhibitory signals such as through pd-1 that limit t cell activity during chronic viral infection, but little is known about the stimulatory signals that allow maintenance o ...201222969431
homeostatic division is not necessary for antigen-specific cd4+ memory t cell persistence.cd4(+) memory t cells are generated in response to infection or vaccination, provide protection to the host against reinfection, and persist through a combination of enhanced survival and slow homeostatic turnover. we used timed deletion of the tcr-signaling adaptor molecule src homology 2 domain-containing phosphoprotein of 76 kda (slp-76) with mhc:peptide tetramers to study the requirements for tonic tcr signals in the maintenance of polyclonal ag-specific cd4(+) memory t cells. slp-76-deficie ...201222956580
nkg2d blockade facilitates diabetes prevention by antigen-specific tregs in a virus-induced model of diabetes.it is thought that viral infections might jeopardize regulatory t cell therapy in type 1 diabetes. viral infections can lead to surface expression of ligands for the activating nkg2d receptor, such as retinoic acid early transcript 1 (rae-1), whose expression on beta-cells recruits nkg2d(+) autoreactive cd8(+) t cells. both in men and mice, autoreactive cytotoxic t cells express nkg2d. we showed that nkg2d expression increased on cd4(+) and cd8(+) t cells during virus-induced diabetes developmen ...201322944096
immune senescence: relative contributions of age and cytomegalovirus infection.immune senescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterised by impaired protective immunity and decreased efficacy of vaccines. recent clinical, epidemiological and immunological studies suggest that cytomegalovirus (cmv) infection may be associated with accelerated immune senescence, possibly by restricting the naïve t cell repertoire. however, direct evidence whether and how cmv-infection is implicated in immune senescence is still lack ...201222916013
foxp4 is dispensable for t cell development, but required for robust recall responses.transcription factors regulate t cell fates at every stage of development and differentiation. members of the foxp family of forkhead transcription factors are essential for normal t lineage development; foxp3 is required for t regulatory cell generation and function, and foxp1 is necessary for generation and maintenance of naïve t cells. foxp4, an additional member of the foxp family, is highly homologous to foxp1 and has been shown to dimerize with other foxp proteins. we report the initial ch ...201222912696
targeting pkcθ in alloreactivity and graft-versus-host-disease: unanswered questions and therapeutic potential.protein kinase c isoform θ (pkcθ) is a key modulator of tcr signaling and mediates activation of nf-κb, nf-at, and ap-1 transcription factors. although in vitro studies of pkcθ(-/-) t cells have shown impaired activation responses, in vivo studies indicate that pkcθ requirement is not universal. while pkcθ is important in induction of experimentally induced autoimmune diseases in mice and generation of th2 responses, it is not essential for induction of t cell proliferative and cytotoxic respons ...201222912640
notes from the field: lymphocytic choriomeningitis virus infections in employees of a rodent breeding facility--indiana, may-june 2012.in late april 2012, an infectious disease physician contacted cdc regarding a patient with aseptic meningitis who worked at a rodent breeding facility in indiana. lymphocytic choriomeningitis virus (lcmv) infection was suspected, and lcmv-specific antibody was detected in blood and cerebrospinal fluid from the patient, confirming the diagnosis. lcmv is an arenavirus carried by the common house mouse. persons become infected through close contact with infected rodents, through infected organ tran ...201222895387
the lcmv gp33-specific memory t cell repertoire narrows with age.the memory response to lcmv in mice persists for months to years with only a small decrease in the number of epitope specific cd8 t cells. this long persistence is associated with resistance to lethal lcmv disease. in contrast to studies focused on the number and surface phenotype of the memory cells, relatively little attention has been paid to the diversity of tcr usage in these cells. cd8+ t cell responses with only a few clones of identical specificity are believed to be relatively ineffecti ...201222894656
lymphocytic choriomeningitis virus: an underrecognized cause of neurologic disease in the fetus, child, and adult.lymphocytic choriomeningitis virus (lcmv) is an important cause of neurologic disease in humans. carried and secreted principally by wild mice, lcmv covers a large geographic range and infects great numbers of people. humans acquire lcmv disease when they come into contact with the secretions of infected mice. because it has a strong neurotropism, the clinical signs and symptoms of lcmv infection are mostly neurologic. when the virus is acquired postnatally by children or adults, the clinical ma ...201222889536
cutting edge: a novel mechanism bridging innate and adaptive immunity: il-12 induction of cd25 to form high-affinity il-2 receptors on nk cells.nk cell expression and use of the il-2rα-chain (cd25), required for the high-affinity il-2r, remain poorly understood. the studies reported in this article demonstrate that infections with murine cmv (mcmv), but not with lymphocytic choriomeningitis virus, induce cd25 on nk cells, along with high levels of il-12 and il-18. the cytokines act ex vivo to increase cd25 levels, and il-12, il-12r, and stat4, but not the nk activating receptor ly49h, are required for peak induction in vivo. all examine ...201222888135
role of interferon regulatory factor 7 in t cell responses during acute lymphocytic choriomeningitis virus infection.type i interferons (ifns), predominantly ifn-α and -β, play critical roles in both innate and adaptive immune responses against viral infections. interferon regulatory factor 7 (irf7), a key innate immune molecule in the type i ifn signaling pathway, is essential for the type i ifn response to many viruses, including lymphocytic choriomeningitis virus (lcmv). here, we show that although irf7 knockout (ko) mice failed to control the replication of lcmv in the early stages of infection, they were ...201222875973
memory t cells are uniquely resistant to melanoma-induced suppression.we have previously observed that in vivo exposure to growing melanoma tumors fundamentally alters activated t cell homeostasis by suppressing the ability of naïve t cells to undergo antigen-driven proliferative expansion. we hypothesized that exposure of t cells in later stages of differentiation to melanoma would have similar suppressive consequences. c57bl/6 mice were inoculated with media or syngeneic b16f10 melanoma tumors 8 or 60 days after infection with lymphocytic choriomeningitis virus ...201322865267
the rig-i-like receptor lgp2 controls cd8(+) t cell survival and fitness.the rig-i-like receptors (rlrs) signal innate immune defenses upon rna virus infection, but their roles in adaptive immunity have not been clearly defined. here, we showed that the rlr lgp2 was not essential for induction of innate immune defenses, but rather was required for controlling antigen-specific cd8(+) t cell survival and fitness during peripheral t cell-number expansion in response to virus infection. adoptive transfer and biochemical studies demonstrated that t cell-receptor signaling ...201222841161
solid organ transplant-associated lymphocytic choriomeningitis, united states, 2011.three clusters of organ transplant-associated lymphocytic choriomeningitis virus (lcmv) transmissions have been identified in the united states; 9 of 10 recipients died. in february 2011, we identified a fourth cluster of organ transplant-associated lcmv infections. diabetic ketoacidosis developed in the organ donor in december 2010; she died with generalized brain edema after a short hospitalization. both kidneys, liver, and lung were transplanted to 4 recipients; in all 4, severe posttransplan ...022839997
unexpected t-cell recognition of an altered peptide ligand is driven by reversed thermodynamics.the molecular basis underlying t-cell recognition of mhc molecules presenting altered peptide ligands is still not well-established. a hierarchy of t-cell activation by mhc class i-restricted altered peptide ligands has been defined using the t-cell receptor p14 specific for h-2d(b) in complex with the immunodominant lymphocytic choriomeningitis virus peptide gp33 (kavynfatm). while substitution of tyrosine to phenylalanine (y4f) or serine (y4s) abolished recognition by p14, the tcr unexpectedly ...201222837158
signal 3 cytokines as modulators of primary immune responses during infections: the interplay of type i ifn and il-12 in cd8 t cell responses.signal 3 cytokines, such as il-12 or type i ifn, support expansion and differentiation of cd8 t cells in vivo. if and how these two signal 3 cytokines compensate each other in t cell activation during different infections is so far unknown. using cd8 t cells lacking receptors for il-12, type i ifn or both, we show that the expansion of cd8 t cells depends on type i ifn (lcmv infection), type i ifn and il-12 (listeria and vesicular stomatitis virus infection) or is largely independent of the two ...201222815848
molecular surveillance and phylogenetic analysis of old world arenaviruses in zambia.in order to survey arenaviruses in the republic of zambia, we captured 335 rodents from three cities between 2010 and 2011. eighteen luna virus (lunv) and one lymphocytic choriomeningitis virus (lcmv)-related virus rnas were detected by one-step rt-pcr from mastomys natalensis and mus minutoides, respectively. four lunv strains and one lcmv-related virus were isolated, and the whole genome nucleotide sequence was determined by pyrosequencing. phylogenetic analyses revealed that the lunv clade co ...201222815269
protective capacity of virus-specific t cell receptor-transduced cd8 t cells in vivo.the transfer of t cell receptor (tcr) genes by viral vectors represents a promising technique to generate antigen-specific t cells for adoptive immunotherapy. tcr-transduced t cells specific for infectious pathogens have been described, but their protective function in vivo has not yet been examined. here, we demonstrate that cd8 t cells transduced with the p14 tcr specific for the gp33 epitope of lymphocytic choriomeningitis virus exhibit protective activities in both viral and bacterial infect ...201222787223
genomic analysis and pathogenic characteristics of lymphocytic choriomeningitis virus strains isolated in japan.lymphocytic choriomeningitis virus (lcmv) is a zoonotic pathogen of which mice are the natural reservoir. different strains and clones of lcmv show different pathogenicity in mice. here we determined the complete genomic sequences of 3 lcmv strains (oq28 and brc which were isolated from mice in japan and we(ngs) which was derived from strain we). strains oq28 and brc showed high sequence homology with other lcmv strains. although phylogenetic analyses placed these 2 japanese strains in different ...201222776051
stable antigen is most effective for eliciting cd8+ t-cell responses after dna vaccination and infection with recombinant vaccinia virus in vivo.the induction of strong cd8(+) t-cell responses against infectious diseases and cancer has remained a major challenge. depending on the source of antigen and the infectious agent, priming of cd8(+) t cells requires direct and/or cross-presentation of antigenic peptides on major histocompatibility complex (mhc) class i molecules by professional antigen-presenting cells (apcs). however, both pathways show distinct preferences concerning antigen stability. whereas direct presentation was shown to e ...201222761378
cathepsin b controls the persistence of memory cd8+ t lymphocytes.the persistence of memory t lymphocytes confers lifelong protection from pathogens. memory t cells survive and undergo homeostatic proliferation (hsp) in the absence of ag, although the cell-intrinsic mechanisms by which cytokines drive the hsp of memory t cells are not well understood. in this study we report that lysosome stability limits the long-term maintenance of memory cd8(+) t cell populations. serine protease inhibitor (spi) 2a, an anti-apoptotic cytosolic cathepsin inhibitor, is induce ...201222745374
commensal bacteria calibrate the activation threshold of innate antiviral immunity.signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. however, the mechanisms by which commensal bacteria regulate protective immunity after exposure to systemic pathogens remain poorly understood. here, we demonstrate that antibiotic-treated (abx) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic lcmv or mucosal influenza virus. furth ...201222705104
toll-like receptor 7 is required for effective adaptive immune responses that prevent persistent virus infection.tlr7 is an innate signaling receptor that recognizes single-stranded viral rna and is activated by viruses that cause persistent infections. we show that tlr7 signaling dictates either clearance or establishment of life-long chronic infection by lymphocytic choriomeningitis virus (lcmv) cl 13 but does not affect clearance of the acute lcmv armstrong 53b strain. tlr7(-/-) mice infected with lcmv cl 13 remained viremic throughout life from defects in the adaptive antiviral immune response-notably, ...022704624
timing and magnitude of type i interferon responses by distinct sensors impact cd8 t cell exhaustion and chronic viral infection.type i interferon (ifn-i) promotes antiviral cd8(+)t cell responses, but the contribution of different ifn-i sources and signaling pathways are ill defined. while plasmacytoid dendritic cells (pdcs) produce ifn-i upon tlr stimulation, ifn-i is induced in most cells by helicases like mda5. using acute and chronic lymphocytic choriomeningitis virus (lcmv) infection models, we determined that pdcs transiently produce ifn-i that minimally impacts cd8(+)t cell responses and viral persistence. rather, ...201222704623
plasmacytoid dendritic cells are productively infected and activated through tlr-7 early after arenavirus infection.the antiviral response is largely mediated by dendritic cells (dcs), including conventional (c) dcs that function as antigen-presenting cells, and plasmacytoid (p) dcs that produce type i interferons, making them an attractive target for viruses. we find that the old world arenaviruses lymphocytic choriomeningitis virus clone 13 (lcmv cl13) and lassa virus bind pdcs to a greater extent than cdcs. consistently, lcmv cl13 targets pdcs early after in vivo infection of its natural murine host and es ...201222704622
epitope specificity of memory cd8+ t cells dictates vaccination-induced mortality in lcmv-infected perforin-deficient mice.perforin-deficient (pko) mice serve as models for familial hemophagocytic lympho-histiocytosis, a uniformly fatal disease associated with viral infection of perforin-deficient humans. naïve perforin-deficient balb/c mice survive while vaccinated pko mice containing virus-specific memory cd8(+) t cells rapidly succumb to lymphocytic choriomeningitis virus (lcmv) infection. thus, vaccination converts a nonlethal persistent infection into a fatal disease mediated by virus-specific memory cd8(+) t c ...201222678903
foxo3 regulates the cd8 t cell response to a chronic viral infection.chronic infections with viruses such as hepatitis b virus, hepatitis c virus, and hiv constitute a major global public health problem. studies of chronic viral infections in humans and mice show that persistent antigenic stimulation induces dysregulation of t cell responses; virus-specific t cells either undergo clonal deletion or lose their ability to display the full spectrum of effector functions, a condition termed functional exhaustion. the ability to generate and retain sufficient numbers ...201222675000
interleukin-1r signaling is essential for induction of proapoptotic cd8 t cells, viral clearance, and pathology during lymphocytic choriomeningitis virus infection in mice.the t cell granule exocytosis pathway is essential to control hepatotropic lymphocytic choriomeningitis virus strain we (lcmv-we) but also contributes to the observed pathology in mice. although effective antiviral t cell immunity and development of viral hepatitis are strictly dependent on perforin and granzymes, the molecular basis underlying induction of functionally competent virus-immune t cells, including participation of the innate immune system, is far from being resolved. we demonstrate ...201222674984
cell surface molecules involved in infection mediated by lymphocytic choriomeningitis virus glycoprotein.the glycoprotein (gp) of lymphocytic choriomeningitis virus (lcmv), the prototype arenavirus, is a promising envelope protein of lentiviral pseudotype vectors for gene therapy. the distribution of dystroglycan, a known receptor for lcmv, cannot explain the narrow tropism of lcmv-gp-pseudotypes. here, we examined whether infection of lcmv-gp-pseudotypes was affected by the expression of four cell surface molecules-axl and tyro3 (from the tam family) and dc-sign and lsectin (from the c-type lectin ...201222673088
isolation and characterization of a new strain of lymphocytic choriomeningitis virus from rodents in southwestern france.a total of 821 tissue samples from rodents trapped during field campaigns organized in europe and africa were screened for the presence of arenaviruses by molecular methods and cell culture inoculation when feasible. two mus musculus domesticus trapped in the southwestern part of france were infected with a potentially new strain of lymphocytic choriomeningitis virus (lcmv), here referred to as lcmv strain hp65-2009, which was isolated and genetically characterized by whole genome sequencing. ge ...201222651393
sphingosine kinase 1 in viral infections.sphingosine kinase 1 (sphk1) is an enzyme that phosphorylates the lipid sphingosine to generate sphingosine-1-phosphate (s1p). s1p can act intracellularly as a signaling molecule and extracellularly as a receptor ligand. the sphk1/s1p axis has well-described roles in cell signaling, the cell death/survival decision, the production of a pro-inflammatory response, immunomodulation, and control of vascular integrity. agents targeting the sphk1/s1p axis are being actively developed as therapeutics f ...201322639116
development of a new hydrogen peroxide–based vaccine platform.safe and effective vaccines are crucial for maintaining public health and reducing the global burden of infectious disease. here we introduce a new vaccine platform that uses hydrogen peroxide (h(2)o(2)) to inactivate viruses for vaccine production. h(2)o(2) rapidly inactivates both rna and dna viruses with minimal damage to antigenic structure or immunogenicity and is a highly effective method when compared with conventional vaccine inactivation approaches such as formaldehyde or β-propiolacton ...022635006
arenavirus nucleoproteins prevent activation of nuclear factor kappa b.arenaviruses include several causative agents of hemorrhagic fever (hf) disease in humans that are associated with high morbidity and significant mortality. morbidity and lethality associated with hf arenaviruses are believed to involve the dysregulation of the host innate immune and inflammatory responses that leads to impaired development of protective and efficient immunity. the molecular mechanisms underlying this dysregulation are not completely understood, but it is suggested that viral in ...201222623788
tgf-β blockade does not improve control of an established persistent viral infection.acute resolving viral infections are often associated with a strong and multi-specific t-cell response, whereas in persistent viral infections t-cell responses are often impaired. it has been suggested that the resuscitation of the antiviral t-cell response could be a powerful tool to target persisting viruses. several immunoregulatory pathways, such as il-10 and tgf-β, have been shown to be involved in the induction of t-cell exhaustion and viral persistence. in this study, we sought to investi ...201222620718
accelerated and improved quantification of lymphocytic choriomeningitis virus (lcmv) titers by flow cytometry.lymphocytic choriomeningitis virus (lcmv), a natural murine pathogen, is a member of the arenavirus family, may cause atypical meningitis in humans, and has been utilized extensively as a model pathogen for the study of virus-induced disease and immune responses. historically, viral titers have been quantified by a standard plaque assay, but for non-cytopathic viruses including lcmv this requires lengthy incubation, so results cannot be obtained rapidly. additionally, due to specific technical c ...201222615984
emergence of distinct multiarmed immunoregulatory antigen-presenting cells during persistent viral infection.during persistent viral infection, adaptive immune responses are suppressed by immunoregulatory factors, contributing to viral persistence. although this suppression is mediated by inhibitory factors, the mechanisms by which virus-specific t cells encounter and integrate immunoregulatory signals during persistent infection are unclear. we show that a distinct population of il-10-expressing immunoregulatory antigen-presenting cells (apcs) is amplified during chronic versus acute lymphocytic chori ...201222607801
gene-based vaccination with a mismatched envelope protects against simian immunodeficiency virus infection in nonhuman primates.the rv144 trial demonstrated that an experimental aids vaccine can prevent human immunodeficiency virus type 1 (hiv-1) infection in humans. because of its limited efficacy, further understanding of the mechanisms of preventive aids vaccines remains a priority, and nonhuman primate (nhp) models of lentiviral infection provide an opportunity to define immunogens, vectors, and correlates of immunity. in this study, we show that prime-boost vaccination with a mismatched siv envelope (env) gene, deri ...201222593152
cd8 t cell defect of tnf-α and il-2 in dnam-1 deficient mice delays clearance in vivo of a persistent virus infection.dnam-1 gene-deficient (-/-) mice take significantly longer to clear an acute and persistent lcmv infection in vivo than dnam-1 +/+ mice. during acute lcmv priming, at the single cell level, dnam-1 -/- mice made significantly less cytoplasmic cd8 tnf-α and il-2 but not ifn-γ than their dnam-1 +/+ counterparts. restimulated immune memory cd8 t cells from dnam-1 -/- and dnam-1 +/+ mice were equivalent in cytolytic activity against lcmv-infected target cells but dnam-1 -/- cd8 t cells had significan ...201222579352
platelets support a protective immune response to lcmv by preventing splenic necrosis.severe arenaviral infections in humans are characterized by clinical findings common to other viral hemorrhagic fevers (vhfs), including thrombocytopenia, leukopenia, skin and internal organ hemorrhages, high viral replication, splenic necrosis, and death. host responses, rather than direct damage by the arenaviral replication, account for most of the observed pathology, but it is not known what protective roles platelets may have in each of the manifestations. to address this issue in an animal ...201322566603
therapeutic blockade of transforming growth factor beta fails to promote clearance of a persistent viral infection.persistent viral infections often overburden the immune system and are a major cause of disease in humans. during many persistent infections, antiviral t cells are maintained in a state of immune exhaustion characterized by diminished effector and helper functions. in mammalian systems, an extensive immune regulatory network exists to limit unwanted, potentially fatal immunopathology by inducing t cell exhaustion. however, this regulatory network at times overprotects the host and fosters viral ...201222553324
immortalized clones of fibroblastic reticular cells activate virus-specific t cells during virus infection.fibroblastic reticular cells (frcs) are lymphoid stromal cells essential to t-cell migration and survival. although frcs are targets of multiple viral infections, little is known about their role during infection due to the cells' scarcity and difficulty in isolating in vivo. to initiate studies of interactions among frcs, viruses, and immune cells, we isolated and immortalized cd45(-)gp38(+)cd35(-)cd31(-)cd44(+)vcam1(+) cell lines from c57bl/6 mice designated as immortalized frc. using these cl ...201222550183
loss of anti-viral immunity by infection with a virus encoding a cross-reactive pathogenic epitope.t cell cross-reactivity between different strains of the same virus, between different members of the same virus group, and even between unrelated viruses is a common occurrence. we questioned here how an intervening infection with a virus containing a sub-dominant cross-reactive t cell epitope would affect protective immunity to a previously encountered virus. pichinde virus (pv) and lymphocytic choriomeningitis virus (lcmv) encode subdominant cross-reactive np₂₀₅₋₂₁₂ cd8 t cell epitopes sharin ...201222536152
arenavirus nucleoprotein targets interferon regulatory factor-activating kinase ikkε.arenaviruses perturb innate antiviral defense by blocking induction of type i interferon (ifn) production. accordingly, the arenavirus nucleoprotein (np) was shown to block activation and nuclear translocation of interferon regulatory factor 3 (irf3) in response to virus infection. here, we sought to identify cellular factors involved in innate antiviral signaling targeted by arenavirus np. consistent with previous studies, infection with the prototypic arenavirus lymphocytic choriomeningitis vi ...201222532683
pathogenic old world arenaviruses inhibit tlr2/mal-dependent proinflammatory cytokines in vitro.lymphocytic choriomeningitis virus (lcmv), the prototype arenavirus, and lassa virus (lasv), the causative agent of lassa fever (lf), have extensive strain diversity and significant variations in pathogenicity for humans and experimental animals. the we strain of lcmv (lcmv-we), but not the armstrong (arm) strain, induces a fatal lf-like disease in rhesus macaques. we also demonstrated that lasv infection of human macrophages and endothelial cells resulted in reduced levels of proinflammatory cy ...201222532679
lymphocytic choriomeningitis virus-associated meningitis, southern spain.lymphocytic choriomeningitis virus (lcmv) was detected in 2 patients with acute meningitis in southern spain within a 3-year period. although the prevalence of lcmv infection was low (2 [1.3%] of 159 meningitis patients), it represents 2.9% of all pathogens detected. lcmv is a noteworthy agent of neurologic illness in immunocompetent persons.022515986
differential impact of interferon regulatory factor 7 in initiation of the type i interferon response in the lymphocytic choriomeningitis virus-infected central nervous system versus the periphery.interferon (ifn) regulatory factors (irfs) are a family of transcription factors involved in regulating type i ifn genes and other genes participating in the early antiviral host response. to better understand the mechanisms involved in virus-induced central nervous system (cns) inflammation, we studied the influence of irf1, -3, -7, and -9 on the transcriptional activity of key genes encoding antiviral host factors in the cns of mice infected with lymphocytic choriomeningitis virus (lcmv). a ke ...201222514347
mice deficient in stat1 but not stat2 or irf9 develop a lethal cd4+ t-cell-mediated disease following infection with lymphocytic choriomeningitis virus.interferon (ifn) signaling is crucial for antiviral immunity. while type i ifn signaling is mediated by stat1, stat2, and irf9, type ii ifn signaling requires only stat1. here, we studied the roles of these signaling factors in the host response to systemic infection with lymphocytic choriomeningitis virus (lcmv). in wild-type (wt) mice and mice lacking either stat2 or irf9, lcmv infection was nonlethal, and the virus either was cleared (wt) or established persistence (stat2 knockout [ko] and ir ...201222496215
chronic hiv infection affects the expression of the 2 transcription factors required for cd8 t-cell differentiation into cytolytic effectors.cd8 t cells lose the capacity to control hiv infection, but the extent of the impairment of cd8 t-cell functions and the mechanisms that underlie it remain controversial. here we report an extensive ex vivo analysis of hiv-specific cd8 t cells, covering the expression of 16 different molecules involved in cd8 function or differentiation. this approach gave remarkably homogeneous readouts in different donors and showed that cd8 dysfunction in chronic hiv infection was much more severe than descri ...201222490682
combined costimulatory and leukocyte functional antigen-1 blockade prevents transplant rejection mediated by heterologous immune memory alloresponses.recent evidence suggests that alloreactive memory t cells are generated by the process of heterologous immunity, whereby memory t cells arising in response to pathogen infection crossreact with donor antigens. because of their diminished requirements for costimulation during recall, these pathogen-elicited allocrossreactive memory t cells are of particular clinical importance, especially given the emergence of costimulatory blockade as a transplant immunosuppression strategy.201222475765
mutagenesis-mediated virus extinction: virus-dependent effect of viral load on sensitivity to lethal defection.lethal mutagenesis is a transition towards virus extinction mediated by enhanced mutation rates during viral genome replication, and it is currently under investigation as a potential new antiviral strategy. viral load and virus fitness are known to influence virus extinction. here we examine the effect or the multiplicity of infection (moi) on progeny production of several rna viruses under enhanced mutagenesis.201222442668
inflammation-associated nitrotyrosination affects tcr recognition through reduced stability and alteration of the molecular surface of the mhc complex.nitrotyrosination of proteins, a hallmark of inflammation, may result in the production of mhc-restricted neoantigens that can be recognized by t cells and bypass the constraints of immunological self-tolerance. here we biochemically and structurally assessed how nitrotyrosination of the lymphocytic choriomeningitis virus (lcmv)-associated immunodominant mhc class i-restricted epitopes gp33 and gp34 alters t cell recognition in the context of both h-2d(b) and h-2k(b). comparative analysis of the ...201222431983
low 2-dimensional cd4 t cell receptor affinity for myelin sets in motion delayed response kinetics.t cells recognizing self-peptides that mediate autoimmune disease and those that are responsible for efficacious immunity against pathogens may differ in affinity for antigen due to central and peripheral tolerance mechanisms. here we utilize prototypical self-reactive (myelin) and viral-specific (lcmv) t cells from t cell receptor (tcr) transgenic mice (2d2 and smarta, respectively) to explore affinity differences. the t cells responsive to virus possessed >10,000 fold higher 2d affinity as com ...201222412888
preformed cd40l is stored in th1, th2, th17, and t follicular helper cells as well as cd4+ 8- thymocytes and invariant nkt cells but not in treg cells.cd40l is essential for the development of adaptive immune responses. it is generally thought that cd40l expression in cd4(+) t cells is regulated transcriptionally and made from new mrna following antigen recognition. however, imaging studies show that the majority of cognate interactions between effector cd4(+) t cells and apcs in vivo are too short to allow de novo cd40l synthesis. we previously showed that th1 effector and memory cells store preformed cd40l (pcd40l) in lysosomal compartments ...201222363608
foxo3 regulates cd8 t cell memory by t cell-intrinsic mechanisms.cd8 t cell responses have three phases: expansion, contraction, and memory. dynamic alterations in proliferation and apoptotic rates control cd8 t cell numbers at each phase, which in turn dictate the magnitude of cd8 t cell memory. identification of signaling pathways that control cd8 t cell memory is incomplete. the pi3k/akt signaling pathway controls cell growth in many cell types by modulating the activity of foxo transcription factors. but the role of foxos in regulating cd8 t cell memory r ...201222359505
molecular characterization of the processing of arenavirus envelope glycoprotein precursors by subtilisin kexin isozyme-1/site-1 protease.a crucial step in the life cycle of arenaviruses is the biosynthesis of the mature fusion-active viral envelope glycoprotein (gp) that is essential for virus-host cell attachment and entry. the maturation of the arenavirus gp precursor (gpc) critically depends on proteolytic processing by the cellular proprotein convertase (pc) subtilisin kexin isozyme-1 (ski-1)/site-1 protease (s1p). here we undertook a molecular characterization of the ski-1/s1p processing of the gpcs of the prototypic arenavi ...201222357276
the pi3k/akt pathway contributes to arenavirus budding.several arenaviruses, chiefly lassa virus (lasv), cause hemorrhagic fever (hf) disease in humans and pose a significant public health concern in regions where they are endemic. on the other hand, evidence indicates that the globally distributed prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) is a neglected human pathogen. the phosphatidylinositol 3-kinase (pi3k)/akt pathway participates in many cellular processes, including cell survival and differentiation, and also has been sho ...201222345463
plasmacytoid dendritic cells control t-cell response to chronic viral infection.infections with persistent viruses are a frequent cause of immunosuppression, autoimmune sequelae, and/or neoplastic disease. plasmacytoid dendritic cells (pdcs) are innate immune cells that produce type i interferon (ifn-i) and other cytokines in response to virus-derived nucleic acids. persistent viruses often cause depletion or functional impairment of pdcs, but the role of pdcs in the control of these viruses remains unclear. we used conditional targeting of pdc-specific transcription factor ...201222315415
arenavirus budding.several arenaviruses cause hemorrhagic fever disease in humans and pose a significant public health concern in their endemic regions. on the other hand, the prototypic arenavirus lcmv is a superb workhorse for the investigation of virus-host interactions and associated disease. the arenavirus small ring finger protein called z has been shown to be the main driving force of virus budding. the budding activity of z is mediated by late (l) domain motifs, pt/sap, and ppxy, located at the c-terminus ...201122312335
an intermediate dose of lcmv clone 13 causes prolonged morbidity that is maintained by cd4+ t cells.wasting is a sign of various underlying disorders and is a common feature of cancer, sepsis, and aids. we have developed an in vivo model to study the various stages of wasting following infection of mice with lymphocytic choriomeningitis virus cl-13. using this model we have identified four distinct stages of wasting and have discovered that all stages occur in the different groups of mice regardless of whether the virus is cleared or persists. however, the degree and extent of wasting vary bet ...201222305620
differential regulation of primary and memory cd8 t cell immune responses by diacylglycerol kinases.the manipulation of signals downstream of the tcr can have profound consequences for t cell development, function, and homeostasis. diacylglycerol (dag) produced after tcr stimulation functions as a secondary messenger and mediates the signaling to ras-mek-erk and nf-κb pathways in t cells. dag kinases (dgks) convert dag into phosphatidic acid, resulting in termination of dag signaling. in this study, we demonstrate that dag metabolism by dgks can serve a crucial function in viral clearance upon ...201222271650
self-association of lymphocytic choriomeningitis virus nucleoprotein is mediated by its n-terminal region and is not required for its anti-interferon function.arenaviruses have a bisegmented, negative-strand rna genome. both the large (l) and small (s) genome segments use an ambisense coding strategy to direct the synthesis of two viral proteins. the l segment encodes the virus polymerase (l protein) and the matrix z protein, whereas the s segment encodes the nucleoprotein (np) and the glycoprotein precursor (gpc). nps are the most abundant viral protein in infected cells and virions and encapsidate genomic rna species to form an np-rna complex that, ...201222258244
psgl-1 regulates the migration and proliferation of cd8+ t cells under homeostatic conditions.p-selectin glycoprotein ligand-1 (psgl-1), a heavily glycosylated sialomucin expressed on most leukocytes, has dual function as a selectin ligand for leukocyte rolling on vascular selectins expressed in inflammation and as a facilitator of resting t cell homing into lymphoid organs. in this article, we document disturbances in t cell homeostasis present in psgl-1(null) mice. naive cd4(+) and cd8(+) t cell frequencies were profoundly reduced in blood, whereas t cell numbers in lymph nodes and spl ...201222250093
serine protease inhibitor 6 is required to protect dendritic cells from the kiss of death.how dendritic cells (dc) present ag to cytotoxic t cells (ctl) without themselves being killed through contact-mediated cytotoxicity (so-called kiss of death) has proved to be controversial. using mice deficient in serine protease inhibitor 6 (spi6), we show that spi6 protects dc from the kiss of death by inhibiting granzyme b (grb) delivered by ctl. infection of spi6 knockout mice with lymphocytic choriomeningitis virus revealed impaired survival of cd8α dc. the impaired survival of spi6 knocko ...201222227570
cns recruitment of cd8+ t lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge.although viruses have been implicated in central nervous system (cns) diseases of unknown etiology, including multiple sclerosis and amyotrophic lateral sclerosis, the reproducible identification of viral triggers in such diseases has been largely unsuccessful. here, we explore the hypothesis that viruses need not replicate in the tissue in which they cause disease; specifically, that a peripheral infection might trigger cns pathology. to test this idea, we utilized a transgenic mouse model in w ...201122216008
foxp3(+) regulatory t cells, immune stimulation and host defence against infection.the immune system is intricately regulated allowing potent effectors to expand and become rapidly mobilized after infection, while simultaneously silencing potentially detrimental responses that averts immune-mediated damage to host tissues. this relies in large part on the delicate interplay between immune suppressive regulatory cd4(+) t (treg) cells and immune effectors that without active suppression by treg cells cause systemic and organ-specific autoimmunity. although these beneficial roles ...201222211994
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