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notes from the field: a cluster of lymphocytic choriomeningitis virus infections transmitted through organ transplantation - iowa, 2013.on april 26, 2013, the united network for organ sharing reported to cdc a cluster of ill organ transplant recipients in iowa with a common organ donor. infection with lymphocytic choriomeningitis virus (lcmv) was suspected. lcmv is a rodent-borne virus that most commonly causes nonfatal, influenza-like illness and occasional aseptic meningitis, but when transmitted through organ transplantation or in utero can cause severe, life-threatening disease.201424647402
ifn-λ exerts opposing effects on t cell responses depending on the chronicity of the virus infection.ifn-λ induces an antiviral state in many cell types and may contribute to the overall inflammatory environment after infection. either of these effects may influence adaptive immune responses, but the role of type 3 ifns in the development of primary and memory t cell responses to infection has not been evaluated. in this study, we examined t cell responses to acute or persistent lymphocytic choriomeningitis virus infection in ifn-λr1-deficient mice. following acute infection, we find that ifn-λ ...201424646741
b cell antigen presentation in the initiation of follicular helper t cell and germinal center differentiation.high-affinity class-switched abs and memory b cells are products of the germinal center (gc). the cd4+ t cell help required for the development and maintenance of the gc is delivered by follicular th cells (t(fh)), a cd4+ th cell subset characterized by expression of bcl-6 and secretion of il-21. the cellular interactions that mediate differentiation of tfh and gc b cells remain an important area of investigation. we previously showed that mhc class ii (mhcii)-dependent dendritic cell ag present ...201424646739
platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways.bh3 mimetic drugs that target bcl-2 family pro-survival proteins to induce tumour cell apoptosis represent a new era in cancer therapy. clinical trials of navitoclax (abt-263, which targets bcl-2, bcl-xl and bcl-w) have shown great promise, but encountered dose-limiting thrombocytopenia. recent work has demonstrated that this is due to the inhibition of bcl-xl, which is essential for platelet survival. these findings raise new questions about the established model of platelet shedding by megakar ...201424632563
transcription factor stat3 and type i interferons are corepressive insulators for differentiation of follicular helper and t helper 1 cells.follicular helper t (tfh) cells are required for the establishment of t-dependent b cell memory and high affinity antibody-secreting cells. we have revealed herein opposing roles for signal transducer and activator of transcription 3 (stat3) and type i interferon (ifn) signaling in the differentiation of tfh cells following viral infection. stat3-deficient cd4(+) t cells had a profound defect in tfh cell differentiation, accompanied by decreased germinal center (gc) b cells and antigen-specific ...201424631156
the p75 neurotrophin receptor is required for the major loss of sympathetic nerves from islets under autoimmune attack.our goal was to determine the role of the p75 neurotrophin receptor (p75ntr) in the loss of islet sympathetic nerves that occurs during the autoimmune attack of the islet. the islets of transgenic (tg) mice in which β-cells express a viral glycoprotein (gp) under the control of the insulin promotor (ins2) were stained for neuropeptide y before, during, and after virally induced autoimmune attack of the islet. ins2-gp(tg) mice injected with lymphocytic choriomeningitis virus (lcmv) lost islet sym ...201424608438
sphingosine analog aal-r promotes activation of lcmv-infected dendritic cells.sphingosine analogs display diverse immunoregulatory activities with curative potential in autoimmune diseases and viral infections. recently, the sphingosine analog aal-r was shown to increase dc activation upon tlr7 stimulation. here, we investigated the effect of aal-r on activation of dendritic cells (dcs) infected by lymphocytic choriomeningitis virus (lcmv). concomitant treatment of lcmv-infected dcs with aal-r enhanced dc maturation and dc ability to stimulate and expand antiviral cd8(+) ...201424605791
intrahepatic innate lymphoid cells secrete il-17a and il-17f that are crucial for t cell priming in viral infection.intrahepatic cell-derived, early il-17 is important for activating apcs in viral infection; however, the source and regulation of this il-17 surge in the liver microenvironment are not well defined. in this article, we present evidence for a significant expansion of il-17a/f-producing cells in mouse liver within 24 h of adenovirus infection. in addition to γδ t cells, a subset of il-17a/f(+) cells expressed no myeloid or lymphoid lineage markers. instead, they expressed high levels of stem cell ...201424600029
duality of the murine cd8 compartment.cd8αβ plays crucial roles in the thymic selection, differentiation, and activation of some, but not all, cd8(+) t cells, whereas cd8αα does not. to investigate these roles, we produced mice that expressed transgene p14 t-cell receptor β (tcrβ) chain and cd8β or did not (wt and ko mice, respectively). the primary cd8(+) t-cell response to acute lymphocytic choriomeningitis virus (lcmv) infection was predominantly d(b)/gp33 specific and cd8 independent in ko mice and was mostly cd8 dependent in wt ...201424594598
blimp-1 represses cd8 t cell expression of pd-1 using a feed-forward transcriptional circuit during acute viral infection.programmed cell death 1 (pd-1) is an inhibitory immune receptor that regulates t cell function, yet the molecular events that control its expression are largely unknown. we show here that b lymphocyte-induced maturation protein 1 (blimp-1)-deficient cd8 t cells fail to repress pd-1 during the early stages of cd8 t cell differentiation after acute infection with lymphocytic choriomeningitis virus (lcmv) strain armstrong. blimp-1 represses pd-1 through a feed-forward repressive circuit by regulati ...201424590765
engagement of nkg2d on bystander memory cd8 t cells promotes increased immunopathology following leishmania major infection.one of the hallmarks of adaptive immunity is the development of a long-term pathogen specific memory response. while persistent memory t cells certainly impact the immune response during a secondary challenge, their role in unrelated infections is less clear. to address this issue, we utilized lymphocytic choriomeningitis virus (lcmv) and listeria monocytogenes immune mice to investigate whether bystander memory t cells influence leishmania major infection. despite similar parasite burdens, lcmv ...201424586170
beta-cell specific production of il6 in conjunction with a mainly intracellular but not mainly surface viral protein causes diabetes.inflammatory mechanisms play a key role in the pathogenesis of type 1 and type 2 diabetes. il6, a pleiotropic cytokine with impact on immune and non-immune cell types, has been proposed to be involved in the events causing both forms of diabetes and to play a key role in experimental insulin-dependent diabetes development. the aim of this study was to investigate how beta-cell specific overexpression of il-6 influences diabetes development. we developed two lines of rat insulin promoter (rip)-ly ...201424582317
vsv-gp: a potent viral vaccine vector that boosts the immune response upon repeated applications.antivector immunity limits the response to homologous boosting for viral vector vaccines. here, we describe a new, potent vaccine vector based on replication-competent vesicular stomatitis virus pseudotyped with the glycoprotein of the lymphocytic choriomeningitis virus (vsv-gp), which we previously showed to be safe in mice. in mice, vsv and vsv-gp encoding ovalbumin (ova) as a model antigen (vsv-ova and vsv-gp-ova) induced equal levels of ova-specific humoral and cellular immune responses upon ...201424554655
irf4 and batf are critical for cd8⁺ t-cell function following infection with lcmv.cd8(+) t-cell functions are critical for preventing chronic viral infections by eliminating infected cells. for healthy immune responses, beneficial destruction of infected cells must be balanced against immunopathology resulting from collateral damage to tissues. these processes are regulated by factors controlling cd8(+) t-cell function, which are still incompletely understood. here, we show that the interferon regulatory factor 4 (irf4) and its cooperating binding partner b-cell-activating tr ...201424531538
high-resolution structure of the n-terminal endonuclease domain of the lassa virus l polymerase in complex with magnesium ions.lassa virus (lasv) causes deadly hemorrhagic fever disease for which there are no vaccines and limited treatments. lasv-encoded l polymerase is required for viral rna replication and transcription. the functional domains of l-a large protein of 2218 amino acid residues-are largely undefined, except for the centrally located rna-dependent rna polymerase (rdrp) motif. recent structural and functional analyses of the n-terminal region of the l protein from lymphocytic choriomeningitis virus (lcmv), ...201424516554
cd4+ t-cell help is required for effective cd8+ t cell-mediated resolution of acute viral hepatitis in mice.cytotoxic cd8+ t cells are essential for the control of viral liver infections, such as those caused by hbv or hcv. it is not entirely clear whether cd4+ t-cell help is necessary for establishing anti-viral cd8+ t cell responses that successfully control liver infection. to address the role of cd4+ t cells in acute viral hepatitis, we infected mice with lymphocytic choriomeningitis virus (lcmv) of the strain we; lcmv-we causes acute hepatitis in mice and is cleared from the liver by cd8+ t cells ...201424466045
b cell depletion curtails cd4+ t cell memory and reduces protection against disseminating virus infection.dynamic interactions between cd4(+) t cells and b cells are needed for humoral immunity and cd4(+) t cell memory. it is not known whether b cells are needed early on to induce the formation of memory precursor cells or are needed later to sustain memory cells. in this study, primary and memory cd4(+) t cells responses were followed in wild-type mice that were depleted of mature b cells by anti-cd20 before or different times after acute lymphocytic choriomeningitis virus infection. the ab treatme ...201424453250
trace-forward investigation of mice in response to lymphocytic choriomeningitis virus outbreak.during follow-up of a 2012 us outbreak of lymphocytic choriomeningitis virus (lcmv), we conducted a trace-forward investigation. lcmv-infected feeder mice originating from a us rodent breeding facility had been distributed to >500 locations in 21 states. all mice from the facility were euthanized, and no additional persons tested positive for lcmv infection.201424447898
lymphocytic choriomeningitis virus in employees and mice at multipremises feeder-rodent operation, united states, 2012.we investigated the extent of lymphocytic choriomeningitis virus (lcmv) infection in employees and rodents at 3 commercial breeding facilities. of 97 employees tested, 31 (32%) had igm and/or igg to lcmv, and aseptic meningitis was diagnosed in 4 employees. of 1,820 rodents tested in 1 facility, 382 (21%) mice (mus musculus) had detectable igg, and 13 (0.7%) were positive by reverse transcription pcr; lcmv was isolated from 8. rats (rattus norvegicus) were not found to be infected. s-segment rna ...201424447605
to investigate the necessity of stra6 upregulation in t cells during t cell immune responses.our earlier study revealed that stra6 (stimulated by retinoic acid gene 6) was up-regulated within 3 h of tcr stimulation. stra6 is the high-affinity receptor for plasma retinol-binding protein (rbp) and mediates cellular vitamin a uptake. we generated stra6 knockout (ko) mice to assess whether such up-regulation was critical for t-cell activation, differentiation and function. stra6 ko mice under vitamin a sufficient conditions were fertile without apparent anomalies upon visual inspection. the ...201324391722
clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming cd8 t cell response.the balance between protective immunity and immunopathology often determines the fate of the virus-infected host. how rapidly virus is cleared is a function of initial viral load, viral replication rate, and efficiency of the immune response. here, we demonstrate, with three different inocula of lymphocytic choriomeningitis virus (lcmv), how the race between virus replication and t cell responses can result in different disease outcomes. a low dose of lcmv generated efficient cd8 t effector cell ...201324391647
ebi2 is a negative regulator of type i interferons in plasmacytoid and myeloid dendritic cells.epstein-barr virus induced receptor 2 (ebi2), a gαi-coupled g protein-coupled receptor, is a chemotactic receptor for b, t and dendritic cells (dc). genetic studies have also implicated ebi2 as a regulator of an interferon regulatory factor 7 (irf7)-driven inflammatory network (idin) associated with autoimmune diseases, although the corollary in primary type i ifn-producing cells has not been reported. here we demonstrate that ebi2 negatively regulates type i ifn responses in plasmacytoid dc (pd ...201324386204
detection of foreign antigen-specific cd4(+)foxp3(+) regulatory t cells by mhc class ii tetramer and intracellular cd154 staining.the unrestricted population of cd4(+)foxp3(+) regulatory t (treg) cells, which have been known to control the expression of autoimmune diseases and protective immunity to inflammatory reactions, has led to greater appreciation of functional plasticity. detecting and/or isolating ag-specific cd4(+)foxp3(+) tregs at the single cell level are required to study their function and plasticity. in this study, we established and compared both mhc class ii tetramer and intracellular cd154 staining, in or ...201324385945
intravascular staining for discrimination of vascular and tissue leukocytes.characterization of the cellular participants in tissue immune responses is crucial to understanding infection, cancer, autoimmunity, allergy, graft rejection and other immunological processes. previous reports indicate that leukocytes in lung vasculature fail to be completely removed by perfusion. several studies suggest that intravascular staining may discriminate between tissue-localized and blood-borne cells in the mouse lung. here we outline a protocol for the validation and use of intravas ...201424385150
graded defects in cytotoxicity determine severity of hemophagocytic lymphohistiocytosis in humans and mice.primary hemophagocytic lymphohistiocytosis (hlh) is a life-threatening disease of hyperinflammation resulting from immune dysregulation due to inherited defects in the cytolytic machinery of natural killer and t cells. in humans, mutations in seven genes encoding proteins involved in cytolytic effector functions have so far been identified that predispose to hlh. however, although most affected patients develop hlh eventually, disease onset and severity are highly variable. due to the genetic he ...201324379813
distinct neural stem cell tropism, early immune activation, and choroid plexus pathology following coxsackievirus infection in the neonatal central nervous system.coxsackievirus b3 (cvb3) and lymphocytic choriomeningitis virus (lcmv) are both neurotropic rna viruses, which can establish a persistent infection and cause meningitis and encephalitis in the neonatal host. utilizing our neonatal mouse model of infection, we evaluated the consequences of early viral infection upon the host central nervous system (cns) by comparing cvb3 and lcmv infection. both viruses expressed high levels of viral protein in the choroid plexus and subventricular zone (svz), a ...201424378643
functional limitations of plasmacytoid dendritic cells limit type i interferon, t cell responses and virus control in early life.infant mortality from viral infection remains a major global health concern: viruses causing acute infections in immunologically mature hosts often follow a more severe course in early life, with prolonged or persistent viral replication. similarly, the we strain of lymphocytic choriomeningitis virus (lcmv-we) causes acute self-limiting infection in adult mice but follows a protracted course in infant animals, in which lcmv-specific cd8⁺ t cells fail to expand and control infection. by disruptin ...201324376875
combining regulatory t cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific cd8+ t cells and efficiently reduces chronic retroviral loads.chronic infections with human viruses, such as hiv and hcv, or mouse viruses, such as lcmv or friend virus (fv), result in functional exhaustion of cd8(+) t cells. two main mechanisms have been described that mediate this exhaustion: expression of inhibitory receptors on cd8(+) t cells and expansion of regulatory t cells (tregs) that suppress cd8(+) t cell activity. several studies show that blockage of one of these pathways results in reactivation of cd8(+) t cells and partial reduction in chro ...201324339778
inhibitors of apoptosis proteins (iaps) are required for effective t-cell expansion/survival during antiviral immunity in mice.inhibitors of apoptosis proteins (iaps) were originally described as regulating apoptosis by direct binding to caspases. more recently, iaps have been identified as important modulators of canonical and noncanonical nuclear factor κb signaling via their ubiquitin-e3 ligase activity. iaps are therefore, not only gatekeepers of cell death, but are probably also involved in the regulation of inflammation, as well as innate and adaptive immunity. in this study, we analyzed the role of iaps in t-cell ...201424335231
genetic disruption of cd8+ treg activity enhances the immune response to viral infection.the immunological interactions that regulate the t-cell response to chronic viral infection are insufficiently understood. here we study a cellular interaction that may enhance the antiviral immune response and constrain immunopathology. we analyze the contribution of qa-1-restricted cd8(+) regulatory t cells (treg cells) to antiviral immunity after infection by lymphocytic choriomeningitis virus. these cd8(+) treg cells recognize and eliminate target cells through an interaction with the murine ...201324324159
immunotherapy with tcr-redirected t cells: comparison of tcr-transduced and tcr-engineered hematopoietic stem cell-derived t cells.redirecting ag specificity by transfer of tcr genes into pbls is an attractive method to generate large numbers of cytotoxic t cells for immunotherapy of cancer and viral diseases. however, transferred tcr chains can pair with endogenous tcr chains, resulting in the formation of mispaired tcr dimers and decreased or unspecific reactivity. tcr gene transfer into hematopoietic stem cells (hscs) is an alternative to create t cells with desired ag specificity, because in this case expression of endo ...201424293634
therapeutic depletion of natural killer cells controls persistent infection.persistent viral infections are associated with host and viral factors that impair effective antiviral immunity. natural killer (nk) cells contribute to establishment of persistent lymphocytic choriomeningitis virus (lcmv) infection in mice through suppression of virus-specific t cell responses during the first few days of infection, but nk cell depletion during those early time points can enable severe t cell-mediated immune pathology and death of the host. here we show that long after their pe ...201424284324
etoposide selectively ablates activated t cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis.hemophagocytic lymphohistiocytosis (hlh) is an inborn disorder of immune regulation caused by mutations affecting perforin-dependent cytotoxicity. defects in this pathway impair negative feedback between cytotoxic lymphocytes and apcs, leading to prolonged and pathologic activation of t cells. etoposide, a widely used chemotherapeutic drug that inhibits topoisomerase ii, is the mainstay of treatment for hlh, although its therapeutic mechanism remains unknown. we used a murine model of hlh, invol ...201424259502
macrophage and t cell produced il-10 promotes viral chronicity.chronic viral infections lead to cd8(+) t cell exhaustion, characterized by impaired cytokine secretion. presence of the immune-regulatory cytokine il-10 promotes chronicity of lymphocytic choriomeningitis virus (lcmv) clone 13 infection, while absence of il-10/il-10r signaling early during infection results in viral clearance and higher percentages and numbers of antiviral, cytokine producing t cells. il-10 is produced by several cell types during lcmv infection but it is currently unclear whic ...201324244162
virus-specific cd4 and cd8 t cell responses in the absence of th1-associated transcription factors.effector and memory cd4 and cd8 t cell responses are critical for the control of many intracellular pathogens. the development of these populations is governed by transcription factors that molecularly control their differentiation, function, and maintenance. two transcription factors known to be involved in these processes are tbet and stat4. although tbet has been shown to regulate cd8 t cell fate decisions and effector cd4 t cell choices, the contribution of stat4 is less well understood. to ...201424231259
decoding the complexity of type i interferon to treat persistent viral infections.type i interferons (ifn-i) are a broad family of cytokines that are central to the innate immune response. these proteins have long been appreciated for the critical roles they play in restraining viral infections and shaping antiviral immune responses. however, in recent years there has been increased awareness of the immunosuppressive actions of these proteins as well. although there are many current therapeutic applications to manipulate ifn-i pathways, we have limited understanding of the me ...201324216022
inhibition of arenavirus by a3, a pyrimidine biosynthesis inhibitor.arenaviruses merit significant interest as important human pathogens, since several of them cause severe hemorrhagic fever disease that is associated with high morbidity and significant mortality. currently, there are no fda-licensed arenavirus vaccines available, and current antiarenaviral therapy is limited to an off-labeled use of the nucleoside analog ribavirin, which has limited prophylactic efficacy. the pyrimidine biosynthesis inhibitor a3, which was identified in a high-throughput screen ...201324198417
distinct roles of nk cells in viral immunity during different phases of acute friend retrovirus infection.in many virus infections natural killer (nk) cells are critical for the rapid containment of virus replication. polymorphisms in nk cell receptors as well as viral escape from nk cell responses are associated with pathogenesis and viral loads in hiv-infected individuals, emphasizing their importance in retroviral immunity. in contrast, nk cells of lcmv-infected mice dampened virus-specific t cell responses resulting in impaired virus control. thus, the exact role of nk cells during different pha ...201324182203
sodium hydrogen exchangers contribute to arenavirus cell entry.several arenaviruses, chiefly lassa virus (lasv), cause hemorrhagic fever (hf) disease in humans and pose a great public health concern in the regions in which they are endemic. moreover, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) is a neglected human pathogen of clinical significance. the limited existing armamentarium to combat human-pathogenic arenaviruses underscores the importance of developing novel antiarenaviral drugs ...201324173224
deletion of naïve t cells recognizing the minor histocompatibility antigen hy with toxin-coupled peptide-mhc class i tetramers inhibits cognate ctl responses and alters immunodominance.alloreactive t-cell responses directed against minor histocompatibility (h) antigens, which arise from diverse genetic disparities between donor and recipient outside the mhc, are an important cause of rejection of mhc-matched grafts. because clinically significant responses appear to be directed at only a few antigens, the selective deletion of naïve t cells recognizing donor-specific, immunodominant minor h antigens in recipients before transplantation may be a useful tolerogenic strategy. we ...201324161680
confounding roles for type i interferons during bacterial and viral pathogenesis.although type i interferons (ifn-i) were initially defined as potent antiviral agents, they can also cause decreased host resistance to some bacterial and viral infections. the many antiviral functions of the ifn-i include direct suppression of viral replication and activation of the immune response against viruses. in addition to their antiviral effects, ifn-i are also protective against several extracellular bacterial infections, in part, by promoting the induction of tnf-α and nitric oxide. i ...201324158954
human plasmacytoid dendritic cells sense lymphocytic choriomeningitis virus-infected cells in vitro.we previously reported that exosomal transfer of hepatitis c virus (hcv) positive-strand rna from human huh-7 hepatoma cells to human plasmacytoid dendritic cells (pdcs) triggers pdc alpha/beta interferon (ifn-α/β) production in a toll-like receptor 7 (tlr7)-dependent, virus-independent manner. here we show that human pdcs are also activated by a tlr7-dependent, virus-independent, exosomal rna transfer mechanism by human and mouse hepatoma and nonhepatoma cells that replicate the negative-strand ...201424155390
targeted deletion of fgl2 leads to increased early viral replication and enhanced adaptive immunity in a murine model of acute viral hepatitis caused by lcmv we.mounting effective innate and adaptive immune responses are critical for viral clearance and the generation of long lasting immunity. it is known that production of inhibitory factors may result in the inability of the host to clear viruses, resulting in chronic viral persistence. fibrinogen-like protein 2 (fgl2) has been identified as a novel effector molecule of cd4(+)cd25(+) foxp3(+) regulatory t (treg) cells that inhibits immune activity by binding to fcγriib expressed primarily on antigen p ...201324146739
differential t cell responses to residual viral antigen prolong cd4+ t cell contraction following the resolution of infection.the contraction phase of the t cell response is a poorly understood period after the resolution of infection when virus-specific effector cells decline in number and memory cells emerge with increased frequencies. cd8(+) t cells plummet in number and quickly reach stable levels of memory following acute lymphocytic choriomeningitis virus infection in mice. in contrast, virus-specific cd4(+) t cells gradually decrease in number and reach homeostatic levels only after many weeks. in this study, we ...201324146043
[microbiological diagnosis of emerging arboviral and rodent borne diseases].vector borne viruses (vbv) include viruses transmitted by arthropods, rodents and other animals. in spain the three main autochthonous vbvs causing human diseases are: toscana, west nile and lymphocytic choriomeningitis viruses. there are also other imported viruses that are potential threats to our public health, due to the presence of competent transmission vectors (dengue and chikungunya viruses in areas infested with aedes albopictus), or due to the potential person-to-person transmission (l ...201524139129
disparate epitopes mediating protective heterologous immunity to unrelated viruses share peptide-mhc structural features recognized by cross-reactive t cells.closely related peptide epitopes can be recognized by the same t cells and contribute to the immune response against pathogens encoding those epitopes, but sometimes cross-reactive epitopes share little homology. the degree of structural homology required for such disparate ligands to be recognized by cross-reactive tcrs remains unclear. in this study, we examined the mechanistic basis for cross-reactive t cell responses between epitopes from unrelated and pathogenic viruses, lymphocytic choriom ...201324127554
differentiation of antigen-specific t cells with limited functional capacity during mycobacterium tuberculosis infection.despite the generation of mycobacterium tuberculosis-specific t cell immune responses during the course of infection, only 5 to 10% of exposed individuals develop active disease, while others develop a latent infection. this phenomenon suggests defective m. tuberculosis-specific immunity, which necessitates more careful characterization of m. tuberculosis-specific t cell responses. here, we longitudinally analyzed the phenotypes and functions of m. tuberculosis-specific t cells. in contrast to t ...201424126533
exogenous ox40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular th cell differentiation and diverts cd4 t cells into the effector lineage by upregulating blimp-1.t cell costimulation is a key component of adaptive immunity to viral infection but has also been associated with pathology because of excessive or altered t cell activity. we recently demonstrated that the tnfr family costimulatory molecule ox40 (cd134) is critically required to sustain antiviral t cell and ab responses that enable control of viral replication in the context of chronic lymphocytic choriomeningitis virus (lcmv) infection. in this study, we investigated whether reinforcing ox40 s ...201324101548
the antiviral activities of isg15.post-translational protein modification is an important strategy for the regulation of the cell proteome independent of the need for new gene expression. ubiquitin and ubiquitin-like modifiers mediate the regulation of protein levels, signaling pathways, vesicular trafficking, and many other cellular processes through their covalent conjugation to proteins. interferon stimulated gene 15 (isg15) is a ubiquitin-like modifier induced by type i interferon. in addition to conjugating to potentially h ...201324095857
pc61 (anti-cd25) treatment inhibits influenza a virus-expanded regulatory t cells and severe lung pathology during a subsequent heterologous lymphocytic choriomeningitis virus infection.prior immunity to influenza a virus (iav) in mice changes the outcome to a subsequent lymphocytic choriomeningitis virus (lcmv) infection and can result in severe lung pathology, similar to that observed in patients that died of the 1918 h1n1 pandemic. this pathology is induced by iav-specific memory cd8(+) t cells cross-reactive with lcmv. here, we discovered that iav-immune mice have enhanced cd4(+) foxp3(+) t-regulatory (treg) cells in their lungs, leading us to question whether a modulation ...201324049180
adenovirus-based vaccine against listeria monocytogenes: extending the concept of invariant chain linkage.the use of replication-deficient adenoviruses as vehicles for transfer of foreign genes offers many advantages in a vaccine setting, eliciting strong cellular immune responses involving both cd8(+) and cd4(+) t cells. further improving the immunogenicity, tethering of the inserted target ag to mhc class ii-associated invariant chain (ii) greatly enhances both the presentation of most target ags, as well as overall protection against viral infection, such as lymphocytic choriomeningitis virus (lc ...201324043891
monocyte-derived dendritic cells perform hemophagocytosis to fine-tune excessive immune responses.because immune responses simultaneously defend and injure the host, the immune system must be finely regulated to ensure the host's survival. here, we have shown that when injected with high toll-like receptor ligand doses or infected with lymphocytic choriomeningitis virus (lcmv) clone 13, which has a high viral turnover, inflammatory monocyte-derived dendritic cells (mo-dcs) engulfed apoptotic erythroid cells. in this process, called hemophagocytosis, phosphatidylserine (ps) served as an "eat- ...201324035363
a cell-intrinsic requirement for nf-κb-inducing kinase in cd4 and cd8 t cell memory.nf-κb-inducing kinase [(nik), map3k14] is an essential kinase linking a subset of tnfr family members to the noncanonical nf-κb pathway. to assess the cell-intrinsic role of nik in murine t cell function, we generated mixed bone marrow chimeras using bone marrow from nik knockout (ko) and wild-type (wt) donor mice and infected the chimeras with lymphocytic choriomeningitis virus (lcmv). the chimeras possess an apparently normal immune system, including a mixture of nik ko and wt t cells, and the ...201324006459
production and biomedical applications of virus-like particles derived from polyomaviruses.virus-like particles (vlps), aggregates of capsid proteins devoid of viral genetic material, show great promise in the fields of vaccine development and gene therapy. these particles spontaneously self-assemble after heterologous expression of viral structural proteins. this review will focus on the use of virus-like particles derived from polyomavirus capsid proteins. since their first recombinant production 27 years ago these particles have been investigated for a myriad of biomedical applicat ...201323999392
cell-intrinsic il-27 and gp130 cytokine receptor signaling regulates virus-specific cd4⁺ t cell responses and viral control during chronic infection.the outcome of chronic viral infections, which affect millions of people worldwide, is greatly dependent on cd4⁺ t cells. here we showed that t cell-specific ablation of the common interleukin-6 (il-6) family receptor, gp130, profoundly compromised virus-specific cd4⁺ t cell survival, t follicular helper responses, and il-21 production at late stages of chronic lymphocytic choriomeningitis virus (lcmv) infection. these effects were cell intrinsic for cd4⁺ t cells and were accompanied by a reduct ...201323993651
interfering with type i interferon: a novel approach to purge persistent viral infection. 201323974094
role of dc-sign in lassa virus entry into human dendritic cells.the arenavirus lassa virus (lasv) causes a severe hemorrhagic fever with high mortality in humans. antigen-presenting cells, in particular dendritic cells (dcs), are early and preferred targets of lasv, and their productive infection contributes to the virus-induced immunosuppression observed in fatal disease. here, we characterized the role of the c-type lectin dc-specific icam-3-grabbing nonintegrin (dc-sign) in lasv entry into primary human dcs using a chimera of the prototypic arenavirus lym ...201323966408
global dna methylation remodeling accompanies cd8 t cell effector function.the differentiation of cd8 t cells in response to acute infection results in the acquisition of hallmark phenotypic effector functions; however, the epigenetic mechanisms that program this differentiation process on a genome-wide scale are largely unknown. in this article, we report the dna methylomes of ag-specific naive and day-8 effector cd8 t cells following acute lymphocytic choriomeningitis virus infection. during effector cd8 t cell differentiation, dna methylation was remodeled such that ...201323956425
the great balancing act: regulation and fate of antiviral t-cell interactions.the fate of t lymphocytes revolves around a continuous stream of interactions between the t-cell receptor (tcr) and peptide-major histocompatibility complex (mhc) molecules. beginning in the thymus and continuing into the periphery, these interactions, refined by accessory molecules, direct the expansion, differentiation, and function of t-cell subsets. the cellular context of t-cell engagement with antigen-presenting cells, either in lymphoid or non-lymphoid tissues, plays an important role in ...201323947351
diverging role for coronin 1 in antiviral cd4+ and cd8+ t cell responses.coronin 1 is a member of the evolutionary conserved wd repeat protein family and is highly expressed in hematopoietic cells. coronin 1 is essential for ca(2+) mobilization upon t cell receptor (tcr) stimulation providing a pro-survival signal for naïve peripheral t cells. both in mouse and in human, coronin 1 deficiency is associated with severe t cell lymphopenia. in this work, we have analyzed antiviral t cell-mediated immunity in the presence and absence of coronin 1 in vivo after infection w ...201323933558
il-4 and il-13 mediated down-regulation of cd8 expression levels can dampen anti-viral cd8⁺ t cell avidity following hiv-1 recombinant pox viral vaccination.we have shown that mucosal hiv-1 recombinant pox viral vaccination can induce high, avidity hiv-specific cd8(+) t cells with reduced interleukin (il)-4 and il-13 expression compared to, systemic vaccine delivery. in the current study how these cytokines act to regulate anti-viral cd8(+) t, cell avidity following hiv-1 recombinant pox viral prime-boost vaccination was investigated. out of a panel of t cell avidity markers tested, only cd8 expression levels were found to be enhanced on, kdgag197-2 ...201323933364
negative regulation of type i ifn expression by oasl1 permits chronic viral infection and cd8⁺ t-cell exhaustion.the type i interferons (ifn-is) are critical not only in early viral control but also in prolonged t-cell immune responses. however, chronic viral infections such as those of human immunodeficiency virus (hiv) and hepatitis c virus (hcv) in humans and lymphocytic choriomeningitis virus (lcmv) in mice overcome this early ifn-i barrier and induce viral persistence and exhaustion of t-cell function. although various t-cell-intrinsic and -extrinsic factors are known to contribute to induction of chr ...201323874199
promotion and prevention of autoimmune disease by cd8+ t cells.until recently, little was known about the importance of cd8+ t effectors in promoting and preventing autoimmune disease development. cd8+ t cells can oppose or promote autoimmune disease through activities as suppressor cells and as cytotoxic effectors. studies in several distinct autoimmune models and data from patient samples are beginning to establish the importance of cd8+ t cells in these diseases and to define the mechanisms by which these cells influence autoimmunity. cd8+ effectors can ...201323871638
rare and emerging viral infections in transplant recipients.emerging viral pathogens include newly discovered viruses as well as previously known viruses that are either increasing, or threatening to increase in incidence. while often first identified in the general population, they may affect transplant recipients, in whom their manifestations may be atypical or more severe. enhanced molecular methods have increased the rate of viral discovery but have not overcome the problem of demonstrating pathogenicity. at the same time, improved clinical diagnosti ...201323839998
signal transducer and activator of transcription 3 (stat3) mutations underlying autosomal dominant hyper-ige syndrome impair human cd8(+) t-cell memory formation and function.the capacity of cd8(+) t cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. il-21 has emerged as a potent inducer of cd8(+) t-cell effector function and memory development in mouse models of infectious disease. however, the role of il-21 and associated signaling pathways in protective cd8(+) t-cell immunity in human subjects is unknown.201323830147
the clinical and immunological significance of gad-specific autoantibody and t-cell responses in type 1 diabetes.antigen-specific interventions are desirable approaches in type 1 diabetes (t1d) as they can alter islet-specific autoimmunity without systemic side effects. glutamic acid decarboxylase of 65 kda (gad65) is a major autoantigen in type 1 diabetes (t1d) and gad-specific autoimmunity is a common feature of t1d in humans but also in mouse models of the disease. in humans, administration of the gad65 protein in an alum formulation has been shown to reduce c-peptide decline in recently diagnosed patie ...201323770292
networking at the level of host immunity: immune cell interactions during persistent viral infections.persistent viral infections are the result of a series of connected events that culminate in diminished immunity and the inability to eliminate infection. by building our understanding of how distinct components of the immune system function both individually and collectively in productive versus abortive responses, new potential therapeutic targets can be developed to overcome immune dysfunction and thus fight persistent infections. using lymphocytic choriomeningitis virus (lcmv) as a model of ...201323768490
nucleoprotein-specific nonneutralizing antibodies speed up lcmv elimination independently of complement and fcγr.cd8(+) t cells have an essential role in controlling lymphocytic choriomeningitis virus (lcmv) infection in mice. here, we examined the contribution of humoral immunity, including nonneutralizing antibodies (abs), in this infection induced by low virus inoculation doses. mice with impaired humoral immunity readily terminated infection with the slowly replicating lcmv strain armstrong but showed delayed virus elimination after inoculation with the faster replicating lcmv strain we and failed to c ...201323749409
non-neutralizing antibodies protect from chronic lcmv infection independently of activating fcγr or complement.chronic viral infections lead to cd8(+) t cell exhaustion, characterized by impaired cytokine secretion. the presence of the immune-regulatory cytokine il-10 promotes chronic lymphocytic choriomeningitis virus (lcmv) clone 13 infection in mice, whereas the absence of il-10/il-10r signaling early during infection results in viral clearance and higher percentages and numbers of antiviral, cytokine-producing t cells. however, it is currently unclear which cell populations and effector molecules are ...201323749374
type i interferon programs innate myeloid dynamics and gene expression in the virally infected nervous system.viral infections of central nervous system (cns) often trigger inflammatory responses that give rise to a wide range of pathological outcomes. the cns is equipped with an elaborate network of innate immune sentinels (e.g. microglia, macrophages, dendritic cells) that routinely serve as first responders to these infections. the mechanisms that underlie the dynamic programming of these cells following cns viral infection remain undefined. to gain insights into this programming, we utilized a combi ...201323737750
inhibition of multiplication of the prototypic arenavirus lcmv by valproic acid.valproic acid (vpa), a short chain fatty acid commonly used for treatment of neurological disorders, has been shown to inhibit production of infectious progeny of different enveloped viruses including the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv). in this study we have investigated the mechanisms by which vpa inhibits lcmv multiplication in cultured cells. vpa reduced production of infectious lcmv progeny and virus propagation without exerting a major blockage on either vir ...201323735299
cell culture and electron microscopy for identifying viruses in diseases of unknown cause.during outbreaks of infectious diseases or in cases of severely ill patients, it is imperative to identify the causative agent. this report describes several events in which virus isolation and identification by electron microscopy were critical to initial recognition of the etiologic agent, which was further analyzed by additional laboratory diagnostic assays. examples include severe acute respiratory syndrome coronavirus, and nipah, lymphocytic choriomeningitis, west nile, cache valley, and he ...023731788
cd4 t cell responses in latent and chronic viral infections.the spectrum of tasks which is fulfilled by cd4 t cells in the setting of viral infections is large, ranging from support of cd8 t cells and humoral immunity to exertion of direct antiviral effector functions. while our knowledge about the differentiation pathways, plasticity, and memory of cd4 t cell responses upon acute infections or immunizations has significantly increased during the past years, much less is still known about cd4 t cell differentiation and their beneficial or pathological fu ...201323717308
thymus-resident memory cd8+ t cells mediate local immunity.the thymus is a primary lymphoid organ responsible for production and selection of t cells. nonetheless, mature t cells and in particular activated t cells can reenter the thymus. here, we identified memory cd8(+) t cells specific for lymphocytic choriomeningitis virus or vaccinia virus in the thymus of mice long-time after the infection. cd8(+) t cells were mainly located in the thymic medulla, but also in the cortical areas. interestingly, virus-specific memory cd8(+) t cells in the thymus exp ...201323715993
differentiation of cd8 memory t cells depends on foxo1.the forkhead o transcription factors (foxo) integrate a range of extracellular signals, including growth factor signaling, inflammation, oxidative stress, and nutrient availability, to substantially alter the program of gene expression and modulate cell survival, cell cycle progression, and many yet to be unraveled cell type-specific responses. naive antigen-specific cd8(+) t cells undergo a rapid expansion and arming of effector function within days of pathogen exposure. in addition, by the pea ...201323712431
enhanced t cell function in a mouse model of human glycosylation.clinical evidence for a more active immune response in humans compared with our closest hominid relative, the chimpanzee, includes the progression of hiv infection to aids, hepatitis b- and c-related inflammation, autoimmunity, and unwanted harmful immune responses to viral gene transfer vectors. humans have a unique mutation of the enzyme cmp-n-acetylneuraminic acid hydroxylase (cmah), causing loss of expression of the sialic acid neu5gc. this mutation, occurring 2 million years ago, likely alt ...201323709682
mavs-mediated host cell defense is inhibited by borna disease virus.viruses often have strategies for preventing host cell apoptosis, which antagonizes viral replication. borna disease virus (bdv) is a neurotropic rna virus that establishes a non-cytolytic persistent infection. although bdv suppresses type i interferon (ifn) through (tank)-binding kinase 1 (tbk-1) associated bdv p protein, it is still unclear how bdv can survive in the host cell and establish a persistent infection. recently, it has been recognized that mitochondria-mediated apoptosis through th ...201323702035
il-21 restricts virus-driven treg cell expansion in chronic lcmv infection.foxp3+ regulatory t (treg) cells are essential for the maintenance of immune homeostasis and tolerance. during viral infections, treg cells can limit the immunopathology resulting from excessive inflammation, yet potentially inhibit effective antiviral t cell responses and promote virus persistence. we report here that the fast-replicating lcmv strain docile triggers a massive expansion of the treg population that directly correlates with the size of the virus inoculum and its tendency to establ ...201323696736
pathogenesis of lassa fever virus infection: i. susceptibility of mice to recombinant lassa gp/lcmv chimeric virus.lassa virus (lasv) is a bsl-4 restricted agent. to allow study of infection by lasv under bsl-2 conditions, we generated a recombinant virus in which the lasv glycoprotein (gp) was placed on the backbone of lymphocytic choriomeningitis virus (lcmv) cl13 nucleoprotein, z and polymerase genes (rlcmv cl13/lasv gp). the recombinant virus displayed high tropism for dendritic cells following in vitro or in vivo infection. inoculation of immunocompetent adults resulted in an acute infection, generation ...201323684417
pd-l1 blockade synergizes with il-2 therapy in reinvigorating exhausted t cells.the inhibitory receptor programmed cell death 1 (pd-1) plays a major role in functional exhaustion of t cells during chronic infections and cancer, and recent clinical data suggest that blockade of the pd-1 pathway is an effective immunotherapy in treating certain cancers. thus, it is important to define combinatorial approaches that increase the efficacy of pd-1 blockade. to address this issue, we examined the effect of il-2 and pd-1 ligand 1 (pd-l1) blockade in the mouse model of chronic lymph ...201323676462
dual role of cxcl10 as conductor of cellular trafficking during type 1 diabetes.one possible way of how autoimmune disease can be initiated is by infection with a foreign pathogen. especially viruses are thought to act as triggering factors, inducing a detrimental attack against 'self' by the immune system of a susceptible host because of two major reasons. first, viruses cause a massive inflammation of the infected tissue and therefore initiate the infiltration of a broad variety of leukocytes, including potentially 'self'-reactive lymphocytes. second, some viruses have be ...200723675028
congenital lymphocytic choriomeningitis virus: when to consider the diagnosis.lymphocytic choriomeningitis virus is a rodent-borne arenavirus that can cause congenital infection affecting the developing central nervous system. when the infection occurs during pregnancy, the virus targets the fetal brain and retina, potentially causing ventriculomegaly, hydrocephalus, chorioretinitis, and neurodevelopmental abnormalities. it has been previously suggested that lymphocytic choriomeningitis virus be added to the list of congenital infections currently included in the torch ac ...201423666045
interleukin-21 is a critical cytokine for the generation of virus-specific long-lived plasma cells.long-lived plasma cells that reside in the bone marrow constitutively produce antibody in the absence of antigen and are the cellular basis of durable humoral immunity. the generation of these long-lived plasma cells depends upon a series of highly orchestrated interactions between antigen-specific cd4 t cells and b cells and the formation of germinal centers (gcs). in this study, we have examined the role of the cytokine interleukin-21 (il-21) in regulating humoral immunity during acute viral i ...201323637417
interferons lambda, new cytokines with antiviral activity.interferons (ifns) are key cytokines in the establishment of a multifaceted antiviral response. three distinct types of ifns are now recognized (type i, type ii, and type iii) based on their receptor usage, structural features and biological activities. although all ifns are important mediators of antiviral protection, their roles in antiviral defence vary. interferon lambda (ifn-λ) is a recently discovered group of small helical cytokines capable of inducing an antiviral response both in vitro ...201323600875
lymphocytic choriomeningitis virus: invisible but not innocent.lymphocytic choriomeningitis virus (lcmv) attracts significant attention both as an important experimental model system to study acute and persistent viral infections, and as a neglected human pathogen of clinical significance. this review focuses on the basic aspects and recent advances in the molecular and cell biology of lcmv, the outcome of lcmv infection on its natural host with an emphasis on persistent infection and the outcome of lcmv infection in humans. lastly, we summarize our contrib ...201323600874
emerging viral infections.this review highlights research and development in the field of emerging viral causes of encephalitis over the past year.201323591683
a myriad of functions and complex regulation of the ccr7/ccl19/ccl21 chemokine axis in the adaptive immune system.the chemokine receptor ccr7 and its ligands ccl19 and ccl21 control a diverse array of migratory events in adaptive immune function. most prominently, ccr7 promotes homing of t cells and dcs to t cell areas of lymphoid tissues where t cell priming occurs. however, ccr7 and its ligands also contribute to a multitude of adaptive immune functions including thymocyte development, secondary lymphoid organogenesis, high affinity antibody responses, regulatory and memory t cell function, and lymphocyte ...201323587803
distinct memory cd4+ t cells with commitment to t follicular helper- and t helper 1-cell lineages are generated after acute viral infection.cd4(+) t follicular helper (tfh) cells provide the required signals to b cells for germinal center reactions that are necessary for long-lived antibody responses. however, it remains unclear whether there are cd4(+) memory t cells committed to the tfh cell lineage after antigen clearance. by using adoptive transfer of antigen-specific memory cd4(+) t cell subpopulations in the lymphocytic choriomeningitis virus infection model, we found that there are distinct memory cd4(+) t cell populations wi ...201323583644
persistent lcmv infection is controlled by blockade of type i interferon signaling.during persistent viral infections, chronic immune activation, negative immune regulator expression, an elevated interferon signature, and lymphoid tissue destruction correlate with disease progression. we demonstrated that blockade of type i interferon (ifn-i) signaling using an ifn-i receptor neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules, and restored lymphoid architecture in mice persistently infected with lymphocytic chor ...201323580529
blockade of chronic type i interferon signaling to control persistent lcmv infection.type i interferons (ifn-i) are critical for antiviral immunity; however, chronic ifn-i signaling is associated with hyperimmune activation and disease progression in persistent infections. we demonstrated in mice that blockade of ifn-i signaling diminished chronic immune activation and immune suppression, restored lymphoid tissue architecture, and increased immune parameters associated with control of virus replication, ultimately facilitating clearance of the persistent infection. the accelerat ...201323580528
cd4(+) t-cell inhibitory ligands: a tool for characterizing dysfunctional cd4(+) t cells during chronic infection.activation of cd4(+) t cells helps to establish and maintain immune responses. during infection with lymphocytic choriomeningitis virus (lcmv) clone 13, the cd4(+) t-cell responses are lost. in this study, we were interested in the nature of the cd4(+) t-cell responses following infection with lcmv clone 13. to pursue this question, we infected c57bl/6 mice with lcmv clone 13. we used a gp66-80 mhc class ii tetramer to determine whether the cd4(+) t cells were present following infection with lc ...201323566283
mcl-1 antagonizes bax/bak to promote effector cd4(+) and cd8(+) t-cell responses.members of the bcl-2 family have critical roles in regulating tissue homeostasis by modulating apoptosis. anti-apoptotic molecules physically interact and restrain pro-apoptotic family members preventing the induction of cell death. however, the specificity of the functional interactions between pro- and anti-apoptotic bcl-2 family members remains unclear. the pro-apoptotic bcl-2 family member bcl-2 interacting mediator of death (bim) has a critical role in promoting the death of activated, effe ...201323558951
epidemiological and phylogenetic analysis of institutional mouse parvoviruses.mouse parvoviruses (mpvs) are small, single-stranded, 5 kb dna viruses that are subclinical and endemic in many laboratory mouse colonies. mpvs cause more distinctive deleterious effects in immune-compromised or genetically-engineered mice than immuno-competent mice. at the university of louisville (u of l), there was an unexpected increase of mpv sero-positivity for mpv infections in mouse colonies between january 2006 and february 2007, resulting in strategic husbandry changes aimed at control ...201323545399
qualitative and quantitative analysis of adenovirus type 5 vector-induced memory cd8 t cells: not as bad as their reputation.it has been reported that adenovirus (ad)-primed cd8 t cells may display a distinct and partially exhausted phenotype. given the practical implications of this claim, we decided to analyze in detail the quality of ad-primed cd8 t cells by directly comparing these cells to cd8 t cells induced through infection with lymphocytic choriomeningitis virus (lcmv). we found that localized immunization with intermediate doses of ad vector induces a moderate number of functional cd8 t cells which qualitati ...201323536658
cooperativity between cd8+ t cells, non-neutralizing antibodies, and alveolar macrophages is important for heterosubtypic influenza virus immunity.seasonal epidemics of influenza virus result in ∼36,000 deaths annually in the united states. current vaccines against influenza virus elicit an antibody response specific for the envelope glycoproteins. however, high mutation rates result in the emergence of new viral serotypes, which elude neutralization by preexisting antibodies. t lymphocytes have been reported to be capable of mediating heterosubtypic protection through recognition of internal, more conserved, influenza virus proteins. here ...201323516357
interferon regulatory factor 7 (irf7) is required for the optimal initial control but not subsequent clearance of lymphocytic choriomeningitis virus infection in mice.the role of irf7 in the host response to lymphocytic choriomeningitis virus (lcmv) armstrong 53b infection of mice was investigated. intracranial infection of irf7 ko mice was associated with delayed onset of lcm, increased survival and significantly reduced expression of the ifng gene in the brain but not in the periphery. irf7 ko mice showed impaired control of lcmv replication and delayed clearance of lcmv. similar numbers of activated anti-lcmv-gp(33-41) cd8+ t cells were present in the brai ...201323490048
il-21 promotes cd8+ ctl activity via the transcription factor t-bet.cd8(+) t cells are fundamental for immune-mediated clearance of viral infections and contribute to immune pathology in autoimmune diseases such as type 1 diabetes. to execute these functions, cd8(+) t cells must differentiate into ctls, a process that is precisely regulated by a variety of cytokines, costimulatory molecules, and transcription factors. il-21 is an il-2 family cytokine and a growth factor for multiple lymphocyte effector lineages, including cytotoxic cd8(+) t cells. recent studies ...201323479229
intrinsic defects in cd8 t cells with aging contribute to impaired primary antiviral responses.aging is associated with altered immune responses, particularly with a diminished cd8 t cell response. although both intrinsic and extrinsic factors are hypothesized to impact this decreased t cell response, the direct evidence of an intrinsic deficiency in virus-specific cd8 t cells is limited. in this study, a tcr transgenic (tg) p14 mouse model was utilized to compare the activation and proliferation of the tg cd8 t cells of young and aged p14 mice upon stimulation with antigen or infection w ...201323473930
lymphocytic choriomeningitis virus infections among american indians. 201323460992
chronic but not acute virus infection induces sustained expansion of myeloid suppressor cell numbers that inhibit viral-specific t cell immunity.resolution of acute and chronic viral infections requires activation of innate cells to initiate and maintain adaptive immune responses. here we report that infection with acute armstrong (arm) or chronic clone 13 (c13) strains of lymphocytic choriomeningitis virus (lcmv) led to two distinct phases of innate immune response. during the first 72 hr of infection, dendritic cells upregulated activation markers and stimulated antiviral cd8(+) t cells, independent of viral strain. seven days after in ...201323438822
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