| decoding arenavirus pathogenesis: essential roles for alpha-dystroglycan-virus interactions and the immune response. | pathogenesis following a virus infection results from interactions between the virus and its host. the outcome is determined by tipping the balance between virulence of the virus or susceptibility/resistance of the host to favor one or the other. this review focuses on two important members of the old world arenavirus family: lassa fever virus (lfv), a robust human pathogen that causes a severe acute hemorrhagic disease; and lymphocytic choriomeningitis virus (lcmv), also a human pathogen but be ... | 2010 | 21185048 |
| high prevalence of low affinity peptide-mhc ii tetramer-negative effectors during polyclonal cd4+ t cell responses. | t cell affinity for antigen initiates adaptive immunity. however, the contribution of low affinity cells to a response is unknown as it has not been possible to assess the entire affinity range of a polyclonal t cell repertoire. in this study, we used a highly sensitive two-dimensional binding assay to identify low affinity cells in polyclonal autoreactive and pathogen-reactive cd4(+) t cell populations specific for myelin oligodendrocyte glycoprotein (mog) and lymphocytic choriomeningitis virus ... | 2011 | 21220453 |
| conserved residues in lassa fever virus z protein modulate viral infectivity at the level of the ribonucleoprotein. | arenaviruses are negative-strand rna viruses that cause human diseases such as lymphocytic choriomeningitis, bolivian hemorrhagic fever, and lassa hemorrhagic fever. no licensed vaccines exist, and current treatment is limited to ribavirin. the prototypic arenavirus, lymphocytic choriomeningitis virus (lcmv), is a model for dissecting virus-host interactions in persistent and acute disease. the ring finger protein z has been identified as the driving force of arenaviral budding and acts as the v ... | 2011 | 21228230 |
| antiviral memory cd8 t-cell differentiation, maintenance, and secondary expansion occur independently of myd88. | inflammatory signals induced during infection regulate t-cell expansion, differentiation, and memory formation. toll-like receptors (tlrs) are inflammatory mediators that allow innate immune cells to recognize and respond to invading pathogens. in addition to their role in innate immune cells, we have found that signals delivered through the tlr adapter protein myeloid differentiation protein 88 (myd88) play a critical, t cell-intrinsic role in supporting the survival and accumulation of antigen ... | 2011 | 21233312 |
| anti-thymoglobulin (atg) treatment does not reverse type 1 diabetes in the acute virally induced rat insulin promoter-lymphocytic choriomeningitis virus (rip-lcmv) model. | immune modulators such as anti-thymoglobulin (atg) are under clinical evaluation for the treatment of type 1 diabetes (t1d). although such agents have cured t1d in the non-obese diabetic (nod) model, their clinical efficacy has been much lower. in order to improve the odds of successful translation from bench to bedside, we propose to evaluate this agent under more stringent conditions. here, we evaluated the capacity of atg to reverse t1d in the acute rat insulin promoter-lymphocytic choriomeni ... | 2011 | 21235534 |
| a highly optimized dna vaccine confers complete protective immunity against high-dose lethal lymphocytic choriomeningitis virus challenge. | protection against infection is the hallmark of immunity and the basis of effective vaccination. for a variety of reasons there is a great demand to develop new, safer and more effective vaccine platforms. in this regard, while 'first-generation' dna vaccines were poorly immunogenic, new genetic 'optimization' strategies and the application of in vivo electroporation (ep) have dramatically boosted their potency. we developed a highly optimized plasmid dna vaccine that expresses the lymphocytic c ... | 2011 | 21238574 |
| increased memory conversion of naïve cd8 t cells activated during late phases of acute virus infection due to decreased cumulative antigen exposure. | memory cd8 t cells form an essential part of protective immunity against viral infections. antigenic load, costimulation, cd4-help, cytokines and chemokines fluctuate during the course of an antiviral immune response thus affecting cd8 t cell activation and memory conversion. | 2011 | 21253594 |
| point mutation in the glycoprotein of lymphocytic choriomeningitis virus is necessary for receptor binding, dendritic cell infection, and long-term persistence. | arenaviruses are a major cause of hemorrhagic fevers endemic to sub-saharan africa and south america, and thus a major public health and medical concern. the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) is widely used as a model system for studying persistent and acute infections, as well as for gaining an understanding of mammalian immune function. when originally characterized three decades ago, the lcmv isolate, armstrong, which causes an acute infection in adult mice, was ... | 2011 | 21270335 |
| memory cd4 t cells that express cxcr5 provide accelerated help to b cells. | cd4 t cell help for b cells is critical for effective ab responses. although many of the molecules involved in helper functions of naive cd4 t cells have been characterized, much less is known about the helper capabilities of memory cd4 t cells, an important consideration for the design of vaccines that aim to prime protective memory cd4 t cells. in this study, we demonstrate that memory cd4 t cells enable b cells to expand more rapidly and class switch earlier than do primary responding cd4 t c ... | 2011 | 21270407 |
| cutting edge: persistently open chromatin at effector gene loci in resting memory cd8+ t cells independent of transcriptional status. | memory cd8(+) t cells are characterized by more rapid and robust effector function upon infection compared with naive t cells, but factors governing effector gene responsiveness are incompletely understood. we sought to understand transcriptional control of the effector genes ifn-? (ifng), granzyme b (gzmb), and perforin 1 (prf1) in murine memory cd8(+) t cells by characterizing their transcriptional profiles and chromatin states during lymphocytic choriomeningitis virus infection. each effector ... | 2011 | 21278341 |
| killing of targets by cd8 t cells in the mouse spleen follows the law of mass action. | it has been difficult to correlate the quality of cd8 t cell responses with protection against viral infections. to investigate the relationship between efficacy and magnitude of t cell responses, we quantify the rate at which individual cd8 effector and memory t cells kill target cells in the mouse spleen. using mathematical modeling, we analyze recent data on the loss of target cells pulsed with three different peptides from the mouse lymphocytic choriomeningitis virus (lcmv) in mouse spleens ... | 2011 | 21283669 |
| il-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. | understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for hiv infection. mice infected with lcmv clone-13 have persistent high-level viremia and a dysfunctional immune response. interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. mechanistically, il-7 downregulate ... | 2011 | 21295337 |
| mouse granzyme k has pro-inflammatory potential. | granzymes (gzms) are key components of t-killer (tc) cells believed to mediate pro-apoptotic activities. recent evidence suggests that gzms also possess non-cytotoxic activities that contribute to host defense. in this study, we show that tc cells from lymphocytic choriomeningitis virus (lcmv)-infected wild-type (wt) and gzm a/b-deficient mice express similar levels of gzmk protein, with both mouse strains efficiently controlling infection. gzmk, in recombinant form or secreted by ex vivo-derive ... | 2011 | 21311565 |
| regulatory t-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. | regulatory t cells (treg) play critical roles in the modulation of immune responses to infectious agents. further understanding of the factors that control treg activation and expansion in response to pathogens is needed to manipulate treg function in acute and chronic infections. here we show that chronic, but not acute, infection of mice with lymphocytic choriomeningitis virus results in a marked expansion of foxp3(+) treg that is dependent on retroviral superantigen (sag) genes encoded in the ... | 2011 | 21321220 |
| arenavirus reverse genetics: new approaches for the investigation of arenavirus biology and development of antiviral strategies. | several arenaviruses, chiefly lassa virus, cause hemorrhagic fever disease in humans and pose a significant public health problem 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 development of novel antiviral strategies to combat pathogenic arenaviruses would be facilitated by a detailed understanding of the arenavirus molecular and cell biology. to this end, the developm ... | 2011 | 21324503 |
| vaccination against lymphocytic choriomeningitis virus infection in mhc class ii-deficient mice. | the impact of prophylactic vaccination against acute and chronic infection in a th-deficient host has not been adequately addressed because of difficulties in generating protective immunity in the absence of cd4(+) t cell help. in this study, we demonstrated that a broad cd8(+) t cell immune response could be elicited in mhc class ii-deficient mice by vaccination with adenovirus encoding lymphocytic choriomeningitis virus (lcmv) glycoprotein tethered to mhc class ii-associated invariant chain. m ... | 2011 | 21357263 |
| phenotype, function, and gene expression profiles of programmed death-1(hi) cd8 t cells in healthy human adults. | t cell dysfunction is an important feature of many chronic viral infections. in particular, it was shown that programmed death-1 (pd-1) regulates t cell dysfunction during chronic lymphocytic choriomeningitis virus infection in mice, and pd-1(hi) cells exhibit an intense exhausted gene signature. these findings were extended to human chronic infections such as hiv, hepatitis c virus, and hepatitis b virus. however, it is not known if pd-1(hi) cells of healthy humans have the traits of exhausted ... | 2011 | 21383243 |
| hypomorphic mutation in the site-1 protease mbtps1 endows resistance to persistent viral infection in a cell-specific manner. | the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv), which naturally persists in rodents, represents a model for hiv, hbv, and hcv. cleavage of the viral glycoprotein precursor by membrane-bound transcription factor peptidase, site 1 (mbtps1 or site-1 protease), is crucial for the life cycle of arenaviruses and therefore represents a potential target for therapy. recently, we reported a viable hypomorphic allele of mbtps1 (woodrat) encoding a protease with diminished enzymatic ac ... | 2011 | 21402360 |
| il-21 and il-6 are critical for different aspects of b cell immunity and redundantly induce optimal follicular helper cd4 t cell (tfh) differentiation. | cytokines are important modulators of lymphocytes, and both interleukin-21 (il-21) and il-6 have proposed roles in t follicular helper (tfh) differentiation, and directly act on b cells. here we investigated the absence of il-6 alone, il-21 alone, or the combined lack of il-6 and il-21 on tfh differentiation and the development of b cell immunity in vivo. c57bl/6 or il-21(-/-) mice were treated with a neutralizing monoclonal antibody against il-6 throughout the course of an acute viral infection ... | 2011 | 21423809 |
| immunotherapeutic effects of il-7 during a chronic viral infection in mice. | viral persistence during chronic viral infections is associated with a progressive loss of t-cell effector function called functional exhaustion. there is therefore a need to develop immunotherapies to remediate the functional deficits of t cells during these infections. we investigated the immunotherapeutic effects of il-7 during chronic lymphocytic choriomeningitis virus infection in mice. our results showed that the effects of il-7 on t cells depend on the viral load, timing, and duration of ... | 2011 | 21436066 |
| comparison of cytotoxic t lymphocyte efficacy in acute and persistent lymphocytic choriomeningitis virus infection. | immune responses mediated by cytotoxic t lymphocytes (ctls) have often been found to be functionally impaired in persistent infections. it is assumed that this impairment contributes to persistence of the infection. in this study, we compare the killing efficacy of cd8(+) t-cell responses in mice acutely and persistently infected with the lymphocytic choriomeningitis virus, using an in vivo ctl killing assay. to infer the killing efficacy of ctls, we developed a new mathematical model describing ... | 2011 | 21450739 |
| pseudotyping vesicular stomatitis virus with lymphocytic choriomeningitis virus glycoproteins enhances infectivity for glioma cells and minimizes neurotropism. | vesicular stomatitis virus (vsv)-based oncolytic virotherapy has the potential to significantly improve the prognosis of aggressive malignancies such as brain cancer. however, vsv's inherent neurotoxicity has hindered clinical development so far. given that this neurotropism is attributed to the glycoprotein vsv-g, vsv was pseudotyped with the nonneurotropic envelope glycoprotein of the lymphocytic choriomeningitis virus (lcmv-gp?vsv-gp). compared to vsv, vsv-gp showed enhanced infectivity for b ... | 2011 | 21450833 |
| cross-dressed dendritic cells drive memory cd8+ t-cell activation after viral infection. | after an infection, cytotoxic t lymphocyte precursors proliferate and become effector cells by recognizing foreign peptides in the groove of major histocompatibility complex (mhc) class i molecules expressed by antigen-presenting cells (apcs). professional apcs specialized for t-cell activation acquire viral antigen either by becoming infected themselves (direct presentation) or by phagocytosis of infected cells, followed by transfer of antigen to the cytosol, processing and mhc class i loading ... | 2011 | 21455179 |
| migration of cytotoxic lymphocytes in cell cycle permits local mhc i-dependent control of division at sites of viral infection. | after virus infection, cytotoxic t lymphocytes (ctls) divide rapidly to eradicate the pathogen and prevent the establishment of persistence. the magnitude of an antiviral ctl response is thought to be controlled by the initiation of a cell cycle program within lymphoid tissues. however, it is presently not known whether this division program proceeds during migration or is influenced locally at sites of viral infection. we demonstrate that antiviral ctls remain in cell cycle while transiting to ... | 2011 | 21464219 |
| suppression of t-cell expansion by melanoma is exerted on resting cells. | background: immunotherapeutic cancer protocols often rely on the ability to promote proliferative expansion of tumor-specific t-cell, but the influence of cancer on in vivo t-cell expansion remains largely undefined. methods: the ability of control and b16f10 melanoma-bearing c57bl/6 mice to expand lymphocytic choriomeningitis virus antigen-specific t-cell populations in response to acute viral infection was compared by using flow cytometric assays of splenocytes. results: the ability to expand ... | 2011 | 21465311 |
| tlr2 signaling improves immunoregulation to prevent type 1 diabetes. | signaling through tlr2 promotes inflammation and modulates cd4(+) cd25(+) tregs. we assessed mechanistically how this molecule would alter immunoregulation in type 1 diabetes (t1d). we also asked whether tlr2 may be involved in our recent discovery that viral infection can protect from autoimmune diabetes by expanding and invigorating tregs. treatment of prediabetic mice with a synthetic tlr2 agonist diminished t1d and increased the number and function of cd4(+) cd25(+) tregs, also conferring dc ... | 2011 | 21469083 |
| il4i1: an inhibitor of the cd8(+) antitumor t-cell response in vivo. | the l-phenylalanine oxidase il4i1 inhibits t-cell proliferation in vitro through h(2) o(2) production, and is highly expressed in tumor-associated macrophages. il4i1 is also detected by immunohistochemistry in neoplastic cells from several b-cell lymphomas and some non-lymphoid tumors. to evaluate il4i1's effect on tumor growth, we developed a mouse melanoma model constitutively coexpressing il4i1 and the gp33 epitope. after gp33 vaccination, tumors developed more frequently in mice injected wit ... | 2011 | 21469114 |
| virus-induced transient immune suppression and the inhibition of t cell proliferation by type i interferon. | vaccine-induced memory is necessary for protective immunity to pathogens, but many viruses induce a state of transient immune suppression that might contribute to the inability of a vaccine to elicit immunity. we evaluated here the fate of bystander t cells activated by third party cognate antigens during acute viral infections in vivo, using distinct models to track and specifically activate hy and p14 transgenic bystander cd8 t cells in vivo during acute arenavirus infections of mice. viral in ... | 2011 | 21471240 |
| altering α-dystroglycan receptor affinity of lcmv pseudotyped lentivirus yields unique cell and tissue tropism. | abstract: | 2011 | 21477292 |
| immunological perspective of self versus tumor antigens: insights from the rip-gp model. | self-reactive t cells in the body are controlled by mechanisms of peripheral tolerance that limit their activation and induction of immune pathology. our understanding of these mechanisms has been advanced by the use of tissue-specific promoters to express neo-self-antigens. here, we present findings using the rip-gp (rat insulin promoter-glycoprotein) transgenic mouse, which expresses the lymphocytic choriomeningitis virus glycoprotein (lcmv-gp) specifically in the pancreatic β islet cells. t c ... | 2011 | 21488897 |
| viral infections in workers in hospital and research laboratory settings: a comparative review of infection modes and respective biosafety aspects. | to compare modes and sources of infection and clinical and biosafety aspects of accidental viral infections in hospital workers and research laboratory staff reported in scientific articles. | 2011 | 21497126 |
| opposing effects of cd70 costimulation during acute and chronic viral infection. | t cell costimulation is important for t cell activation. the cd27/cd70 pathway contributes to effector and memory t cell development, and is involved in t cell and b cell activation. cd27/cd70 is known for having opposing roles during different models of antigenic challenges. during primary t cell responses to influenza infection or during tumor challenges, cd27/cd70 costimulation has a positive role on t cell responses. however, during some chronic infections, constitutive triggering of this si ... | 2011 | 21507976 |
| pnas plus: expression of chemokine receptor cxcr3 on t cells affects the balance between effector and memory cd8 t-cell generation. | generation of a robust immunological memory response is essential for protection on subsequent encounters with the same pathogen. the magnitude and quality of the memory cd8 t-cell population are shaped and influenced by the strength and duration of the initial antigenic stimulus as well as by inflammatory cytokines. although chemokine receptors have been established to play a role in recruitment of effector cd8 t cells to sites of inflammation, their contribution to determination of t-cell fate ... | 2011 | 21518913 |
| programmed death 1 regulates development of central memory cd8 t cells after acute viral infection. | the t cell response possesses a number of inhibitory receptors to regulate the extent of the antiviral response and prevent immune pathology. these receptors are generally transiently upregulated during an effector response and then downregulated during memory. some inhibitory receptors, such as programmed death 1 (pd-1) and lag-3, were shown to be aberrantly upregulated during memory to chronic lymphocytic choriomeningitis virus infection, limiting functional capabilities. however, little is kn ... | 2011 | 21525385 |
| viral persistence redirects cd4 t cell differentiation toward t follicular helper cells. | cd4 t cell responses are crucial to prevent and control viral infection; however, virus-specific cd4 t cell activity is considered to be rapidly lost during many persistent viral infections. this is largely caused by the fact that during viral persistence cd4 t cells do not produce the classical th1 cytokines associated with control of acute viral infections. considering that cd4 t cell help is critical for both cd8 t cell and b cell functions, it is unclear how cd4 t cells can lose responsivene ... | 2011 | 21536743 |
| protective capacity of memory cd8(+) t cells is dictated by antigen exposure history and nature of the infection. | infection or vaccination confers heightened resistance to pathogen rechallenge because of quantitative and qualitative differences between naive and primary memory t cells. herein, we show that secondary (boosted) memory cd8(+) t cells were better than primary memory cd8(+) t cells in controlling some, but not all acute infections with diverse pathogens. however, secondary memory cd8(+) t cells were less efficient than an equal number of primary memory cells at preventing chronic lcmv infection ... | 2011 | 21549619 |
| t cell responses in experimental viral retinitis: mechanisms, peculiarities and implications for gene therapy with viral vectors. | t lymphocytes play a decisive role in the course and clinical outcome of viral retinal infection. this review focuses on aspects of the adaptive cellular immune response against viral pathogens in the retina. two distinct models to study adaptive cell mediated immune responses in viral retinitis are presented: (i) experimental retinitis induced by murine cytomegalovirus (mcmv), where the immune system prevents necrotizing damage to the retina and (ii) retinitis induced by the non-cytopathic lymp ... | 2011 | 21550416 |
| disruption of myd88 signaling suppresses hemophagocytic lymphohistiocytosis in mice. | hemophagocytic lymphohistiocytosis (hlh) is a rare inflammatory disorder with a poor prognosis for affected individuals. to find a means of suppressing the clinical phenotype, we investigated the cellular and molecular mechanisms leading to hlh in unc13d(jinx/jinx) mice, in which cytolytic function of natural killer (nk) and cd8(+) t cells is impaired. unc13d(jinx/jinx) mutants infected with lymphochoriomeningitis virus (lcmv) present typical clinical features of hlh, including splenomegaly, ele ... | 2011 | 21551232 |
| ribavirin can be mutagenic for arenaviruses. | arenaviruses include several important human pathogens for which there are only very limited options of preventive or therapeutic interventions to combat them. an off-labeled use of the purine nucleoside analogue ribavirin (1-β-d-ribofuranosyl-1-h-1,2,4-triazole-3-carboxamide) is the only antiviral treatment currently available for arenavirus infections. however, the ribavirin antiviral mechanism action against arenaviruses remains unknown. here we document that ribavirin is mutagenic for the pr ... | 2011 | 21561907 |
| perforin is a critical physiologic regulator of t-cell activation. | individuals with impaired perforin-dependent cytotoxic function (ctx-) develop a fatal inflammatory disorder called hemophagocytic lymphohistiocytosis (hlh). it has been hypothesized that immune hyperactivation during hlh is caused by heightened infection, defective apoptosis/ responsiveness of ctx- lymphocytes, or enhanced antigen presentation. while clinical and experimental data suggest that increased t cell activation drives hlh, potential abnormalities of t cell activation have not been wel ... | 2011 | 21606480 |
| characterization of the metabolic phenotype of rapamycin-treated cd8 t cells with augmented ability to generate long-lasting memory cells. | cellular metabolism plays a critical role in regulating t cell responses and the development of memory t cells with long-term protections. however, the metabolic phenotype of antigen-activated t cells that are responsible for the generation of long-lived memory cells has not been characterized. | 2011 | 21611151 |
| expanded potential for recombinant tri-segmented lcm viruses: protein production, antibody production and in vivo assessment of biological function of genes of interest. | the recombinant engineering of tri-segmented lcmv to express two genes of interest was recently reported. we used this technology to efficiently express gfp and the immunoregulatory gene il-10 in vitro, assess il-10 function in vivo during viral meningitis and generate specific, robust monoclonal antibody responses to il-10. tripartite viruses were attenuated in wildtype and tlr7-/- mice. however, ifnar1-/- mice sustained systemic viral replication when 2 nucleotide substitutions from a persiste ... | 2011 | 21613399 |
| transcription factor t-bet represses expression of the inhibitory receptor pd-1 and sustains virus-specific cd8(+) t cell responses during chronic infection. | t cell exhaustion has a major role in failure to control chronic infection. high expression of inhibitory receptors, including pd-1, and the inability to sustain functional t cell responses contribute to exhaustion. however, the transcriptional control of these processes remains unclear. here we demonstrate that the transcription factor t-bet regulated the exhaustion of cd8(+) t cells and the expression of inhibitory receptors. t-bet directly repressed transcription of the gene encoding pd-1 and ... | 2011 | 21623380 |
| aberrant cd8(+) t-cell responses and memory differentiation upon viral infection of an ataxia-telangiectasia mouse model driven by hyper-activated akt and mtorc1 signaling. | immune system-related pathology is common in ataxia-telangiectasia (a-t) patients and mice that lack the protein kinase, a-t mutated (atm). however, it has not been studied how atm influences immune responses to a viral infection. using the lymphocytic choriomeningitis virus (lcmv) infection model, we show that atm(-/-) mice, despite having fewer naïve cd8(+) t cells, effectively clear the virus. however, aberrant cd8(+) t-cell responses are observed, including defective expansion and contractio ... | 2011 | 21641396 |
| small molecule cxcr3 antagonist nibr2130 has only a limited impact on type 1 diabetes in a virus-induced mouse model. | cxcl10 is one of the key chemokines involved in trafficking of autoaggressive t cells to the islets of langerhans during the autoimmune destruction of beta cells in type 1 diabetes (t1d). blockade of cxcl10 or genetic deletion of its receptor cxcr3 results in a reduction of t1d in animal models. as an alternative to the use of neutralizing monoclonal antibodies to cxcl10 or cxcr3 we evaluated the small molecule cxcr3 antagonist nibr2130 in a virus-induced mouse model for t1d. we found that the o ... | 2011 | 21649647 |
| retinoic acid as a vaccine adjuvant enhances cd8+ t cell response and mucosal protection from viral challenge. | vaccine-induced memory t cells localized at mucosal sites can provide rapid protection from viral infection. all-trans-retinoic acid (atra) has been shown to act physiologically to induce the expression of gut-homing receptors on lymphocytes. we tested whether the administration of exogenous atra during a systemic vaccination of mice could enhance the generation of mucosal cd8(+) t cell immunity, which might represent a strategy for establishing better protection from viral infection via mucosal ... | 2011 | 21653670 |
| a role for the chemokine rantes in regulating cd8 t cell responses during chronic viral infection. | rantes (ccl5) is a chemokine expressed by many hematopoietic and non-hematopoietic cell types that plays an important role in homing and migration of effector and memory t cells during acute infections. the rantes receptor, ccr5, is a major target of anti-hiv drugs based on blocking viral entry. however, defects in rantes or rantes receptors including ccr5 can compromise immunity to acute infections in animal models and lead to more severe disease in humans infected with west nile virus (wnv). i ... | 2011 | 21814510 |
| novel arenavirus infection in humans, united states. | immunoglobulin g against whitewater arroyo virus or lymphocytic choriomeningitis virus was found in 41 (3.5%) of 1,185 persons in the united states who had acute central nervous system disease or undifferentiated febrile illnesses. the results of analyses of antibody titers in paired serum samples suggest that a north american tacaribe serocomplex virus was the causative agent of the illnesses in 2 persons and that lymphocytic choriomeningitis virus was the causative agent of the illnesses in 3 ... | 2011 | 21801618 |
| analytical validation of a lymphocytic choriomeningitis virus real-time rt-pcr assay. | lymphocytic choriomeningitis virus (lcmv) is a rare cause of central nervous system disease in humans. screening by real-time rt-pcr assay is of interest in the case of aseptic meningitis of unknown etiology. a specific lcmv real-time rt-pcr assay, based on the detection of genomic sequences of the viral nucleoprotein (np), was developed to assess the presence of lcmv in cerebrospinal fluids (csf) sent for viral screening to a swiss university hospital laboratory. a 10-fold dilution series assay ... | 2011 | 21763351 |
| exposure to lymphocytic choriomeningitis virus, new york, usa. | to the editor: lymphocytic choriomeningitis virus (lcmv) is an arenavirus carried by the house mouse, mus musculus. human infections can range from mild febrile illness to severe encephalitis and disseminated disease (1). infection during pregnancy is associated with teratogenic effects, including congenital hydrocephalus and chorioretinitis (2). | 2011 | 21762607 |
| signal 3 requirement for memory cd8(+) t-cell activation is determined by the infectious pathogen. | the relevance of direct inflammatory signals (signal 3) for the activation of memory cd8(+) t cells during recall responses is so far unknown. we therefore investigated the direct impact of il-12 and type i ifn on the formation, recall potential and protective capacity of memory t cells. using cd8(+) t cells deficient for il-12 or type i ifn receptors in an adoptive transfer system, we generated memory populations after infection with vaccinia virus, lymphocytic choriomeningitis virus or listeri ... | 2011 | 21830209 |
| the tetramer transformation. | | 2011 | 21690330 |
| development of autoimmune diabetes in the absence of detectable il-17a in a cd8-driven virally induced model. | recent studies have shown that il-17 can contribute beneficially to pathogen defense but also that excessive il-17 levels are associated with chronic inflammation and autoimmune disorders. to date, the role of il-17 in viral infections and type 1 diabetes is ambiguous. in this study, we used il-17a enhanced green fluorescent protein bicistronic reporter mouse strains to analyze in situ production of il-17a. upon klebsiella pneumoniae bacterial infection, cd4(+) and +¦+¦ t cells produce il-17a. i ... | 2011 | 21832162 |
| lymphocytic choriomeningitis virus (lcmv) infection of macaques: a model for lassa fever. | arenaviruses such as lassa fever virus (lasv) and lymphocytic choriomeningitis virus (lcmv) are benign in their natural reservoir hosts, and can occasionally cause severe viral hemorrhagic fever (vhf) in non-human primates and in human beings. lcmv is considerably more benign for human beings than lassa virus, however certain strains, like the lcmv-we strain, can cause severe disease when the virus is delivered as a high-dose inoculum. here we describe a rhesus macaque model for lassa fever that ... | 2011 | 21820469 |
| rapamycin does not control hemophagocytic lymphohistiocytosis in lcmv-infected perforin-deficient mice. | hemophagocytic lymphohistiocytosis (hlh) is an immunodysregulatory disorder for which more effective treatments are needed. the macrolide rapamycin has immunosuppressive properties, making it an attractive candidate for controlling the aberrant t cell activation that occurs in hlh. to investigate its therapeutic potential, we used rapamycin to treat lymphocytic choriomeningitis virus (lcmv)-infected perforin-deficient (prf1(-/-) ) mice according to a well-established model of hlh. at the regimen ... | 2011 | 21681935 |
| type 1 interferon induction of natural killer cell gamma interferon production for defense during lymphocytic choriomeningitis virus infection. | abstract natural killer (nk) cells are equipped to innately produce the cytokine gamma interferon (ifn-+¦) in part because they basally express high levels of the signal transducer and activator of transcription 4 (stat4). type 1 interferons (ifns) have the potential to activate stat4 and promote ifn-+¦ expression, but concurrent induction of elevated stat1 negatively regulates access to the pathway. as a consequence, it has been difficult to detect type 1 ifn stimulation of nk cell ifn-+¦ durin ... | 2011 | 21828218 |
| melanoma-induced suppression of tumor antigen-specific t cell expansion is comparable to suppression of global t cell expansion. | we have observed that in vivo interaction between melanoma and resting t cells promotes suppression of antigen-driven proliferative t cell expansion. we hypothesized that this suppression would affect tumor antigen-specific t cell populations more potently than tumor-unrelated t cell populations. a b16f10 cell line was stably transfected to express low levels of the lymphocytic choriomeningitis virus (lcmv) glycoprotein gp33 (b16gp33). mice bearing b16f10 or b16gp33 tumors were infected with lcm ... | 2011 | 21741629 |
| defects in apoptosis increase memory cd8(+) t cells following infection of bim(-/-)fas(lpr/lpr) mice. | during many infections, large numbers of effector cd8(+) t cells are generated. after pathogen clearance, the majority of these cells undergo apoptosis, while the survivors differentiate into memory cd8(+) t cells. although loss of both bim and fas function dramatically increased antigen-specific cd8(+) t cells in the lymph nodes following acute lymphocytic choriomeningitis virus (lcmv) infection, it was unclear whether they were pardoned effector or true memory cd8(+) t cells. in this study, we ... | 2011 | 21839428 |
| development of peptide-conjugated morpholino oligomers as pan-arenavirus inhibitors. | members of the arenaviridae are a threat to public health and can cause meningitis and hemorrhagic fever, yet treatment options remain limited by a lack of effective antivirals. in this study, we found that peptide-conjugated phosphorodiamidate morpholino oligomers (ppmo) complementary to viral genomic rna were effective in reducing arenavirus replication in cell cultures and in vivo. ppmo complementary to the jun+¡n virus genome were designed to interfere with viral rna synthesis, translation, ... | 2011 | 21825302 |
| 4-1bb signaling synergizes with programmed death ligand 1 blockade to augment cd8 t cell responses during chronic viral infection. | previous studies have identified the inhibitory role that the programmed death 1 (pd-1) pathway plays during chronic infection. blockade of this pathway results in rescue of viral-specific cd8 t cells, as well as reduction of viral loads in mice chronically infected with lymphocytic choriomeningitis virus (lcmv). we tested the effect of combining pd ligand 1 (pd-l1) blockade with an agonistic regimen that induces 4-1bb costimulation during chronic lcmv infection. there is a boosting effect in th ... | 2011 | 21742975 |
| anterograde or retrograde transsynaptic labeling of cns neurons with vesicular stomatitis virus vectors. | to understand how the nervous system processes information, a map of the connections among neurons would be of great benefit. here we describe the use of vesicular stomatitis virus (vsv) for tracing neuronal connections in vivo. we made vsv vectors that used glycoprotein (g) genes from several other viruses. the g protein from lymphocytic choriomeningitis virus endowed vsv with the ability to spread transsynaptically, specifically in an anterograde direction, whereas the rabies virus glycoprotei ... | 2011 | 21825165 |
| induction of insert-specific immune response in mice by hamster polyomavirus vp1 derived virus-like particles carrying lcmv gp33 ctl epitope. | hamster polyomavirus (hapyv) major capsid protein vp1 based chimeric virus-like particles (vlps) carrying model gp33 ctl epitope derived from lymphocytic choriomeningitis virus (lcmv) were generated in yeast and examined for their capability to induce ctl response in mice. chimeric vp1-gp33 vlps were effectively processed in antigen presenting cells in vitro and in vivo and induced antigen-specific cd8+ t cell proliferation. mice immunized only once with vp1-gp33 vlps without adjuvant developed ... | 2011 | 21864590 |
| vaccinating donors to improve gvl. | | 2011 | 22123908 |
| E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands. | The salivary glands are important effector sites for IgA-mediated humoral immunity to protect oral surfaces. Within murine submandibular glands (SMG), we identified a memory CD8 T-cell population that exhibited a unique cell-surface phenotype distinct from memory CD8 T cells in spleen but similar to memory T cells resident in the intraepithelial lymphocyte compartment of the intestinal mucosa. In mice immune to lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus(VSV), virus-s ... | 2011 | 21930933 |
| memory phenotype cd4 t cells undergoing rapid, nonburst-like, cytokine-driven proliferation can be distinguished from antigen-experienced memory cells. | memory phenotype (cd44(bright), cd25(negative)) cd4 spleen and lymph node t cells (mp cells) proliferate rapidly in normal or germ-free donors, with brdu uptake rates of 6% to 10% per day and ki-67 positivity of 18% to 35%. the rapid proliferation of mp cells stands in contrast to the much slower proliferation of lymphocytic choriomeningitis virus (lcmv)-specific memory cells that divide at rates ranging from <1% to 2% per day over the period from 15 to 60 days after lcmv infection. anti-mhc cla ... | 2011 | 22022231 |
| rare, unusual, and less common virus infections after organ transplantation. | the present article reviews the epidemiology, clinical presentation, prevention, and management of rare, unusual, and less common viruses that infect transplant recipients. | 2011 | 22001713 |
| tight regulation of memory cd8(+) t cells limits their effectiveness during sustained high viral load. | to design successful vaccines for chronic diseases, an understanding of memory cd8(+) t cell responses to persistent antigen restimulation is critical. however, most studies comparing memory and naive cell responses have been performed only in rapidly cleared acute infections. herein, by comparing the responses of memory and naive cd8(+) t cells to acute and chronic lymphocytic choriomeningitis virus infection, we show that memory cells dominated over naive cells and were protective when present ... | 2011 | 21856186 |
| efnb1 and efnb2 proteins regulate thymocyte development, peripheral t cell differentiation, and antiviral immune responses and are essential for interleukin-6 (il-6) signaling. | erythropoietin-producing hepatocellular kinases (eph kinases) constitute the largest family of cell membrane receptor tyrosine kinases, and their ligand ephrins are also cell surface molecules. because of promiscuous interaction between ephs and ephrins, there is considerable redundancy in this system, reflecting the essential roles of these molecules in the biological system through evolution. in this study, both efnb1 and efnb2 were null-mutated in the t cell compartment of mice through loxp-m ... | 2011 | 21976681 |
| Memory T cells from minor histocompatibility antigen-vaccinated and virus-immune donors improve GVL and immune reconstitution. | Donor T cells contribute to the success of allogeneic hematopoietic stem cell transplantation (alloSCT). Alloreactive donor T cells attack leukemia cells, mediating the GVL effect. Donor T cells, including the memory T cells (T(M)) that are generated after infection, also promote immune reconstitution. Nonetheless, leukemia relapse and infection are major sources of treatment failure. Efforts to augment GVL and immune reconstitution have been limited by GVHD, the attack by donor T cells on host ... | 2011 | 21917752 |
| characterization of dsrna-induced pancreatitis model reveals the regulatory role of ifn regulatory factor 2 (irf2) in trypsinogen5 gene transcription. | mice deficient for interferon regulatory factor (irf)2 (irf2(-/-) mice) exhibit immunological abnormalities and cannot survive lymphocytic choriomeningitis virus infection. the pancreas of these animals is highly inflamed, a phenotype replicated by treatment with poly(i:c), a synthetic double-stranded rna. trypsinogen5 mrna was constitutively up-regulated about 1,000-fold in irf2(-/-) mice compared with controls as assessed by quantitative rt-pcr. further knockout of ifnα/β receptor 1(ifnar1) ab ... | 2011 | 22042864 |
| Natural killer cells act as rheostats modulating antiviral T cells. | Antiviral T cells are thought to regulate whether hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections result in viral control, asymptomatic persistence or severe disease, although the reasons for these different outcomes remain unclear. Recent genetic evidence, however, has indicated a correlation between certain natural killer (NK)-cell receptors and progression of both HIV and HCV infection, implying that NK cells have a role in these T-cell-associated diseases. Although ... | 2011 | 22101430 |
| Like-acetylglucosaminyltransferase (LARGE)-dependent modification of dystroglycan at Thr-317/319 is required for laminin binding and arenavirus infection. | a-dystroglycan is a highly O-glycosylated extracellular matrix receptor that is required for anchoring of the basement membrane to the cell surface and for the entry of Old World arenaviruses into cells. Like-acetylglucosaminyltransferase (LARGE) is a key molecule that binds to the N-terminal domain of a-dystroglycan and attaches ligand-binding moieties to phosphorylated O-mannose on a-dystroglycan. Here we show that the LARGE modification required for laminin- and virus-binding occurs on specif ... | 2011 | 21987822 |
| type-i ifn drives the differentiation of short-lived effector cd8(+) t cells in vivo. | two subsets of cd8(+) t cells are generated early during an immune response; one of these subsets forms the memory pool, known as memory precursor effector cells (mpecs), identified by high expression of cd127 and low expression of klrg1, whereas the other subset forms short-lived effector cells (slecs) identified by low expression of cd127 and high expression of klrg1. here, we studied in vivo the role of type-i ifn in this fate decision. we found that under priming conditions dominated by typ ... | 2011 | 22102057 |
| utilizing a retroviral rnai system to investigate in vivo mtor functions in t cells. | rna interference (rnai) is an intracellular mechanism for silencing gene expression utilizing short fragments of double-strand rna that are complementary to the target messenger rna. this gene silencing technique has now become an invaluable research tool due to its specific and strong repressive effect on a target transcript. we have recently applied a retrovirus-based rnai system to investigate the in vivo role of the mammalian target of rapamycin (mtor) in antigen-specific cd8 t cells, and ha ... | 2012 | 22125074 |
| loss of the signaling adaptor traf1 causes cd8+ t cell dysregulation during human and murine chronic infection. | the signaling adaptor tnfr-associated factor 1 (traf1) is specifically lost from virus-specific cd8 t cells during the chronic phase of infection with hiv in humans or lymphocytic choriomeningitis virus (lcmv) clone 13 in mice. in contrast, traf1 is maintained at higher levels in virus-specific t cells of hiv controllers or after acute lcmv infection. traf1 expression negatively correlates with programmed death 1 expression and hiv load and knockdown of traf1 in cd8 t cells from viral controller ... | 2011 | 22184633 |
| evaluation of the immunomodulatory and antiviral effects of the cytokine combination ifn-α and il-7 in the lymphocytic choriomeningitis virus and friend retrovirus mouse infection models. | existing therapies for chronic viral infections are still suboptimal or have considerable side effects, so new therapeutic strategies need to be developed. one option is to boost the host's immune response with cytokines. we have recently shown in an acute ex vivo hiv infection model that co-administration of interferon (ifn)-α and interleukin (il)-7 allows us to combine the potent anti-hiv activity of ifn-α with the beneficial effects of il-7 on t-cell survival and function. here we evaluated t ... | 2011 | 21929334 |
| differential expression of ly6c and t-bet distinguish effector and memory th1 cd4(+) cell properties during viral infection. | cd4(+) t cells differentiate into multiple effector types, but it is unclear how they form memory t cells during infection in vivo. profiling virus-specific cd4(+) t cells revealed that effector cells with t helper 1 (th1) or t follicular helper (tfh) cell characteristics differentiated into memory cells, although expression of tfh cell markers declined over time. in contrast to virus-specific effector cd8(+) t cells, increased il-7r expression was not a reliable marker of cd4(+) memory precurso ... | 2011 | 22018471 |
| the c-terminal region of lymphocytic choriomeningitis virus nucleoprotein contains distinct and segregable functional domains involved in np-z interaction and counteraction of the type i interferon response. | several arenaviruses cause hemorrhagic fever (hf) disease in humans that is associated with high morbidity and significant mortality. arenavirus nucleoprotein (np), the most abundant viral protein in infected cells and virions, encapsidates the viral genome rna, and this np-rna complex, together with the viral l polymerase, forms the viral ribonucleoprotein (vrnp) that directs viral rna replication and gene transcription. formation of infectious arenavirus progeny requires packaging of vrnps int ... | 2011 | 21976642 |
| natural killer cell activation enhances immune pathology and promotes chronic infection by limiting cd8+ t-cell immunity. | infections with hiv, hepatitis b virus, and hepatitis c virus can turn into chronic infections, which currently affect more than 500 million patients worldwide. it is generally thought that virus-mediated t-cell exhaustion limits t-cell function, thus promoting chronic disease. here we demonstrate that natural killer (nk) cells have a negative impact on the development of t-cell immunity by using the murine lymphocytic choriomeningitis virus. nk cell-deficient (nfil3(-/-), e4bp4(-/-)) mice exhib ... | 2011 | 22167808 |
| subtle differences in ctl cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with chediak-higashi syndrome. | perforin-mediated cytotoxicity is important for controlling viral infections, but also for limiting immune reactions. failure of this cytotoxic pathway leads to hemophagocytic lymphohistiocytosis (hlh), a life-threatening disorder of uncontrolled t-cell and macrophage activation. we studied susceptibility to hlh in 2 mouse strains (souris and beige(j)) and a cohort of patients with partial defects in perforin secretion resulting from different mutations in the lyst gene. although both strains la ... | 2011 | 21878672 |
| old world arenaviruses enter the host cell via the multivesicular body and depend on the endosomal sorting complex required for transport. | the highly pathogenic old world arenavirus lassa virus (lasv) and the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) use α-dystroglycan as a cellular receptor and enter the host cell by an unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. upon internalization, the viruses are delivered to acidified endosomes in a rab5-independent manner bypassing classical routes of incoming vesicular trafficking. here we sought to identify cellular factors invol ... | 2011 | 21931550 |
| cross-species analysis of the replication complex of old world arenaviruses reveals two nucleoprotein sites involved in l protein function. | lassa virus (lasv) causing hemorrhagic lassa fever in west africa, mopeia virus (mopv) from east africa, and lymphocytic choriomeningitis virus (lcmv) are the main representatives of the old world arenaviruses. little is known about how the components of the arenavirus replication machinery, i.e., the genome, nucleoprotein (np), and l protein, interact. in addition, it is unknown whether these components can function across species boundaries. we established minireplicon systems for mopv and lcm ... | 2011 | 21917982 |
| human cd8⁺ and cd4⁺ t cell memory to lymphocytic choriomeningitis virus infection. | although cellular immunity to acute lymphocytic choriomeningitis virus (lcmv) infection has been well characterized in experimental studies in mice, the t cell response to this virus in humans is incompletely understood. thus, we analyzed the breadths, magnitudes, and differentiation phenotypes of memory lcmv-specific cd8(+) and cd4(+) t cells in three human donors displaying a variety of disease outcomes after accidental needle stick injury or exposure to lcmv. although only a small cohort of d ... | 2011 | 21900169 |
| destruction of lymphoid organ architecture and hepatitis caused by cd4+ t cells. | immune responses have the important function of host defense and protection against pathogens. however, the immune response also causes inflammation and host tissue injury, termed immunopathology. for example, hepatitis b and c virus infection in humans cause immunopathological sequel with destruction of liver cells by the host's own immune response. similarly, after infection with lymphocytic choriomeningitis virus (lcmv) in mice, the adaptive immune response causes liver cell damage, choriomen ... | 2011 | 21966366 |
| the antiviral immune response in mice devoid of immunoproteasome activity. | the replacement of the catalytically active proteasome subunits β1, β2, and β5 by the immunoproteasome subunits low molecular mass polypeptide (lmp) 2 (β1i), multicatalytic endopeptidase complex-like-1 (mecl-1) (β2i), and lmp7 (β5i) is required for the production of numerous class i ligands. hitherto, investigation of the immunoproteasome was confined to the analysis of mice deficient for one or two immunosubunits. in this study, we characterized lmp2(-/-)/mecl-1(-/-) double-deficient mice and u ... | 2011 | 22013127 |
| antigen-specific cd4 t-cell help rescues exhausted cd8 t cells during chronic viral infection. | cd4 t cells play a critical role in regulating cd8 t-cell responses during chronic viral infection. several studies in animal models and humans have shown that the absence of cd4 t-cell help results in severe dysfunction of virus-specific cd8 t cells. however, whether function can be restored in already exhausted cd8 t cells by providing cd4 t-cell help at a later time remains unexplored. in this study, we used a mouse model of chronic lymphocytic choriomeningitis virus (lcmv) infection to addre ... | 2011 | 22160724 |
| late interleukin-6 escalates t follicular helper cell responses and controls a chronic viral infection. | multiple inhibitory molecules create a profoundly immunuosuppressive environment during chronic viral infections in humans and mice. therefore, eliciting effective immunity in this context represents a challenge. here, we report that during a murine chronic viral infection, interleukin-6 (il-6) was produced by irradiation-resistant cells in a biphasic manner, with late il-6 being absolutely essential for viral control. the underlying mechanism involved il-6 signaling on virus-specific cd4 t cell ... | 2011 | 21960530 |
| cd8+ t cell immunodominance in lymphocytic choriomeningitis virus infection is modified in the presence of toll-like receptor agonists. | currently, we have limited understanding of how toll-like receptor (tlr) engagement by microbial products influences the immune response during a concurrent virus infection. in this study, we established that dual tlr2 plus tlr3 (designated tlr2+3) stimulation alters the immunodominance hierarchies of lymphocytic choriomeningitis virus (lcmv) epitopes by reducing np396-specific cd8+ t cell responses and shifting it to a subdominant position. the shift in immunodominance occurred due to a reducti ... | 2011 | 21957295 |
| an mhc class ib-restricted cd8(+) t cell response to lymphocytic choriomeningitis virus. | conventional mhc class ia-restricted cd8(+) t cells play a dominant role in the host response to virus infections, but recent studies indicate that t cells with specificity for nonclassical mhc class ib molecules may also participate in host defense. to investigate the potential role of class ib molecules in anti-viral immune responses, k(b-/-)d(b-/-)ciita(-/-) mice lacking expression of mhc class ia and class ii molecules were infected with lymphocytic choriomeningitis virus (lcmv). these anima ... | 2011 | 22084437 |
| Protein energy malnutrition impairs homeostatic proliferation of memory CD8 T cells. | Nutrition is a critical but poorly understood determinant of immunity. There is abundant epidemiological evidence linking protein malnutrition to impaired vaccine efficacy and increased susceptibility to infections; yet, the role of dietary protein in immune memory homeostasis remains poorly understood. In this study, we show that protein-energy malnutrition induced in mice by low-protein (LP) feeding has a detrimental impact on CD8 memory. Relative to adequate protein (AP)-fed controls, LP feed ... | 2012 | 22116826 |
| hypoxia induces the gene expression and extracellular transmission of persistent lymphocytic choriomeningitis virus. | the physiological context of virus-infected cells can markedly affect multiplication and spread of the virus progeny. during persistent infection, the virus exploits the host cell without disturbing its vital functions. however, microenvironmental hypoxia can uncouple this intimate relationship and escalate virus pathogenesis. accumulating evidence suggests that hypoxia-inducible factor (hif) modulates gene expression of the viruses that pass through a dna stage, contain hypoxia-responsive promo ... | 2011 | 21957293 |
| RNAi screening reveals requirement for host cell secretory pathway in infection by diverse families of negative-strand RNA viruses. | Negative-strand (NS) RNA viruses comprise many pathogens that cause serious diseases in humans and animals. Despite their clinical importance, little is known about the host factors required for their infection. Using vesicular stomatitis virus (VSV), a prototypic NS RNA virus in the family Rhabdoviridae, we conducted a human genome-wide siRNA screen and identified 72 host genes required for viral infection. Many of these identified genes were also required for infection by two other NS RNA viru ... | 2011 | 22065774 |
| x-ray structure of the arenavirus glycoprotein gp2 in its postfusion hairpin conformation. | arenaviruses are important agents of zoonotic disease worldwide. the virions expose a tripartite envelope glycoprotein complex at their surface, formed by the glycoprotein subunits gp1, gp2 and the stable signal peptide. this complex is responsible for binding to target cells and for the subsequent fusion of viral and host-cell membranes for entry. during this process, the acidic environment of the endosome triggers a fusogenic conformational change in the transmembrane gp2 subunit of the comple ... | 2011 | 22123988 |
| Quantifying antigen-specific CD4 T cells during a viral infection: CD4 T cell responses are larger than we think. | The number of virus-specific CD8 T cells increases substantially during an acute infection. Up to 90% of CD8 T cells are virus specific following lymphocytic choriomeningitis virus (LCMV) infection. In contrast, studies identifying virus-specific CD4 T cell epitopes have indicated that CD4 T cells often recognize a broader array of Ags than CD8 T cells, consequently making it difficult to accurately quantify the total magnitude of pathogen-specific CD4 T cell responses. In this study, we show th ... | 2011 | 22043009 |
| An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells. | Memory CD8(+) T cells are critical for long-term immunity, but the genetic pathways governing their formation remain poorly defined. This study shows that the IL-10-IL-21-STAT3 pathway is critical for memory CD8(+) T cell development after acute LCMV infection. In the absence of either interleukin-10 (IL-10) and IL-21 or STAT3, virus-specific CD8(+) T cells retain terminal effector (TE) differentiation states and fail to mature into protective memory T cells that contain self-renewing central me ... | 2011 | 22118527 |
| inhibition of the type i interferon antiviral response during arenavirus infection. | arenaviruses merit interest both as tractable experimental model systems to study acute and persistent viral infections, and as clinically-important human pathogens. several arenaviruses cause hemorrhagic fever (hf) disease in humans. in addition, evidence indicates that the globally-distributed prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) is a human pathogen of clinical significance in congenital infections, and also poses a great danger to immunosuppressed individuals. arena ... | 2010 | 21994626 |
| The Proapoptotic Bcl-2 Family Member Bim Plays a Central Role during the Development of Virus-Induced Hepatitis. | The proapoptotic Bcl-2 homolog Bim was shown to control the apoptosis of both T cells and hepatocytes. This dual role of Bim might be particularly relevant for the development of viral hepatitis, in which both the sensitivity of hepatocytes to apoptosis stimuli and the persistence of cytotoxic T cells are essential factors for the outcome of the disease. The relevance of Bim in regulating survival of cytotoxic T cells or induction of hepatocyte death has only been investigated in separate system ... | 2011 | 22156338 |
| Interferon-gamma induces monopoiesis and inhibits neutrophil development during inflammation. | Steady-state hematopoiesis is altered upon infection, but the cellular and molecular mechanisms driving these changes are largely unknown. Modulation of hematopoiesis is essential to increase the output of the appropriate type of effector cell required to combat the invading pathogen. Here we demonstrate that the pro-inflammatory cytokine interferon-gamma (IFN?) is involved in orchestrating inflammation-induced myelopoiesis. Using both mouse models and in vitro assays we show that IFN? induces d ... | 2011 | 22117048 |
| multiple layers of cd80/86-dependent costimulatory activity regulate primary, memory and secondary lcmv-specific t cell immunity. | the lymphocytic choriomeningitis virus (lcmv) system constitutes one of the most widely used models for the study of infectious disease and the regulation of virus-specific t cell immunity. yet with respect to the activity of costimulatory and associated regulatory pathways, lcmv-specific t cell responses have long been regarded as relatively independent and thus distinct from the regulation of t cell immunity directed against many other viral pathogens. here, we have re-evaluated the contributi ... | 2011 | 22156513 |
| caveolin-1 orchestrates tcr synaptic polarity, signal specificity, and function in cd8 t cells. | tcr engagement triggers the polarized recruitment of membrane, actin, and transducer assemblies within the t cell-apc contact that amplify and specify signaling cascades and t effector activity. we report that caveolin-1, a scaffold that regulates polarity and signaling in nonlymphoid cells, is required for optimal tcr-induced actin polymerization, synaptic membrane raft polarity, and function in cd8, but not cd4, t cells. in cd8(+) t cells, caveolin-1 ablation selectively impaired tcr-induced n ... | 2011 | 21849673 |