| selective delivery of augmented il-2 receptor signals to responding cd8+ t cells increases the size of the acute antiviral response and of the resulting memory t cell pool. | cd8(+) t cells respond to il-2 produced both endogenously and by cd4(+) th during an antiviral response. however, il-2r signals can potentially promote cd8(+) t cell death as well as proliferation, making it unclear whether il-2r signals provide a predominantly positive or negative effect upon cd8(+) t cell responses to viral infection. to more precisely define the direct role of il-2r signaling on cd8(+) t cells during the response to a virus, we examined the effect of delivering augmented il-2 ... | 2002 | 12391213 |
| perforin-mediated ctl cytolysis counteracts direct cell-cell spread of listeria monocytogenes. | the immune system has evolved various effector cells and functions to combat diverse infectious agents equipped with different virulence strategies. cd8 t cells play a critical role in protective immunity to listeria monocytogenes (lm), a bacterium that grows within the host cell cytosol and spreads directly into neighboring cells. the importance of cd8 t cells during lm infection is currently attributed to the cytosolic niche of this organism, which allows it to evade many aspects of immune sur ... | 2002 | 12391238 |
| exposure to rodents and rodent-borne viruses among persons with elevated occupational risk. | persons who have frequent contact with rodents as part of their occupation may be at increased risk of exposure to rodent-borne viruses such as sin nombre virus (snv), the agent of hantavirus pulmonary syndrome, and whitewater arroyo virus (wwa), a new world arenavirus. eighty-one persons with possible occupational exposure to rodents completed questionnaires and provided specimens for serologic testing. seventy-two participants reported handling rodents as part of their job. the mean total numb ... | 2002 | 12391776 |
| t cell responses to viral infections: lessons from lymphocytic choriomeningitis virus. | the elaboration of a successful immune response is critical for the clearance of viral infections. cd8 t cells can directly kill virus-infected cells and also produce cytokines that modulate virus replication. thus, the failure to induce or sustain these responses can profoundly impact the outcome of infections. lymphocytic choriomeningitis virus (lcmv) infection of mice has proven to be one of the most informative experimental systems for examining antiviral t cell responses. in recent years, t ... | 2002 | 12403369 |
| homeostatic proliferation but not the generation of virus specific memory cd8 t cells is impaired in the absence of il-15 or il-15ralpha. | the generation and efficient maintenance of antigen specific memory t cells is essential for long-lasting immunological protection. antigen specific memory cd8 t cells are known to be maintained via antigen-independent homeostatic proliferation. however, signals that drive memory t cell generation and/or influence the slow turnover of memory t cells are unknown. recently, il-15 has received attention for its potential effect on memory cd8 t cells. in this report we examine the role of il-15 in t ... | 2002 | 12405201 |
| neonates mount robust and protective adult-like cd8(+)-t-cell responses to dna vaccines. | neonates are thought to mount less vigorous adaptive immune responses than adults to antigens and infectious agents. this concept has led to a delay in the administration of many currently available vaccines until late infancy or early childhood. it has recently been shown that vaccines composed of plasmid dna can induce both humoral and cell-mediated antimicrobial immunity when administered within hours of birth. in most of these studies, immune responses were measured weeks or months after the ... | 2002 | 12414933 |
| cutting edge: persistent viral infection prevents tolerance induction and escapes immune control following cd28/cd40 blockade-based regimen. | a continuing concern with cd28 and/or cd40 blockade-based strategies to induce tolerance and mixed chimerism is their potential to disrupt protective immunity to preexisting infections. in this report, we find that preexisting persistent infection with lymphocytic choriomeningitis virus (lcmv) clone 13 prevents the induction of tolerance, mixed chimerism, and donor-reactive t cell deletion. mice continue to be refractory to tolerance induction even after viremia has been resolved and virus is pr ... | 2002 | 12421910 |
| lack of effector cell function and altered tetramer binding of tumor-infiltrating lymphocytes. | tumor-specific cd8 t cell responses to mca102 fibrosarcoma cells expressing the cytotoxic t cell epitope gp33 from lymphocytic choriomeningitis virus were studied. mca102(gp33) tumors grew progressively in c57bl/6 mice, despite induction of peripheral gp33-tetramer(+) t cells that were capable of mediating antiviral protection, specific cell rejection, and concomitant tumor immunity. mca102(gp33) tumors were infiltrated with a high number ( approximately 20%) of cd11b(+)cd11c(-) macrophage-pheno ... | 2002 | 12421928 |
| nonsecreted bacterial proteins induce recall cd8 t cell responses but do not serve as protective antigens. | secreted or nonsecreted ag expressed by recombinant listeria monocytogenes can prime cd8 t cells. however, ag-specific memory cd8 t cells confer protection against bacteria secreting ag, but not against bacteria expressing the nonsecreted form of the same ag. this dichotomy may be explained by a long-standing hypothesis that nonsecreted ags are less effective than secreted ags at inducing a protective immune response at the onset of infection. we tested this hypothesis by examining whether these ... | 2002 | 12421961 |
| a unique mechanism for innate cytokine promotion of t cell responses to viral infections. | the kinetics of cd8 t cell ifn-gamma responses as they occur in situ are defined here during lymphocytic choriomeningitis virus (lcmv) infections, and a unique mechanism for the innate cytokines ifn-alphabeta and il-18 in promoting these responses is defined. infections of mice with armstrong or we strains of lcmv induced an unexpectedly early day 4 ifn-gamma response detectable in serum samples and spleen and liver homogenates. production of ifn-gamma was mhc class i/cd8 dependent, but did not ... | 2002 | 12421964 |
| t cells in the central nervous system: the delicate balance between viral clearance and disease. | the central nervous system (cns) is considered an "immunoprivileged" site with restricted access and a unique microenvironment that profoundly affects the capacity of t cells to exert their functions. the lymphocytic choriomeningitis virus model offers a unique system in which to evaluate the contrasting roles of specific t cells in causing lethal cns disease or curing pervasive and life-long cns infection. specific t cell kinetics in the periphery is briefly discussed. the t cell-mediated mecha ... | 2002 | 12424690 |
| rag-dependent peripheral t cell receptor diversification in cd8+ t lymphocytes. | rearrangement of t cell receptor (tcr) genes is driven by transient expression of v(d)j recombination-activating genes (rags) during lymphocyte development. immunological dogma holds that t cells irreversibly terminate rag expression before exiting the thymus, and that all of the progeny arising from mature t cells express the parental tcrs. when single pancreatic islet-derived, nrp-a7 peptide-reactive cd8(+) t cells from nonobese diabetic (nod) mice were repeatedly stimulated with peptide-pulse ... | 2002 | 12432095 |
| role of icos versus cd28 in antiviral immunity. | the costimulatory protein icos is inducibly expressed on activated t cells. previous results have shown that icos(-/-) mice are defective in germinal center formation, antibody (ab) production and class switch as well as th1 and th2 cytokine production in response to protein or parasite antigens. however, icos-ig failed to block antiviral ab responses. to date the immune response to viruses has not been examined in icos(-/-) mice. in this report we compared antiviral ab responses to lcmv, vsv an ... | 2002 | 12432568 |
| control of biochemical reactions through supramolecular ring domain self-assembly. | ring domains act in a variety of unrelated biochemical reactions, with many of these domains forming key parts of supramolecular assemblies in cells. here, we observe that purified rings from a variety of functionally unrelated proteins, including promyelocytic leukemia protein, kap-1tif1beta, z, mel18, breast cancer susceptibility gene product 1 (brca1), and brca1-associated ring domain (bard1), self-assemble into supramolecular structures in vitro that resemble those they form in cells. ring b ... | 2002 | 12438698 |
| cd4+ tcr repertoire heterogeneity in schistosoma mansoni-induced granulomas. | the hallmark of schistosoma mansoni infection is the formation of liver granulomas around deposited ova. the initiation of granuloma formation is t cell-dependent since granulomas are not formed in their absence. we investigated whether a few t cells arrive to initiate the inflammatory lesion and subsequently expand locally, or whether a large repertoire of systemically activated t cells home to the delayed type hypersensitivity reaction induced by the ova. the tcr repertoire of single granuloma ... | 2002 | 12444146 |
| a structural basis for lcmv immune evasion: subversion of h-2d(b) and h-2k(b) presentation of gp33 revealed by comparative crystal structure.analyses. | lcmv infection of h-2(b) mice generates a cd8(+) ctl response mainly directed toward three immunodominant epitopes. one of these, gp33, is presented by both h-2d(b) and h-2k(b) mhc class i molecules. the virus can escape immune recognition in the context of both these mhc class i molecules through single mutations of the peptide. in order to understand the underlying structural mechanism, we determined the crystal structures of both complexes. the structures reveal that the peptide is presented ... | 2002 | 12479822 |
| immunology: remembrance of things past. | | 2002 | 12490927 |
| induction of telomerase activity and maintenance of telomere length in virus-specific effector and memory cd8+ t cells. | acute viral infections induce extensive proliferation and differentiation of virus-specific cd8+ t cells. one mechanism reported to regulate the proliferative capacity of activated lymphocytes is mediated by the effect of telomerase in maintaining the length of telomeres in proliferating cells. we examined the regulation of telomerase activity and telomere length in naive cd8+ t cells and in virus-specific cd8+ t cells isolated from mice infected with lymphocytic choriomeningitis virus. these st ... | 2003 | 12496394 |
| ablation of cd8 and cd4 t cell responses by high viral loads. | to evaluate the impact of sustained viral loads on anti-viral t cell responses we compared responses that cleared acute lymphocytic choriomeningitis virus infection with those that were elicited but could not resolve chronic infection. during acute infection, as replicating virus was cleared, cd8 t cell responses were down-regulated, and a pool of resting memory cells developed. in chronically infected hosts, the failure to control the infection was associated with pronounced and prolonged activ ... | 2003 | 12496434 |
| lymphocytic choriomeningitis virus: emerging fetal teratogen. | lymphocytic choriomeningitis virus (lcmv), a rodent-borne arenavirus, is an often undiagnosed human fetal teratogen. we describe a neonate born with hydrocephalus and chorioretinitis after maternal second-trimester symptomatic lcmv infection. previously reported affected infants are reviewed. we strongly suggest that obstetricians counsel their pregnant patients regarding the potential hazard that contact with infected pet, laboratory, and household mice and hamsters poses to pregnant women and ... | 2002 | 12501090 |
| characterization of the genomic promoter of the prototypic arenavirus lymphocytic choriomeningitis virus. | the genome of the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) consists of two negative-sense, single-strand rna segments designated l and s. arenavirus genomes exhibit high sequence conservation at their 3' ends. all arenavirus genomes examined to date have a conserved terminal sequence element (3'-terminal 20 nucleotides [nt]) thought to be a highly conserved viral promoter. terminal complementarity between the 5' and 3' ends of the l and s rnas predicts the formation of a t ... | 2003 | 12502835 |
| heterologous immunity and the cd8 t cell network. | | 2002 | 12503062 |
| control of lymphocytic choriomeningitis virus infection in granzyme b deficient mice. | we have investigated whether granzyme b (gzmb) is required for effective cytotoxic t lymphocyte (ctl) mediated control of lymphocytic choriomeningitis virus (lcmv) infection. clearance of lcmv from tissues of gzmb-deficient (gzmb-) mice following intraperitoneal infection with lcmv was impaired compared with control mice; however, the virus was ultimately eliminated. the impaired clearance of lcmv in gzmb- mice was not due to a deficiency in the generation of lcmv-specific t cells. in addition, ... | 2003 | 12504535 |
| neonatal viral infection decreases neuronal progenitors and impairs adult neurogenesis in the hippocampus. | while adult neurogenesis has been demonstrated in the hippocampal dentate gyrus of several mammalian species, including humans, the impact of viral infections has not been well studied. to examine this question we used a model in which neonatal rats are infected with lymphocytic choriomeningitis virus (lcmv) leading to a gradual loss of dentate granule cells (dgcs), which becomes fully evident in adulthood. stereological cell counts performed 8 months after infection revealed that the loss of ma ... | 2002 | 12505418 |
| dynamics of ly49 expressing cytotoxic lymphocyte subsets in response to virus infection. | viral infections induce first a loss and then an increase in natural killer (nk) and cd8(+) t cells. nk cells expressing ly49g2 were selectively expanded by several viruses and poly i:c. cd8(+) t cells expressing ly49g2 were selectively expanded by poly i:c and participated in the antigen-specific response to lymphocytic choriomeningitis virus. | 2002 | 12505520 |
| transgenic animal models for type 1 diabetes: linking a tetracycline-inducible promoter with a virus-inducible mouse model. | autoimmunity is thought to emerge as a consequence of genetic predispositions and environmental tiggering factors. often the etiology and the mechanisms involved in the autoaggressive destruction of self-components are rather complex and in many cases poorly understood. chemokines and cytokines are central mediators of inflammatory processes that are involved in initiation and progression of autoimmunity. many animal models for human autoimmune diseases use transgenic technology to express chemo ... | 2002 | 12509133 |
| complement component 3 is required for optimal expansion of cd8 t cells during a systemic viral infection. | in addition to its established role in innate immune mechanisms, complement component c3 is also of critical importance in b cell activation and t cell-dependent ab responses. in this study, we have examined the requirement for c3 in the generation of primary cd8 t cell responses to an acute systemic viral infection. we compared ag-specific cd8 t cell responses to lymphocytic choriomeningitis virus (lcmv) between wild-type (+/+) and c3-deficient (c3(-/-)) mice on both 129/b6 and b6 backgrounds. ... | 2003 | 12517942 |
| arenavirus-mediated liver pathology: acute lymphocytic choriomeningitis virus infection of rhesus macaques is characterized by high-level interleukin-6 expression and hepatocyte proliferation. | lymphocytic choriomeningitis virus (lcmv) and lassa virus can cause hemorrhagic fever and liver disease in primates. the we strain of lcmv (lcmv-we) causes a fatal lassa fever-like disease in rhesus macaques and provides a model for arenavirus pathogenesis in humans. lcmv-we delivered intravenously or intragastrically to rhesus macaques targets hepatocytes and induces high levels of liver enzymes, interleukin-6 (il-6), soluble il-6 receptor (sil-6r), and soluble tumor necrosis factor receptors ( ... | 2003 | 12525606 |
| sap is required for generating long-term humoral immunity. | long-lived plasma cells and memory b cells are the primary cellular components of long-term humoral immunity and as such are vitally important for the protection afforded by most vaccines. the sap gene has been identified as the genetic locus responsible for x-linked lymphoproliferative disease, a fatal immunodeficiency. mutations in sap have also been identified in some cases of severe common variable immunodeficiency disease. the underlying cellular basis of this genetic disorder remains uncle ... | 2003 | 12529646 |
| preferential escape of subdominant cd8+ t cells during negative selection results in an altered antiviral t cell hierarchy. | negative selection is designed to purge the immune system of high-avidity, self-reactive t cells and thereby protect the host from overt autoimmunity. in this in vivo viral infection model, we show that there is a previously unappreciated dichotomy involved in negative selection in which high-avidity cd8(+) t cells specific for a dominant epitope are eliminated, whereas t cells specific for a subdominant epitope on the same protein preferentially escape deletion. although this resulted in signif ... | 2003 | 12538681 |
| autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. | pancreatic islets of langerhans are enveloped by peri-islet schwann cells (psc), which express glial fibrillary acidic protein (gfap) and s100beta. psc-autoreactive t- and b-cell responses arise in 3- to 4-week-old diabetes-prone non-obese diabetic (nod) mice, followed by progressive psc destruction before detectable beta-cell death. humans with probable prediabetes generate similar autoreactivities, and autoantibodies in islet-cell autoantibody (lca) -positive sera co-localize to psc. moreover, ... | 2003 | 12539039 |
| transcriptional and posttranscriptional control of hepatitis b virus gene expression. | hepatitis b virus (hbv) infects humans and certain nonhuman primates. viral clearance and acute disease are associated with a strong, polyclonal, multispecific cytotoxic t lymphocyte response. infiltrating t cells, as well as other activated inflammatory cells, produce cytokines that can regulate hepatocellular gene expression. using an hbv transgenic mouse model, our laboratory has previously demonstrated that adoptive transfer of hbv-specific cytotoxic t lymphocytes or injection of il-2 can no ... | 2003 | 12552098 |
| lineage relationship and protective immunity of memory cd8 t cell subsets. | memory cd8 t cells can be divided into two subsets, central (t(cm)) and effector (t(em)), but their lineage relationships and their ability to persist and confer protective immunity are not well understood. our results show that t(cm) have a greater capacity than t(em) to persist in vivo and are more efficient in mediating protective immunity because of their increased proliferative potential. we also demonstrate that, following antigen clearance, t(em) convert to t(cm) and that the duration of ... | 2003 | 12563257 |
| ntp toxicology and carcinogenesis studies of 2,3-dibromo-1-propanol (cas no. 96-13-9) in f344/n rats and b6c3f1 mice (dermal studies). | 2,3-dibromo-l-propanol, a colorless liquid, has been used as a flame retardant, as an intermediate in the preparation of the flame retardant tris(2,3-dibromopropyl) phosphate, and as an intermediate in the manufacture of pesticides and pharmaceutical preparations. toxicology and carcinogenicity studies were conducted by applying 2,3-dibromo-1-propanol (approximately 98% pure) in ethanol to the subscapular area of the skin of male and female f344/n rats and b6c3f1 mice 5 days per week for 16 days ... | 1993 | 12563345 |
| cd4-independent protective cytotoxic t cells induced in early life by a non-replicative delivery system based on virus-like particles. | the relative immaturity of the neonatal immune system limits cd4(+) th1 and cytotoxic t lymphocyte (ctl) responses, and represents a significant challenge for the development of vaccines against intracellular pathogens. in this report, we demonstrate the ability of a non-replicative delivery system based on parvovirus-like particles (vlp) to induce ctl responses in the neonatal period. a single immunization of 1-week-old balb/c mice with recombinant vlp carrying a cd8(+) t cell determinant from ... | 2003 | 12573588 |
| efficient t cell repertoire selection in tetraparental chimeric mice independent of thymic epithelial mhc. | nonthymic epithelial cells were compared with thymic epithelial cells for their role in t cell repertoire selection. tetraparental aggregation chimeras were generated from t and b cell-deficient mice (h-2(d) scid or h-2(b) rag-/-) and thymus-deficient nude mice (h-2(b) or h-2(d)). these tetraparental mice showed primary protective cd8(+) t cell responses, after lymphocytic choriomeningitis virus infection, that were peptide-specifically restricted to either thymic or nonthymic epithelial mhc at ... | 2003 | 12574503 |
| role of cell cycle regulator p19arf in regulating t cell responses. | although it is well established that the processes of cellular proliferation and apoptosis are linked, the role of cell cycle regulators in t cell responses in vivo is not well understood. in recent years, tumor suppressor molecule p19(arf) has emerged as a key cell cycle regulator important in cellular apoptosis against strong mitogenic stimuli. in this study, we compared the antigen-specific t cell responses between wild type (+/+) and p19(arf)-deficient (p19-/-) mice following an acute infect ... | 2002 | 12576030 |
| endoproteolytic processing of the lymphocytic choriomeningitis virus glycoprotein by the subtilase ski-1/s1p. | the envelope glycoprotein (gp) of lymphocytic choriomeningitis virus (lcmv) is posttranslationally cleaved into two subunits. we show here that this endoproteolytic processing is not required for transport to the cell surface but is essential for lcmv gp to mediate infectivity of pseudotyped retroviral vectors. by systematic mutational analysis of the lcmv gp cleavage site, we determined that the consensus motif r-(r/k/h)-l-(a/l/s/t/f)(265) is essential for the endoproteolytic processing. in agr ... | 2003 | 12584310 |
| a new look at viruses in type 1 diabetes. | type 1 diabetes (t1d) results from the destruction of pancreatic beta cells. genetic factors are believed to be a major component for the development of t1d, but the concordance rate for the development of diabetes in identical twins is only about 40%, suggesting that nongenetic factors play an important role in the expression of the disease. viruses are one environmental factor that is implicated in the pathogenesis of t1d. to date, 14 different viruses have been reported to be associated with ... | 2003 | 12592641 |
| primary and secondary immunocompetence in mixed allogeneic chimeras. | targeted disruption of t cell costimulatory pathways, particularly cd28 and cd40, has allowed for the development of minimally myeloablative strategies for the induction of mixed allogeneic chimerism and donor-specific tolerance across full mhc barriers. in this study we analyze in depth the ability of mixed allogeneic chimeras in two strain combinations to mount effective host-restricted and donor-restricted antiviral cd4 and cd8 responses, as well as the impact of development of mixed chimeris ... | 2003 | 12594261 |
| cd4+ t cells are required for secondary expansion and memory in cd8+ t lymphocytes. | a long-standing paradox in cellular immunology concerns the conditional requirement for cd4+ t-helper (t(h)) cells in the priming of cytotoxic cd8+ t lymphocyte (ctl) responses in vivo. whereas ctl responses against certain viruses can be primed in the absence of cd4+ t cells, others, such as those mediated through 'cross-priming' by host antigen-presenting cells, are dependent on t(h) cells. a clearer understanding of the contribution of t(h) cells to ctl development has been hampered by the fa ... | 2003 | 12594515 |
| beta cell-specific cd80 (b7-1) expression disrupts tissue protection from autoantigen-specific ctl-mediated diabetes. | t cell responses toward pancreatic beta cell autoantigens arise spontaneously or on immunization in many mouse strains, yet sustained islet infiltration and progressive diabetes rarely ensues. most mouse diabetes models overcome the innocuous coexistence of anti-islet specific t cells and endogenous islets via incompletely understood mechanisms (e.g. the spontaneous disease onset of the non-obese diabetic mouse) or depend on overwhelming numbers of peripheral islet-specific t cells. we report th ... | 2003 | 12604308 |
| role of the virus nucleoprotein in the regulation of lymphocytic choriomeningitis virus transcription and rna replication. | the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) has a bisegmented negative-strand rna genome. each segment carries two viral genes in opposite orientation and separated by an intergenic region (igr). the rna-dependent rna polymerase (rdrp) l of lcmv produces subgenomic mrna and full-length genomic and antigenomic rna species in two different processes termed transcription and replication, respectively. it is widely accepted that intracellular nucleoprotein (np) levels regulat ... | 2003 | 12610166 |
| weak agonist self-peptides promote selection and tuning of virus-specific t cells. | recent progress has begun to define the interactions and signaling pathways that are triggered during positive selection. to identify and further examine self-peptides that can mediate positive selection, we searched a protein-database to find peptides that have minimal homology with the viral peptide (p33) that activates a defined p14 transgenic tcr. we identified four peptides that could bind the restriction element h-2d(b) and induce proliferation of p14 transgenic splenocytes at high concent ... | 2003 | 12616489 |
| meningitis and encephalitis in children. an update. | over the course of the past decade, much has changed on the landscape of meningitis and encephalitis in children. west nile virus has emerged in the united states as a new etiologic pathogen causing encephalitis. human herpesvirus-6 has been identified as a cause of encephalitis and febrile seizures. lymphocytic choriomeningitis virus has been identified as an underrecognized neuroteratogen. the emergence of penicillin-resistant streptococcus pneumoniae has complicated the treatment of bacterial ... | 2002 | 12616679 |
| detection of lymphocytic choriomeningitis virus by use of fluorogenic nuclease reverse transcriptase-polymerase chain reaction analysis. | lymphocytic choriomeningitis virus (lcmv) induces persistent infections in laboratory mice; is a known contaminant of biological materials, such as transplantable tumor cell lines; and is of great concern in animal facilities due to its zoonotic potential. fluorogenic nuclease reverse transcriptase-polymerase chain reaction (fnrt-pcr) assays combine rt-pcr with an internal fluorogenic hybridization probe, thereby potentially enhancing specificity and eliminating post-pcr processing. an fnrt-pcr ... | 2003 | 12625508 |
| hypergammaglobulinemia and autoantibody induction mechanisms in viral infections. | polyclonal hypergammaglobulinemia is a characteristic of chronic inflammatory conditions, including persisting viral infections and autoimmune diseases. here we have studied hypergammaglobulinemia in mice infected with lymphocytic choriomeningitis virus (lcmv), which induces nonspecific immunoglobulins as a result of switching natural igm specificities to igg. the process is dependent on help from cd4+ t cells that specifically recognize lcmv peptides presented by b cells on major histocompatibi ... | 2003 | 12627229 |
| modelling the dynamics of lcmv infection in mice: ii. compartmental structure and immunopathology. | in this study, we develop a mathematical model for analysis of the compartmental aspects and immunopathology of lymphocytic choriomeningitis virus (lcmv) infection in mice. we used sets of original and published data on systemic (extrasplenic) virus distribution to estimate the parameters of virus growth and elimination for spleen and other anatomical compartments, such as the liver, kidney, thymus and lung as well as transfer rates between blood and the above organs. a mathematical model quanti ... | 2003 | 12642113 |
| viral persistence alters cd8 t-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. | chronic viral infections often result in ineffective cd8 t-cell responses due to functional exhaustion or physical deletion of virus-specific t cells. however, how persisting virus impacts various cd8 t-cell effector functions and influences other aspects of cd8 t-cell dynamics, such as immunodominance and tissue distribution, remains largely unknown. using different strains of lymphocytic choriomeningitis virus (lcmv), we compared responses to the same cd8 t-cell epitopes during acute or chroni ... | 2003 | 12663797 |
| combinatorial immunoglobulin light chain variability creates sufficient b cell diversity to mount protective antibody responses against pathogen infections. | to analyze how combinatorial light (l) chain diversity influences the b cell repertoire, we studied mice with a homozygous immunoglobulin-heavy-chain null mutation (mu mt), in which the b cell developmental block was overridden by the expression of a transgenic immunoglobulin mu heavy (h) chain derived from a vesicular stomatitis virus indiana serotype (vsv-ind)-neutralizing ab (t11 mu mt mice). the randomly integrated transgene could not undergo secondary rearrangements and was expressed in com ... | 2003 | 12672061 |
| direct visualization of cross-reactive effector and memory allo-specific cd8 t cells generated in response to viral infections. | cd8 t cell cross-reactivity between heterologous viruses has been shown to provide protective immunity, induce immunopathology, influence the immunodominance of epitope-specific t cell responses, and shape the overall memory population. virus infections also induce cross-reactive allo-specific ctl responses. in this study, we quantified the allo-specific cd8 t cells elicited by infection of c57bl/6 (b6) mice with lymphocytic choriomeningitis virus (lcmv). cross-reactive lcmv-specific cd8 t cells ... | 2003 | 12682237 |
| requirement for cd4 t cell help in generating functional cd8 t cell memory. | although primary cd8 responses to acute infections are independent of cd4 help, it is unknown whether a similar situation applies to secondary responses. we show that depletion of cd4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory cd8 cells to reinfection. memory cd8 cells generated in cd4+/+ mice responded normally when transferred into cd4-/- hosts, whereas memory cd8 cells generated in cd4-/- mice mounted de ... | 2003 | 12690201 |
| therapeutic use of il-2 to enhance antiviral t-cell responses in vivo. | interleukin (il)-2 is currently used to enhance t-cell immunity but can have both positive and negative effects on t cells. to determine whether these opposing results are due to il-2 acting differently on t cells depending on their stage of differentiation, we examined the effects of il-2 therapy during the expansion, contraction and memory phases of the t-cell response in lymphocytic choriomeningitis virus (lcmv)-infected mice. il-2 treatment during the expansion phase was detrimental to the s ... | 2003 | 12692546 |
| lymphocytic choriomeningitis virus infection in a province of spain: analysis of sera from the general population and wild rodents. | lymphocytic choriomeningitis virus (lcmv) is a rodent-borne virus belonging to the family arenaviridae, genus arenavirus, which causes a wide spectrum of human disease. however, data on lcmv infection in spain is scant. to investigate whether this virus causes infection in spain, 400 serum samples from the general population (191 males, 209 females) and 100 from wild rodents were studied by immunofluorescence assay (ifa) using l-929 cells infected with lcmv. the study was performed in the "commu ... | 2003 | 12696116 |
| sensitizing antigen-specific cd8+ t cells for accelerated suicide causes immune incompetence. | death receptor-mediated activation-induced apoptosis of antigen-specific t cells is a major mechanism of peripheral tolerance induction and immune homeostasis. failure to undergo activation-induced cell death (aicd) is an important underlying cause of many autoimmune diseases. thus, enhancing the t cell's own suicide mechanism may provide an efficient therapy for the treatment of autoimmune diseases. bisindolylmaleimide viii (bis viii), a pkc inhibitor, can sensitize t cells for death receptor-i ... | 2003 | 12697738 |
| viral infection results in massive cd8+ t cell expansion and mortality in vaccinated perforin-deficient mice. | perforin-mediated cytotoxicity is essential for clearance of primary lcmv infection. balb/c-perforin-deficient (pko) mice survived lcmv infection by deleting np(118)-specific cd8(+) t cells whereas vaccination of pko mice with listeria expressing np(118) generated a stable memory cd8(+) t cell population. however, >85% of vaccinated balb/c-pko mice died after lcmv infection. mortality was associated with enormous expansion of np(118)-specific cd8(+) t cells in both lymphoid and nonlymphoid tissu ... | 2003 | 12705850 |
| lethal mutagenesis of the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv). | passage of the prototypic arenavirus lymphocytic choriomenigitis virus (lcmv) in cultured cells in the presence of the mutagenic agent 5-fluorouracil (fu) resulted in efficient and systematic virus extinction under conditions that did not significantly affect cell survival. fu-mediated extinction of lcmv was associated with 3.6- to 10-fold increases in the mutation frequencies for the three viral genes examined, but with only very modest effects on virus replication and transcription during a si ... | 2003 | 12706088 |
| mitochondrial potential and reactive oxygen intermediates in antigen-specific cd8+ t cells during viral infection. | following many viral infections, there are large expansions of ag-specific cd8(+) t cells. after viral clearance, mechanisms exist to ensure that the vast majority of effector cells undergo apoptosis. in studies of thymocyte apoptosis, loss of mitochondrial potential (deltapsi(m)) and excess production of reactive oxygen intermediates have been implicated as key events in cellular apoptosis. the purpose of the experiments presented in this work was to determine these parameters in ag-specific cd ... | 2003 | 12707355 |
| public versus personal serotypes of a viral quasispecies. | noncytopathic rna viruses persist in their natural hosts at various levels as highly mutating quasispecies. they exhibit only one known serotype. in most inbred dba2 mice infected with 2 x 10(4) or 2 x 10(6) plaque-forming units (pfu) of lymphocytic choriomeningitis virus (lcmv), the virus is transiently controlled below detectable levels measured with conventional assays (<1.7 pfu), but reemerges despite a common neutralizing ab (nab) response. wild-type virus and cloned mutant viruses that had ... | 2003 | 12730366 |
| expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. | background & aims hepatitis c virus (hcv) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. the majority of patients treated with interferon alpha do not have a sustained response with clearance of the virus. the molecular mechanisms underlying interferon resistance are poorly understood. interferon-induced activation of the jak-stat (signal transducer and activator of transcription) signal transduction pathway is essential for the induction of an anti ... | 2003 | 12730885 |
| regulation of cd8+ t cells undergoing primary and secondary responses to infection in the same host. | naive ag-specific cd8(+) t cells expand, contract, and become memory cells after infection and/or vaccination. memory cd8(+) t cells provide faster, more effective secondary responses against repeated exposure to the same pathogen. using an adoptive transfer system with low numbers of trackable nontransgenic memory cd8(+) t cells, we showed that secondary responses can be comprised of both primary (naive) and secondary (memory) cd8(+) t cells after bacterial (listeria monocytogenes) and/or viral ... | 2003 | 12734336 |
| of mice and men: cytotoxic t cells and aids pathogenesis. | cd8+ cytotoxic t lymphocytes (ctls) represent a first line of defense against hiv infection, although their precise role in disease pathogenesis remains enigmatic. they play an important part in viral control but may also contribute to disease progression through destruction of cd4+ helper t cells. the role of ctls in lymphocytic choriomeningitis virus (lcmv) infection in mice has been studied extensively, and the effects of ctl activity on host and virus are well defined. although lcmv is not a ... | 1999 | 12737139 |
| clonal exhaustion as a result of immune deviation. | an overwhelming virus infection that spreads within a few days throughout the host can cause deletion of the specific cytotoxic t lymphocytes (ctl). this phenomenon is known as 'clonal exhaustion'. current explanations for this phenomenon are 'clonal', and consider either the terminal differentiation of the virus-specific ctl to an effector phenotype, or the lack of help and antigen presentation for a specific ctl clone. the virus remains controlled by some other form of immunity in the exhauste ... | 2003 | 12749529 |
| the cholera toxin b subunit is a mucosal adjuvant for oral tolerance induction in type 1 diabetes. | when conjugated to various proteins, the nontoxic b-chain of cholera toxin (ctb) significantly increases the ability of these proteins to induce immunological tolerance after oral administration. here, we investigated if a nonconjugated form of ctb enhances the induction of immune tolerance after oral insulin administration. induction of immunological tolerance was studied after oral administration of insulin preparations in three mouse models; an insulin/ovalbumin coimmunization model, a model ... | 2003 | 12753499 |
| virus-specific cd8 t cells in peripheral tissues are more resistant to apoptosis than those in lymphoid organs. | cd8 t cells persist at high frequencies in peripheral organs after resolution of an immune response, and their presence in the periphery is important for resistance to secondary challenge. we show here that lcmv-specific t cells in peripheral tissue (peritoneal cavity, lung, fat pads) reacted much less with the apoptotic marker annexin-v than those in spleen and lymph nodes. this was not due to a tcr-based selection. in comparison to lymphoid tissue, t cells in the periphery expressed lower leve ... | 2003 | 12753740 |
| role of toll-like receptors in costimulating cytotoxic t cell responses. | stimulation of toll-like receptors (tlr) by pathogen-derived compounds leads to activation of apc, facilitating the induction of protective immunity. this phenomenon is the basis of most adjuvant formulations currently in development. here, we tested the ability of tlr2, 3, 4, 5, 7 and 9 signaling to enhance ctl responses upon vaccination with virus-like particles. stimulation of tlr2 and 4 failed to increase ctl responses, whereas ligands for tlr3, 5 and 7 exhibited moderate adjuvant function. ... | 2003 | 12778463 |
| infection of dendritic cells by lymphocytic choriomeningitis virus. | dendritic cells (dcs) comprise the major antigen-presenting cells (apcs) of the host, uniquely programmed to stimulate immunologically naïve t lymphocytes. viruses that can target and disorder the function of these cells enjoy a selective advantage. the cellular receptor for lymphocytic choriomeningitis virus (lcmv), lassa fever virus (lfv), and several other arenaviruses is alpha-dystroglycan (alpha-dg). among cells of the immune system, cd11c+ and dec-205+ dcs primarily and preferentially expr ... | 2003 | 12797446 |
| the virus-encoded chemokine vmip-ii inhibits virus-induced tc1-driven inflammation. | the human herpesvirus 8-encoded protein vmip-ii is a potent in vitro antagonist of many chemokine receptors believed to be associated with attraction of t cells with a type 1 cytokine profile. for the present report we have studied the in vivo potential of this viral chemokine antagonist to inhibit virus-induced t-cell-mediated inflammation. this was done by use of the well-established model system murine lymphocytic choriomeningitis virus infection. mice were infected in the footpad, and the in ... | 2003 | 12805438 |
| recombinant lymphocytic choriomeningitis virus expressing vesicular stomatitis virus glycoprotein. | a recombinant s segment rna (sr) of the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) where the glycoprotein of vesicular stomatitis virus (vsvg) was substituted for the glycoprotein of lcmv (lcmv-gp) was produced intracellularly from cdna under the control of a polymerase i promoter. coexpression of the lcmv proteins np and l allowed expression of vsvg from sr. infection of transfected cells with wt lcmv (lcmvwt) resulted in reassortment of the l segment of lcmvwt with the sr ... | 2003 | 12808132 |
| "bystander" recruitment of systemic memory t cells delays the immune response to respiratory virus infection. | the concept of heterologous t cell immunity postulates that nonspecific memory t cells recruited and reactivated in the context of an unrelated virus infection may contribute to protective antiviral immunity. pulmonary infection with respiratory syncytial virus (rsv) of mice immune to lymphocytic choriomeningitis virus (lcmv) leads to substantial recruitment of systemic lcmv-specific memory cd8 t cells to the lung. using a sensitive tcr-transgenic model, we show that such "bystander" recruitment ... | 2003 | 12811844 |
| cutting edge: rapid in vivo killing by memory cd8 t cells. | in this study, we examined the cytotoxic activity of effector and memory cd8 t cells in vivo. at the peak of the ctl response following an acute lymphocytic choriomeningitis virus infection, effector cd8 t cells exhibited extremely rapid killing and started to eliminate adoptively transferred target cells within 15 min by a perforin-dependent mechanism. although resting memory cd8 t cells are poorly cytolytic by in vitro (51)cr release assays, there was rapid elimination (within 1-4 h) of target ... | 2003 | 12816979 |
| viral infection switches non-plasmacytoid dendritic cells into high interferon producers. | type i interferons (ifn-i) are important cytokines linking innate and adaptive immunity. plasmacytoid dendritic cells make high levels of ifn-i in response to viral infection and are thought to be the major source of the cytokines in vivo. here, we show that conventional non-plasmacytoid dendritic cells taken from mice infected with a dendritic-cell-tropic strain of lymphocytic choriomeningitis virus make similarly high levels of ifn-i on subsequent culture. similarly, non-plasmacytoid dendritic ... | 2003 | 12819664 |
| involvement of mkk6 in tcralphabeta(int)cd69lo: a target population for apoptotic cell death in thymocytes. | by analyzing real-time caspase activity and dna fragmentation in live thymocytes, we found that apoptosis occurs predominantly in a tcralphabeta(int)/hicd69lo population. the number of caspase-active cells and dna-fragmented cells in mkk6-deficient mice, which were originally generated in our laboratory by gene targeting, was decreased in the tcralphabeta(int)cd69lo population but not in the tcralphabetahicd69lo population. the percentage of caspase-active cells in the h-y-specific tcrint popula ... | 2003 | 12824301 |
| attrition of virus-specific memory cd8+ t cells during reconstitution of lymphopenic environments. | viruses can cause a severe lymphopenia early in infection and a subsequent, lasting loss of pre-existing cd8(+) memory t cells. we therefore questioned how well virus ag-specific memory cd8(+) t cells could reconstitute mice rendered lymphopenic as a consequence of genetics, irradiation, or viral or poly(i:c)-induced cytokines. in each case, reconstitution of the cd8(+) compartment was associated with limited division of virus-specific memory t cells and a reduction in their proportion. this ind ... | 2003 | 12847230 |
| innate immunity together with duration of antigen persistence regulate effector t cell induction. | proliferation of t cells is important for the expansion of specific t cell clones during immune responses. in addition, for the establishment of protective immunity against viruses, bacteria, and tumors, the expanded t cells must differentiate into effector t cells. here we show that effector t cell generation is driven by activation of apcs and duration of antigenic stimulation. adoptively transferred tcr-transgenic t cells extensively proliferated upon immunization. however, these t cells fail ... | 2003 | 12847247 |
| absence of preproenkephalin increases the threshold for t cell activation. | certain forms of the neuroendocrine hormone preproenkephalin (ppnk) are produced by t cells, b cells and macrophages. this hormone has been shown to be important in regulating a variety of immune responses; however, the basic mechanisms of this regulation are unknown. here we examine the ability of cd8 and cd4 ppnk-deficient t lymphocytes to proliferate to antigenic and mitogenic stimuli. we found that lymphocyte activation and proliferation to suboptimal concentrations of both anti-cd3 and anti ... | 2003 | 12864972 |
| viral meningitis and encephalitis: traditional and emerging viral agents. | in the united states, the annual number of central nervous system (cns) infections that occur as a result of viral agents far exceeds that of infections caused by bacteria, yeast, molds, and protozoa combined. the recent incursion of west nile virus (wnv) into north america has led to a dramatic change in the incidence and epidemiology of summer-associated viral cns disease. as a result of increased testing for wnv, lesser known viral causes of cns infection have been identified. even the epidem ... | 2003 | 12881794 |
| diabetogenic potential of human pathogens uncovered in experimentally permissive beta-cells. | pancreatic beta-cell antiviral defense plays a critical role in protection from coxsackievirus b4 (cvb4)-induced diabetes. in the present study, we tested the hypothesis that interferon (ifn)-induced antiviral defense determines beta-cell survival after infection by the human pathogen cvb3, cytomegalovirus (cmv), and lymphocytic choriomeningitis virus (lcmv). we demonstrated that mice harboring beta-cells that do not respond to ifn because of the expression of the suppressor of cytokine signalin ... | 2003 | 12882919 |
| enhanced t cell responses due to diacylglycerol kinase zeta deficiency. | much is known about how t cell receptor (tcr) engagement leads to t cell activation; however, the mechanisms terminating tcr signaling remain less clear. diacylglycerol, generated after tcr ligation, is essential in t cells. its function must be controlled tightly to maintain normal t cell homeostasis. previous studies have shown that diacylglycerol kinase zeta (dgkzeta), which converts diacylglycerol to phosphatidic acid, can inhibit tcr signaling. here we show that dgkzeta-deficient t cells ar ... | 2003 | 12883552 |
| incomplete effector/memory differentiation of antigen-primed cd8+ t cells in gene gun dna-vaccinated mice. | dna vaccination is an efficient way to induce cd8+ t cell memory, but it is still unclear to what extent such memory responses afford protection in vivo. to study this, we induced cd8+ memory responses directed towards defined viral epitopes, using dna vaccines encoding immunodominant mhc class i-restricted epitopes of lymphocytic choriomeningitis virus covalently linked to beta2-microglobulin. this vaccine construct primed for a stronger recall response than did a more conventional minigene con ... | 2003 | 12884860 |
| protection against ctl escape and clinical disease in a murine model of virus persistence. | ctl escape mutations have been identified in several chronic infections, including mice infected with mouse hepatitis virus strain jhm. one outstanding question in understanding ctl escape is whether a cd8 t cell response to two or more immunodominant ctl epitopes would prevent ctl escape. although ctl escape at multiple epitopes seems intuitively unlikely, ctl escape at multiple cd8 t cell epitopes has been documented in some chronically infected individual animals. to resolve this apparent con ... | 2003 | 12902505 |
| long-lived signal peptide of lymphocytic choriomeningitis virus glycoprotein pgp-c. | signal peptides (sps) direct nascent secretory and membrane proteins to the membrane of the endoplasmic reticulum. they are usually cleaved from the nascent polypeptide by signal peptidase and then further proteolytically processed. the sp of the pre-glycoprotein (pgp-c) of the lymphocytic choriomeningitis virus spgp-c (signal peptide of pgp-c) shows different properties: 1) the spgp-c is unusually long (58 amino acid residues) and contains two hydrophobic segments interrupted by a lysine residu ... | 2003 | 12917426 |
| the b7 family member b7-h3 preferentially down-regulates t helper type 1-mediated immune responses. | we investigated the in vivo function of the b7 family member b7-h3 (also known as b7rp-2) by gene targeting. b7-h3 inhibited t cell proliferation mediated by antibody to t cell receptor or allogeneic antigen-presenting cells. b7-h3-deficient mice developed more severe airway inflammation than did wild-type mice in conditions in which t helper cells differentiated toward type 1 (t(h)1) rather than type 2 (t(h)2). b7-h3 expression was consistently enhanced by interferon-gamma but suppressed by int ... | 2003 | 12925852 |
| cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific ctl to the brain. | the number and localization of effector cells to the tumor site are crucial elements for immune rejection of solid tumors. however, for cerebral malignancies, antitumor responses need to be finely tuned to avoid neuropathologic consequences. in this study, we determine factors that regulate ctl localization and tumoricidal function after intracerebral implantation of tumors expressing model ag. h-2(bxd) mice implanted with a cw3(+) murine glioma lacking h-2k(d) molecules necessary to present the ... | 2003 | 12928361 |
| a transgenic mouse model genetically tags all activated cd8 t cells. | identifying and characterizing ag-specific cd8+ t cells are central to the study of immunological memory. although powerful strategies such as mhc tetramers and peptide-induced cytokine production assays exist for identifying ag-specific cd8+ t cells, alternate strategies that are not dependent upon a priori knowledge of the immunodominant and subdominant antigenic epitopes, as well as the mhc background of the animal are of obvious utility. in this study, we present a transgenic mouse model tha ... | 2003 | 12928386 |
| tcr binding kinetics measured with mhc class i tetramers reveal a positive selecting peptide with relatively high affinity for tcr. | the interaction between tcr and peptide-mhc (pmhc) complexes is crucial for the activation of t cells as well as for positive and negative selection in the thymus. the kinetics and affinity of this interaction and the densities of tcr and pmhc complexes on the cell surface are determining factors for different outcomes during thymic selection. in general, it is thought that agonist pmhc, which cause negative selection, have higher affinities and, in particular, slower off-rates than partial or w ... | 2003 | 12928390 |
| the bcl-2 family pro-apoptotic molecule, bnip3 regulates activation-induced cell death of effector cytotoxic t lymphocytes. | bnip3 is a recently described pro-apoptotic member of the bcl-2 family and in bnip3 cdna-transfected cell lines, cell death occurs via a caspase-independent pathway with opening of the mitochondrial permeability transition (pt) pore and rapid loss of mitochondrial transmembrane potential (delta psi m). however, its expression or function in physiologic cell types is not known. our results using the t-cell receptor transgenic mice p14, specific for lymphocyte choreomeningitis virus (lcmv) glycopr ... | 2003 | 12941136 |
| expression and functional importance of collagen-binding integrins, alpha 1 beta 1 and alpha 2 beta 1, on virus-activated t cells. | adhesive interactions are crucial to cell migration into inflammatory sites. using murine lymphocytic choriomeningitis virus as an ag model system, we have investigated expression and function of collagen-binding integrins, alpha(1)beta(1) and alpha(2)beta(1), on activated and memory t cells. using this system and mhc tetramers to define ag-specific t cells, we demonstrate that contrary to being vlas, expression of alpha(1)beta(1) and alpha(2)beta(1) can be rapidly induced on acutely activated t ... | 2003 | 12960301 |
| measles virus infection induces chemokine synthesis by neurons. | the role that neurons play in the induction of the immune response following cns viral infection is poorly understood, largely owing to the belief that these cells are immunologically quiescent. in this report, we show that virus infection of neurons results in the synthesis of proinflammatory chemokines, which are early and important mediators of leukocyte recruitment to sites of viral infection. for these studies, a transgenic mouse model of neuron-restricted measles virus (mv) infection was u ... | 2003 | 12960336 |
| lassa virus z protein is a matrix protein and sufficient for the release of virus-like particles [corrected]. | lassa virus is an enveloped virus with glycoprotein spikes on its surface. it contains an rna ambisense genome that encodes the glycoprotein precursor gp-c, the nucleoprotein np, the polymerase l, and the z protein. here we demonstrate that the lassa virus z protein (i). is abundant in viral particles, (ii). is strongly membrane associated, (iii). is sufficient in the absence of all other viral proteins to release enveloped particles, and (iv). contains two late domains, ptap and ppxy, necessary ... | 2003 | 12970458 |
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