Publications

a lymphocytic choriomeningitis virus glycoprotein variant that is retained in the endoplasmic reticulum efficiently cross-primes cd8(+) t cell responses.	recent studies indicate that t cell cross-priming preferentially occurs against long-lived, stable proteins. we have studied cross-priming by using the glycoprotein (gp) of lymphocytic choriomeningitis virus (lcmv), a protein that normally is not mhc class i cross-presented. this study shows that a c-terminally truncated, noncleavable variant of lcmv-gp led to the accumulation of stable, soluble gp trimers in the endoplasmic reticulum (er) of the antigen donor cell, and thereby converted lcmv-gp ...	2007	17686978
lymphocytic choriomeningitis virus infection of the developing brain: critical role of host age.	lymphocytic choriomeningitis virus (lcmv) is a common human pathogen that causes substantial injury to the developing brain when the infection occurs during pregnancy. however, among children with congenital lcmv infection, there is considerable variability in the site, nature, and severity of neuropathology and in the clinical outcome. we hypothesize that the variability in neuropathology and outcome is due to differences in the gestational timing of lcmv infection.	2007	17696127
early antibodies specific for the neutralizing epitope on the receptor binding subunit of the lymphocytic choriomeningitis virus glycoprotein fail to neutralize the virus.	lymphocytic choriomeningitis virus (lcmv) is a murine arenavirus whose glycoprotein consists of a transmembrane subunit (gp-2) and a receptor-binding subunit (gp-1). lcmv-neutralizing antibodies (nabs) are directed against a single site on gp-1 and occur 1 month after the infection of cytotoxic-t-lymphocyte (ctl) deficient mice. in wild-type mice, however, ctls control early infection, and weak nab titers emerge very late (after 70 to 150 days) if at all. production of recombinant gp-1 in native ...	2007	17699567
a role for tnf in limiting the duration of ctl effector phase and magnitude of cd8 t cell memory.	it is known that tnf-alpha (tnf) exerts distinct tissue-protective or -destructive effects in the pathogenesis of t cell-dependent immunopathology, depending on the context and amount of cytokine produced. to better understand the cellular mechanisms underlying the regulation of t cells by tnf, we have analyzed the role of tnf in regulating various facets of the antigen-specific cd8 t cell response to lymphocytic choriomeningitis virus (lcmv) in mice. we show that expansion and differentiation o ...	2007	17704295
dynamics of cd8+ t cell responses during acute and chronic lymphocytic choriomeningitis virus infection.	infection of mice with lymphocytic choriomeningitis virus (lcmv) is frequently used to study the underlying principles of viral infections and immune responses. we fit a mathematical model to recently published data characterizing ag-specific cd8+ t cell responses during acute (armstrong) and chronic (clone 13) lcmv infection. this allows us to analyze the differences in the dynamics of cd8+ t cell responses against different types of lcmv infections. for the four cd8+ t cell responses studied, ...	2007	17709509
cd8+ t cell activation is governed by tcr-peptide/mhc affinity, not dissociation rate.	binding of peptide/mhc (pmhc) complexes by tcr initiates t cell activation. despite long interest, the exact relationship between the biochemistry of tcr/pmhc interaction (particularly tcr affinity or ligand off-rate) and t cell responses remains unresolved, because the number of complexes examined in each independent system has been too small to draw a definitive conclusion. to test the current models of t cell activation, we have analyzed the interactions between the mouse p14 tcr and a set of ...	2007	17709510
complement-dependent enhancement of cd8+ t cell immunity to lymphocytic choriomeningitis virus infection in decay-accelerating factor-deficient mice.	decay-accelerating factor (daf, cd55) is a gpi-anchored membrane protein that regulates complement activation on autologous cells. in addition to protecting host tissues from complement attack, daf has been shown to inhibit cd4+ t cell immunity in the setting of model ag immunization. however, whether daf regulates natural t cell immune response during pathogenic infection is not known. we describe in this study a striking regulatory effect of daf on the cd8+ t cell response to lymphocytic chori ...	2007	17709533
cross-priming of a single viral protein from lymphocytic choriomeningitis virus alters immunodominance hierarchies of cd8+ t cells during subsequent viral infections.	immunogenic epitopes that stimulate cd8+ t cells can be organized into an immunodominance hierarchy, based on their ability to induce t-cell priming and subsequent expansion. cytotoxic cd8+ t cells can be primed through the cross-priming pathway, where exogenous viral proteins are acquired by professional antigen-presenting cells (papcs). we have previously reported that lymphocytic choriomeningitis nucleoprotein (lcmv-np) expressed in hek cells (hek-np) induces cross-priming of cd8+ t cells in ...	2007	18158732
phenotypic and functional analysis of lcmv gp33-41-specific cd8 t cells elicited by multiple peptide immunization in mice revealed the up-regulation of pd-1 expression on antigen-specific cd8 t cells.	the phenotype and function of antigen-specific cd8 t cells are closely associated with the efficacy of a therapeutic vaccination. here we showed that multiple immunizations with lcmv gp33-41 peptide (kav) in freund's adjuvant could induce kav-specific cd8 t cells with low expression of cd127 and cd62l molecules. the inhibitory receptor pd-1 was also expressed on a substantial part of kav-specific cd8 t cells, and its expression level on kav-specific cd8 t cells in spleen and lymph nodes was much ...	2007	18163954
dual role of cxcl10 as conductor of cellular trafficking during type 1 diabetes.	one possible way of how autoimmune disease can be initiated is by infection with a foreign pathogen. especially viruses are thought to act as triggering factors, inducing a detrimental attack against 'self' by the immune system of a susceptible host because of two major reasons. first, viruses cause a massive inflammation of the infected tissue and therefore initiate the infiltration of a broad variety of leukocytes, including potentially 'self'-reactive lymphocytes. second, some viruses have be ...	2007	23675028
critical role for dna vaccination frequency in induction of antigen-specific cytotoxic responses.	since antigen-persistence plays a role for induction of immunity, we investigated the in vivo pharmacokinetic of a naked dna vaccine at the site of its action, i.e., in the lymph node. after direct intralymphatic injection, naked dna vaccine degraded within a few hours. in correlation with the short persistence of the dna vaccine we found that the frequency of vaccination critically influenced the strength of the immune response. in mice vaccinated every 3 days, cytotoxic t-cell responses were e ...	2006	16225968
viral persistence: parameters, mechanisms and future predictions.	for a virus to persist, it must actively curtail the host's antiviral immune response. here, we review the conceptual basis by which this can occur and discuss the subsequent fate of differentiated cells infected over long periods of time. we also consider how the compromised antiviral immune response can be revigorated or replaced with a potent response that purges the virus and thereby terminates persistent infection.	2006	16364742
ly9 (cd229)-deficient mice exhibit t cell defects yet do not share several phenotypic characteristics associated with slam- and sap-deficient mice.	signaling lymphocyte activation molecule (slam) family receptors are critically involved in modulating innate and adaptive immune responses. several slam family receptors have been shown to interact with the adaptor molecule sap; however, subsequent intracellular signaling is poorly defined. notably, mutations in slam-associated protein (sap) lead to x-linked lymphoproliferative disease, a rare but fatal immunodeficiency. although the slam family member ly9 (cd229) is known to interact with sap, ...	2006	16365421
hantavirus and arenavirus antibody prevalence in rodents and humans in trentino, northern italy.	the spatial and temporal distribution of hantavirus and arenavirus antibody-positive wild rodents in trentino, italy, was studied using immunofluorescence assays (ifa) in two long-term sites trapped in 2000-2003, and six other sites trapped in 2002. the overall hantavirus seroprevalence in the bank voles, clethrionomys glareolus (n=229) screened for puumala virus (puuv) antibodies was 0.4%, and that for apodemus flavicollis mice (n=1416) screened for dobrava virus (dobv) antibodies was 0.2%. ant ...	2006	16371172
augmenting the immunogenicity of dna vaccines: role of plasmid-encoded flt-3 ligand, as a molecular adjuvant in genetic vaccination.	in this study, we have taken advantage of the unique property of a potent dendritic cell (dc) growth factor, flt-3 ligand (fl), which could act as a vaccine adjuvant. accordingly, a single injection of plasmid dna coding for soluble fl (flex) was shown to induce large numbers of dcs in various tissue compartments and was critical for generating high frequencies of antigen-specific (hiv gp120 and lcmv np) immune responses in mice. interestingly, this enhanced level of immune response is strictly ...	2006	16563456
adventitious agent test methods.		2006	16566441
arenavirus diversity and evolution: quasispecies in vivo.	arenaviruses exist as viral quasispecies due to the high mutation rates of the low-fidelity viral rna-dependent rna polymerase (rdrp). this genomic heterogeneity is advantageous to the population, allowing for adaptation to rapidly changing environments that present varying types and degrees of selective pressure. the significant variation in biological properties observed among lymphocytic choriomeningitis virus (lcmv) strains, the prototypic arenavirus, indicates to what extent a quasis-pecies ...	2006	16568904
cdc on the offensive to stamp out rodent virus.		2006	16579771
cd8 t cells specific for lymphocytic choriomeningitis virus require type i ifn receptor for clonal expansion.	the role of type i ifn signaling in cd8 t cells was analyzed in an adoptive transfer model using p14 tcr transgenic cd8 t cells specific for lymphocytic choriomeningitis virus (lcmv) but deficient in type i ifnr. in the present study, we demonstrate severe impairment in the capacity of p14 t cells lacking type i ifnr to expand in normal type i ifnr wild-type c57bl/6 hosts after lcmv infection. in contrast, following infection of recipient mice with recombinant vaccinia virus expressing lcmv glyc ...	2006	16585541
dna methylation by dna methyltransferase 1 is critical for effector cd8 t cell expansion.	transcriptional silencing mediated by dna methylation is a critical component of epigenetic regulation during early embryonic development in animals. however, the requirement for dna methylation during activation and differentiation of mature cd8+ t cells into effector and memory cells is not clear. using cre-mediated deletion of dna methyltransferase 1 (dnmt1) at the time of cd8+ t cell activation, we investigated the obligation for maintaining patterns of dna methylation during the generation ...	2006	16585546
lymphocytic choriomeningitis virus mx strain does not induce the expression of tumor-associated carbonic anhydrase ix in persistently infected hela cells.	summary. - lymphocytic choriomeningitis virus (lcmv) is an arenavirus that readily causes persistent infections, in which it does not interfere with vital functions of the cells, but can affect expression of "luxurious" genes. mx strain of lcmv (mx lcmv) has been identified as an agent transmissible by cell-to-cell contact in the human carcinoma matu cells grown in a mixed culture with hela cells. when compared to uninfected hela, the matu-mx-infected hela cells, to which the virus was transmitt ...	2006	16599186
activation of tyk2 and stat3 is required for the apoptotic actions of interferon-beta in primary pro-b cells.	the growth-inhibitory effects of type 1 interferons (ifns) (ifnalpha/beta) are complex, and the role of apoptosis in their antigrowth effects is variable and not well understood. we have examined primary murine interleukin-7-dependent bone marrow-derived pro-b cells, where ifnbeta, but not ifnalpha, induces programmed cell death (pcd). ifnbeta-stimulated apoptosis is the same in pro-b cells derived from wild type and stat1(-/-) mice. however, in pro-b cells from tyk2(-/-) mice, where there is no ...	2006	16601124
arenavirus z protein as an antiviral target: virus inactivation and protein oligomerization by zinc finger-reactive compounds.	several disulfide-based and azoic compounds have shown antiviral and virucidal properties against arenaviruses in virus yield-inhibition and inactivation assays, respectively. the most effective virucidal agent, the aromatic disulfide nsc20625, was able to inactivate two strains of the prototype arenavirus species lymphocytic choriomeningitis virus (lcmv). inactivated viral particles retained the biological functions of the virion envelope glycoproteins in virus binding and uptake, but were unab ...	2006	16603524
"viral déjà vu" elicits organ-specific immune disease independent of reactivity to self.	autoimmune diseases are often precipitated by viral infections. yet our current understanding fails to explain how viruses trigger organ-specific autoimmunity despite thymic tolerance extending to many non-lymphohematopoietic self antigens. additionally, a key epidemiological finding needs to be explained: in genetically susceptible individuals, early childhood infections seem to predispose them to multiple sclerosis (ms) or type 1 diabetes years or even decades before clinical onset. in the pre ...	2006	16604192
lambda interferon (ifn-lambda), a type iii ifn, is induced by viruses and ifns and displays potent antiviral activity against select virus infections in vivo.	type iii interferons (ifns) (interleukin-28/29 or lambda interferon [ifn-lambda]) are cytokines with ifn-like activities. here we show that several classes of viruses induce expression of ifn-lambda1 and -lambda2/3 in similar patterns. the ifn-lambdas were-unlike alpha/beta interferon (ifn-alpha/beta)-induced directly by stimulation with ifn-alpha or -lambda, thus identifying type iii ifns as ifn-stimulated genes. in vitro assays revealed that ifn-lambdas have appreciable antiviral activity agai ...	2006	16611910
narrowed tcr repertoire and viral escape as a consequence of heterologous immunity.	why some virus-specific cd8 tcr repertoires are diverse and others restricted or "oligoclonal" has been unknown. we show here that oligoclonality and extreme clonal dominance can be a consequence of t cell cross-reactivity. lymphocytic choriomeningitis virus (lcmv) and pichinde virus (pv) encode np(205-212) epitopes that induce different but highly cross-reactive diverse tcr repertoires. homologous viral challenge of immune mice only slightly skewed the repertoire and enriched for predictable tc ...	2006	16614754
survey of lymphocytic choriomeningitis virus diagnosis and testing--connecticut, 2005.	lymphocytic choriomeningitis virus (lcmv) is a rodent borne virus that can be transmitted to humans through exposure to rodent urine, feces, saliva, or blood. lcmv infection is often asymptomatic or mild but can cause aseptic meningitis, encephalitis, life-threatening infections in immunosuppressed persons, and severe congenital defects . in may 2005, lcmv was implicated in the deaths of three organ transplant recipients who had received organs from a common donor who had likely been infected fr ...	2006	16617288
serine protease inhibitor 6 protects cytotoxic t cells from self-inflicted injury by ensuring the integrity of cytotoxic granules.	how cytotoxic t lymphocytes (ctls) kill intracellular pathogens without killing themselves has been a recurring question ever since their discovery. by using mice deficient in serine protease inhibitor 6 (spi6), we show that by inhibiting granzyme b (grb), spi6 protects ctls from self-inflicted injury. infection with either lymphocytic choriomeningitis virus (lcmv) or listeria monocytogenes (lm) revealed increased apoptosis and diminished survival of spi6 knockout (ko) ctls, which was cell auton ...	2006	16618603
role of very late antigen-1 in t-cell-mediated immunity to systemic viral infection.	the t-cell response to lymphocytic choriomeningitis virus was studied in mice lacking very late antigen-1 (vla-1). the generation of virus-specific effector t cells was unimpaired in vla-1(-/-) mice. in the memory phase, vla-1 deficiency did not influence the number of memory cd8(+) t cells or their distribution between lymphoid and nonlymphoid organs. regarding a functional role of vla-1, we found that intracerebral infection of both vla-1(-/-) and wild-type (wt) mice resulted in lethal t-cell- ...	2006	16623929
reviving exhausted t lymphocytes during chronic virus infection by b7-h1 blockade.	cytotoxic t lymphocytes (ctls) are killer cells that are crucial in the control of viral pathogens and cancers. they can become exhausted during chronic viral infection, a phenomenon that consists of a reduction in both number and functionality of ctls. recently, barber and colleagues demonstrated that b7-h1 (also called pd-l1), a cell-surface molecule that is widely distributed in tissues, was necessary for the maintenance of t-cell exhaustion in a chronic-infection mouse model of lymphocytic c ...	2006	16650803
lymphocytic choriomeningitis in michigan.	we summarize the first reported case of acquired lymphocytic choriomeningitis virus (lcmv) infection in michigan to be investigated by public health authorities and provide evidence of the focal nature of lcmv infection in domestic rodents. results of serologic and virologic testing in rodents contrasted, and negative serologic test results should be confirmed by tissue testing.	2006	16704853
an altered t cell repertoire in mecl-1-deficient mice.	immunoproteasome subunits low-molecular mass polypeptide (lmp)2 and lmp7 affect ag presentation by mhc class i molecules. in the present study, we investigated the function of the third immunosubunit lmp10/multicatalytic endopeptidase complex-like (mecl)-1 (beta2i) in mecl-1 gene-targeted mice. the number of cd8+ splenocytes in mecl-1-/- mice was 20% lower than in wild-type mice. infection with lymphocytic choriomeningitis virus (lcmv) elicited a markedly reduced cytotoxic t cell (ctl) response ...	2006	16709825
lymphocytic choriomeningitis virus--an old enemy up to new tricks.		2006	16723613
transmission of lymphocytic choriomeningitis virus by organ transplantation.	in december 2003 and april 2005, signs and symptoms suggestive of infection developed in two groups of recipients of solid-organ transplants. each cluster was investigated because diagnostic evaluations were unrevealing, and in each a common donor was recognized.	2006	16723615
lymphocytic choriomeningitis virus: an emerging obstetric pathogen?	a report in may 2005 from the centers for disease control and prevention describing a cluster of lymphocytic choriomeningitis virus (lcmv) infections among 4 solid organ recipients has increased awareness of and clinical interest in this pathogen. human infection with lcmv results from direct or indirect contact with rodents. lcmv has particular relevance to obstetrics, as it is likely an under-recognized abortifacient and fetal teratogen. there have been 54 cases of congenital lcmv reported sin ...	2006	16731068
identification of an n-terminal trimeric coiled-coil core within arenavirus glycoprotein 2 permits assignment to class i viral fusion proteins.	the lymphocytic choriomeningitis virus (lcmv) glycoprotein (gp) consists of the transmembrane subunit gp-2 and the receptor binding subunit gp-1. both are synthesized as one precursor protein and stay noncovalently attached after cleavage. in this study, we determined the oligomeric state of the lcmv gp and expressed it in two different conformations suitable for structural analysis. sequence analysis of gp-2 identified a trimeric heptad repeat pattern containing an n-terminal alpha-helix. an al ...	2006	16731928
congenital lymphocytic choriomeningitis virus: an underdiagnosed cause of neonatal hydrocephalus.	we report a case of congenital hydrocephalus caused by lymphocytic choriomeningitis virus with severe neurologic sequelae, including hydrocephalus, chorioretinitis, blindness and developmental delay. this is the first report of lymphocytic choriomeningitis virus isolation in the cerebrospinal fluid of a congenitally infected infant.	2006	16732159
strong tcr signaling, tlr ligands, and cytokine redundancies ensure robust development of type 1 effector t cells.	t cell effector function is a central mechanism of adaptive immunity, and accordingly, protection of the host against pathogens. one of the primary effector molecules produced by t cells in response to such pathogens is the cytokine, ifn-gamma. although the signaling pathways associated with the production of ifn-gamma are well established, disparate in vivo and in vitro results indicate that distinct pathways may become more prominent dependent upon the nature of the infection, inflammatory mil ...	2006	16751361
envelope exchange for the generation of live-attenuated arenavirus vaccines.	arenaviruses such as lassa fever virus cause significant mortality in endemic areas and represent potential bioterrorist weapons. the occurrence of arenaviral hemorrhagic fevers is largely confined to third world countries with a limited medical infrastructure, and therefore live-attenuated vaccines have long been sought as a method of choice for prevention. yet their rational design and engineering have been thwarted by technical limitations. in addition, viral genes had not been identified tha ...	2006	16751848
bim mediates apoptosis of cd127(lo) effector t cells and limits t cell memory.	following an acute t cell response, most activated effector cells die, while some survive and become memory cells. the pro-apoptotic bcl-2 family member, bcl-2 interacting mediator of death (bim) is critical for eliminating most effector t cells, while expression of cd127 (il-7ralpha) has been proposed to mark effector cells destined to become memory cells. here, we examined the effects of bim on the death of effector t cells in relationship to cd127 expression and on development of t cell memor ...	2006	16761315
simultaneous assessment of antigen-stimulated cytokine production and memory subset composition of memory cd8 t cells.	the functional identification of antigen-specific cd8 t cell populations is critical to understanding host responses to infection by intracellular pathogens. furthermore, assessing the properties of protective memory cd8 t cell populations generated by immunization is necessary in the rational design of vaccines. recently, a classification scheme was proposed in which memory cd8 t cells were divided into one of two distinct subsets, based on cd62l expression, that have different functional prope ...	2006	16762359
hypogammaglobulinemia and exacerbated cd8 t-cell-mediated immunopathology in sap-deficient mice with chronic lcmv infection mimics human xlp disease.	the human genetic disease x-linked lymphoproliferative disease (xlp), which is caused by mutations in sh2d1a/sap that encode slam-associated protein (sap), is characterized by an inability to control epstein-barr virus (ebv) and hypogammaglobulinemia. it is unclear which aspects of xlp disease are specific to herpesvirus infection and which reflect general immunologic functions performed by sap. we examined sap- mice during a chronic lcmv infection, specifically to address the following question ...	2006	16788096
receptor use by pathogenic arenaviruses.	the arenavirus family contains several important human pathogens including lassa fever virus (lasv), lymphocytic choriomeningitis virus (lcmv) and the new world clade b viruses junin (junv) and machupo (macv). previously, alpha-dystroglycan (alpha-dg) was identified as a receptor recognized by lasv and certain strains of lcmv. however, other studies have suggested that alpha-dg is probably not used by the clade b viruses, and the receptor(s) for these pathogens is currently unknown. using pseudo ...	2006	16797051
a role for the transcription factor relb in ifn-alpha production and in ifn-alpha-stimulated cross-priming.	chimeric mice generated with bone marrow from relb-deficient (-/-), relb-heterozygous (+/-) and wild-type (+/+) mice were used to determine how total or partial absence of the transcription factor relb in haematopoietic cells affects the immune response generated after lymphocytic choriomeningitis virus (lcmv) infection. in relb(-/-) chimeras, early virus replication was enhanced and lcmv clearance was impaired. although plasmacytoid dendritic cell numbers were similar, serum interferon (ifn)-al ...	2006	16810633
immune response to vaccination against argentine hemorrhagic fever in an area where different arenaviruses coexist.	neutralizing antibody (nt ab) titers to candid #1 (c#1) vaccine against argentine hemorrhagic fever were studied for 2 years post-vaccination in 330 volunteers, to assess whether the kinetics and/or magnitude of this immune response is modified by previous infection with the arena viruses junin (jun) and lymphocytic choriomeningitis (lcm). a total of 160 volunteers received c#1, distributed as follows: without detectable pre-infection with arenaviruses (n = 54); with pre-existing antibodies to j ...	2006	16817762
electron transport complex i is required for cd8+ t cell function.	after ag encounter, cd8+ t cells become activated and begin to proliferate. early during infection, when ag-specific effector cd8+ t cells are proliferating, producing cytokines, and lysing infected cells in vivo, their mitochondrial potential is increased. the purpose of the experiments presented here was to determine whether mitochondrial function was required for cd8+ t cell function. to block mitochondrial function, transgenic cd8+ t cells were incubated with increasing doses of rotenone, an ...	2006	16818739
trail deficiency delays, but does not prevent, erosion in the quality of "helpless" memory cd8 t cells.	in this study, we investigated the role of trail in ag-specific cd8 t cell homeostasis after viral infection. trail deficiency does not influence the kinetics of the ag-specific cd8 t cell responses, and cd8 t cells in trail-deficient mice were able to expand, contract, and generate functional memory cell numbers that were indistinguishable from trail-sufficient wild-type cd8 t cells after acute lymphocytic choriomeningitis virus infection. interestingly, the ability of "helpless" cd8 t cells to ...	2006	16818756
5,6-dimethylxanthenone-4-acetic acid treatment of a non-immunogenic tumour does not synergize with active or passive cd8+ t-cell immunotherapy.	the chemotherapeutic drug 5,6-dimethylxanthenone-4-acetic acid (dmxaa) inhibits intratumoural blood flow, causing hypoxia, haemorrhagic necrosis, vascular collapse and tumour cell death. production of tnf-alpha and ifn is also induced, causing local inflammation and activation of immune cells including cd8+ t cells. we used the tumour cell line ll-lcmv, which expresses the gp33 epitope of lymphocytic choriomeningitis virus in a non-immunogenic form, to investigate whether tumour cell death cause ...	2006	16834573
expression of ccl20 and granulocyte-macrophage colony-stimulating factor, but not flt3-l, from modified vaccinia virus ankara enhances antiviral cellular and humoral immune responses.	while modified vaccinia virus ankara (mva) is currently in clinical development as a safe vaccine against smallpox and heterologous infectious diseases, its immunogenicity is likely limited due to the inability of the virus to replicate productively in mammalian hosts. in light of recent data demonstrating that vaccinia viruses, including mva, preferentially infect antigen-presenting cells (apcs) that play crucial roles in generating antiviral immunity, we hypothesized that expression of specifi ...	2006	16840346
expression of lymphotoxin beta governs immunity at two distinct levels.	interaction of lymphotoxin alpha(1)beta(2) (ltalpha(1)beta(2)) with its receptor is key for the generation and maintenance of secondary lymphoid organ microstructure. we used mice conditionally deficient for ltbeta on different lymphocyte subsets to determine how the ltbeta-dependent lymphoid structure influences immune reactivity. all conditionally ltbeta-deficient mice mounted normal immune responses against vesicular stomatitis virus (vsv), and were protected against lymphocytic choriomeningi ...	2006	16841297
hereditary hydrocephalus in laboratory-reared golden hamsters (mesocricetus auratus).	a colony of golden hamsters had an ongoing problem with hydrocephalus. in an attempt to clear the colony of the problem, new breeders from another supplier had been purchased. at termination of a behavioral study, the brain was collected from 35 animals (four of which had died with hydrocephalus during the study) and was examined macroscopically and by light microscopy. although no animals manifested obvious behavioral changes, 31 of 35 (88.6%, 13/15 males and 18/20 females in control and manipu ...	2006	16846994
adoptive immunotherapy induces cns dendritic cell recruitment and antigen presentation during clearance of a persistent viral infection.	given the global impact of persistent infections on the human population, it is of the utmost importance to devise strategies to noncytopathically purge tissues of infectious agents. the central nervous system (cns) poses a unique challenge when considering such strategies, as it is an immunologically specialized compartment that contains a nonreplicative cell population. administration of exogenously derived pathogen-specific memory t cells (referred to as adoptive immunotherapy) to mice burden ...	2006	16847068
innate inflammatory signals induced by various pathogens differentially dictate the ifn-i dependence of cd8 t cells for clonal expansion and memory formation.	type-i ifns (ifn-i) provide direct survival signals to t cells during ag-driven proliferation. because ifn-i production differs depending on the pathogen, we assessed cd8 t cell requirement for direct ifn-i signals during responses to vaccinia virus (vv), vesicular stomatitis virus (vsv), lymphocytic choriomeningitis virus (lcmv), and listeria monocytogenes (lm) immunizations in vivo. ifn-i-receptor-deficient (ifn-ir(o)) cd8 t cells expanded 3- to 5-fold less and formed a diminished memory pool ...	2006	16849484
cd45 is required for type i ifn production by dendritic cells.	cd45 is a leukocyte tyrosine phosphatase, essential for normal immune responses. we have studied the function of splenic dendritic cells of cd45(+/+), cd45(-/-), cd45rabc and cd45ro transgenic mice. we show that there are increased numbers of plasmacytoid dendritic cells in cd45(-/-) mice. dc of all mice are capable of responding to lymphocytic choriomeningitis virus (lcmv) infection by up-regulation of mhc and costimulatory molecules. dc of cd45(-/-) mice have an impaired capacity to produce ty ...	2006	16856204
imatinib mesylate selectively impairs expansion of memory cytotoxic t cells without affecting the control of primary viral infections.	imatinib mesylate (imatinib) is a potent inhibitor of defined tyrosine kinases (tks) and is effective in the treatment of malignancies characterized by constitutive activation of these tks such as chronic myeloid leukemia and gastrointestinal stromal tumors. tks also play an important role in t-cell receptor (tcr) signal transduction. inhibitory as well as stimulating effects of imatinib on t cells and dendritic cells have been described. here, we analyzed the effects of imatinib treatment on an ...	2006	16873671
t cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity.	t cells causing autoimmunity must escape tolerance. we observed that cd8(+) t cells with high avidity for an antigen expressed in the pancreas, kidney, and thymic medulla were efficiently removed from a polyclonal repertoire by central and peripheral tolerance mechanisms. however, both mechanisms spared low-avidity t cells from elimination. neither the introduction of activated, self-antigen-specific cd4(+) helper t cells nor a global inflammatory stimulus were sufficient to activate the low-avi ...	2006	16879996
nonneutralizing antibodies binding to the surface glycoprotein of lymphocytic choriomeningitis virus reduce early virus spread.	the biological relevance of nonneutralizing antibodies elicited early after infection with noncytopathic persistence-prone viruses is unclear. we demonstrate that cytotoxic t lymphocyte-deficient tgh(kl25) mice, which are transgenic for the heavy chain of the lymphocytic choriomeningitis virus (lcmv)-neutralizing monoclonal antibody kl25, mount a focused neutralizing antibody response following lcmv infection, and that this results in the emergence of neutralization escape virus variants. furthe ...	2006	16880253
role of bim in regulating cd8+ t-cell responses during chronic viral infection.	apoptosis is critical for the development and maintenance of the immune system. the proapoptotic bcl-2 family member bim is important for normal immune system homeostasis. although previous experiments have shown that bim is critical for the apoptosis of antigen-specific cd8(+) t cells during acute viral infection, the role of bim during chronic viral infection is unclear. using lymphocytic choriomeningitis virus clone 13 infection of mice, we demonstrate a role for bim in cd8(+) t-cell apoptosi ...	2006	16912311
generation and characterization of b7-h4/b7s1/b7x-deficient mice.	members of the b7 family of cosignaling molecules regulate t-cell proliferation and effector functions by engaging cognate receptors on t cells. in vitro and in vivo blockade experiments indicated that b7-h4 (also known as b7s1 or b7x) inhibits proliferation, cytokine production, and cytotoxicity of t cells. b7-h4 binds to an unknown receptor(s) that is expressed on activated t cells. however, whether b7-h4 plays nonredundant immune regulatory roles in vivo has not been tested. we generated b7-h ...	2006	16914726
the evolving epidemiology of viral encephalitis.	the introduction of west nile virus to north america illustrates the potential emergence of novel encephalitic agents in unexpected settings. there has been continued recognition of emerging neurotropic viruses in both the developed and developing world and novel modes of transmission of these agents. this review describes recent developments in the epidemiology of west nile virus and several other emerging viral encephalitides in the developed and developing world and the emergence of novel mec ...	2006	16914972
upregulation of pd-1 expression on hiv-specific cd8+ t cells leads to reversible immune dysfunction.	the engagement of programmed death 1 (pd-1) to its ligands, pd-l1 and pd-l2, inhibits proliferation and cytokine production mediated by antibodies to cd3 (refs. 5,6,7). blocking the pd-1-pd-l1 pathway in mice chronically infected with lymphocytic choriomeningitis virus restores the capacity of exhausted cd8(+) t cells to undergo proliferation, cytokine production and cytotoxic activity and, consequently, results in reduced viral load. during chronic hiv infection, hiv-specific cd8(+) t cells are ...	2006	16917489
type 1 ifn deficiency in the absence of normal splenic architecture during lymphocytic choriomeningitis virus infection.	the innate immune system uses different mechanisms to respond to infectious pathogens. experiments evaluating the requirements for a type 1 ifn (ifn-alphabeta) response to lymphocytic choriomeningitis virus (lcmv) resulted in the surprising discovery that mice deficient in b and t cell development, i.e., rag-deficient and scid, had profoundly reduced levels of ifn-alphabeta in serum and spleen, despite high viral replication. in addition to lacking an adaptive immune system, these strains exhibi ...	2006	16920967
dendritic cell inhibition: memoirs from immunosuppressive viruses.		2006	16921469
elimination of chronic viral infection by blocking cd27 signaling.	neutralizing antibody (nab) responses to lymphocytic choriomeningitis virus (lcmv) in mice and immunodeficiency virus and hepatitis c virus in humans are usually weak and slow to develop. this may be the result of structural properties of the surface glycoprotein, a low frequency of b cells with neutralizing specificity, and the necessity of prolonged affinity maturation of specific nabs. in this study, we show that during lcmv infection, cd27 signaling on cd4+ t cells enhances the secretion of ...	2006	16923852
direct stimulation of t lymphocytes by immunosomes: virus-like particles decorated with t cell receptor/cd3 ligands plus costimulatory molecules.	many infectious viruses coevolved with the vertebrate immune system. during the assembly of enveloped viruses, lipid ordered domains of the host cell plasma membrane, called lipid rafts, frequently function as a natural meeting point for viral proteins. the role of lipid rafts in the organization of complex combinations of immune receptors during antigen presentation and t cell signaling is widely recognized. in our studies, we determined whether lipid rafts, virus budding, and molecular interac ...	2006	16924110
altered central nervous system gene expression caused by congenitally acquired persistent infection with lymphocytic choriomeningitis virus.	neonatal infection of most mouse strains with lymphocytic choriomeningitis virus (lcmv) leads to a life-long persistent infection characterized by high virus loads in the central nervous system (cns) in the absence of inflammation and tissue destruction. these mice, however, exhibit impaired learning and memory. the occurrence of cognitive defects in the absence of overt cns pathology led us to the hypothesis that chronic virus infection may contribute to neuronal dysfunction by altering the hos ...	2006	16940520
inhibition of the type i interferon response by the nucleoprotein of the prototypic arenavirus lymphocytic choriomeningitis virus.	the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) is a formidable battle horse for the study of viral immunology, as well as viral persistence and associated diseases. investigations with lcmv have uncovered basic mechanisms by which viruses avoid elimination by the host adaptive immune response. in this study we show that lcmv also disables the host innate defense by interfering with beta interferon (ifn-beta) production in response to different stimuli, including infection wi ...	2006	16940530
different neurotropic pathogens elicit neurotoxic ccr9- or neurosupportive cxcr3-expressing microglia.	what mechanism that determines microglia accomplishing destructive or constructive role in cns remains nebulous. we report here that intracranial priming and rechallenging with toxoplasma gondii in mice elicit neurotoxic ccr9+ irg1+ (immunoresponsive gene 1) microglia, which render resistance to apoptosis and produce a high level of tnf-alpha; priming and rechallenging with lymphocytic choriomeningitis virus elicit neurosupportive cxcr3+ irg1- microglia, which are sensitive to apoptosis and prod ...	2006	16951324
transgenic expression of the viral flip mc159 causes lpr/gld-like lymphoproliferation and autoimmunity.	death receptor-induced programmed cell death (pcd) is crucial for the maintenance of immune homeostasis. however, interference of downstream death receptor signaling by genetic ablation or transgenic (tg) expression of different apoptosis inhibitors often impairs lymphocyte activation. the viral flice (caspase-8)-like inhibitor proteins (v-flips) are potent inhibitors of death receptor-induced apoptosis and programmed necrosis. we generated tg mice expressing the v-flip mc159 from molluscum cont ...	2006	16951343
impaired memory cd8 t cell development in the absence of methyl-cpg-binding domain protein 2.	intracellular differentiation events that determine which cells develop into memory cd8 t cells are currently incompletely understood. methyl-cpg-binding domain protein 2 (mbd2) is a transcriptional repressor that binds to methylated dna and mediates the biological consequences of epigenetic gene methylation. the role of mbd2 during the differentiation of naive cd8 t cells into effector and memory cells was determined following acute infection of mbd2-deficient mice with lymphocytic choriomening ...	2006	16951344
listeriolysin o-deficient listeria monocytogenes as a vaccine delivery vehicle: antigen-specific cd8 t cell priming and protective immunity.	strains of listeria monocytogenes (lm) that are deficient in the virulence factor listeriolysin o (llo) are highly attenuated and are thought not to elicit protective immunity. this failure has been attributed to the inability of the bacterium to enter the host cell cytosol and access mhc class i ag processing machinery. we reexamined this issue using recombinant strains of lm that are deficient in llo but express an additional cd8 t cell epitope derived from lymphocytic choriomeningitis virus. ...	2006	16951364
continuous recruitment of naive t cells contributes to heterogeneity of antiviral cd8 t cells during persistent infection.	numerous microbes establish persistent infections, accompanied by antigen-specific cd8 t cell activation. pathogen-specific t cells in chronically infected hosts are often phenotypically and functionally variable, as well as distinct from t cells responding to nonpersistent infections; this phenotypic heterogeneity has been attributed to an ongoing reencounter with antigen. paradoxically, maintenance of memory cd8 t cells to acutely resolved infections is antigen independent, whereas there is a ...	2006	16966427
augmented il-7 signaling during viral infection drives greater expansion of effector t cells but does not enhance memory.	il-7 signals are crucial for the survival of naive and memory t cells, and the il-7r is expressed on the surface of these cells. following viral infection, the il-7r is expressed on only a subset of effector cd8 t cells, and has been demonstrated to be important for the survival of these memory precursors. il-7 message levels remain relatively constant during the t cell response to lymphocytic choriomeningitis virus, but a short-lived burst of gm-csf is observed soon after infection. retroviral ...	2006	16982881
hiv: tired t cells turn around.		2006	16988698
reinvigorating exhausted hiv-specific t cells via pd-1-pd-1 ligand blockade.	the programmed death (pd)-1-pd-1 ligand (pd-l) pathway, which is part of the b7-cd28 family, consists of the pd-1 receptor and its two ligands pd-l1 and pd-l2. engagement of pd-1 by its ligands inhibits immune responses, and recent work has shown that pd-1 is highly expressed on exhausted t cells during chronic lymphocytic choriomeningitis virus (lcmv) infection in mice. blockade of this pathway reinvigorates the exhausted t cells, allowing them to expand and produce effector cytokines, raising ...	2006	17000870
another donor derived pathogen to watch out for.		2006	17001758
increased susceptibility to bacterial superinfection as a consequence of innate antiviral responses.	the reason why severe localized or systemic virus infections enhance and aggravate bacterial superinfection is poorly understood. here we show that virus-induced ifn type i caused apoptosis in bone marrow granulocytes, drastically reduced granulocyte infiltrates at the site of bacterial superinfection, caused up to 1,000-fold higher bacterial titers in solid organs, and increased disease susceptibility. the finding that the innate antiviral immune response reduces the antibacterial granulocyte d ...	2006	17030789
acquired hydrocephalus caused by a variant lymphocytic choriomeningitis virus.		2006	17030840
resolution of a chronic viral infection after interleukin-10 receptor blockade.	a defining characteristic of persistent viral infections is the loss and functional inactivation of antiviral effector t cells, which prevents viral clearance. interleukin-10 (il-10) suppresses cellular immune responses by modulating the function of t cells and antigen-presenting cells. in this paper, we report that il-10 production is drastically increased in mice persistently infected with lymphocytic choriomeningitis virus. in vivo blockade of the il-10 receptor (il-10r) with a neutralizing a ...	2006	17030951
interleukin-10 determines viral clearance or persistence in vivo.	persistent viral infections are a major health concern. one obstacle inhibiting the clearance of persistent infections is functional inactivation of antiviral t cells. although such immunosuppression occurs rapidly after infection, the mechanisms that induce the loss of t-cell activity and promote viral persistence are unknown. herein we document that persistent viral infection in mice results in a significant upregulation of interleukin (il)-10 by antigen-presenting cells, leading to impaired t ...	2006	17041596
socs-1 protects from virally-induced cd8 t cell mediated type 1 diabetes.	cd8(+) cytotoxic t lymphocytes (ctl) can rapidly kill beta-cells and therefore contribute to the development of type 1 diabetes (t1d). ctl-mediated beta-cell killing can occur via perforin-mediated lysis, fas-fas-l interaction, and the secretion of tnf-alpha or ifn-gamma. the secretion of ifn-gamma can contribute to beta-cell death directly by eliciting nitric oxide production, and indirectly by upregulating mhc class i and 'unmasking' beta-cells for recognition by ctl. earlier studies in the ri ...	2006	17045460
lcmv transmission by organ transplantation.		2006	17050901
lcmv transmission by organ transplantation.		2006	17054324
immunoproteasomes are essential for clearance of listeria monocytogenes in nonlymphoid tissues but not for induction of bacteria-specific cd8+ t cells.	microbial infections induce the replacement of constitutive proteasomes by immunoproteasomes (i-proteasomes). i-proteasomes support efficient generation of mhc class i epitopes and influence immunodominance hierarchies of cd8(+) t cells. recently, the function of i-proteasomes in antimicrobial responses was challenged by showing that the lack of i-proteasomes has no effect on induction and function of lymphocytic choriomeningitis virus-specific cd8(+) t cells. here, we show that infection with l ...	2006	17056553
the price of the cd27-cd70 costimulatory axis: you can't have it all.	t cells require costimulatory signals for optimal proliferation, differentiation, and survival and thus to induce protective immune responses. recent data, however, show that during chronic lymphocyte choriomeningitis virus (lcmv) infection, triggering of the costimulatory receptor cd27 by its ligand cd70 impedes neutralizing antibody production and leads to viral persistence. thus, while being crucial for the induction of some adaptive effector pathways, costimulation may block the development ...	2006	17060478
high prevalence of antibodies to lymphocytic choriomeningitis virus in a murine typhus endemic region in croatia.	a retrospective serological survey was carried out by the indirect immunofluorescence assay (ifa) and complement fixation (cf) test in a sample of 425 healthy residents (240 females and 185 males) to investigate whether lymphocytic choriomeningitis virus (lcmv) circulates in the rural area of the northern croatian island of vir, which is known to be endemic for murine typhus. the overall prevalence of lcmv antibodies detected by ifa was found to be 36% (155 out of 425) and 13% (54 out of 425) by ...	2006	17063527
[analysis of in vitro delivering cd8+ t epitopes by attenuated bacteria].	to analyze the efficiency of delivery for cd8(+) t cell epitopes by recombinant bacteria vectors.	2006	17077012
cutting edge: the direct action of type i ifn on cd4 t cells is critical for sustaining clonal expansion in response to a viral but not a bacterial infection.	the action of type i ifn (ifn-i) on apcs is well studied, but their direct effect on cd4 t cells is unclear. to address this, we transferred ifn-i receptor-deficient (ifn-ir(0)) and -sufficient (wild-type, wt) tcr-transgenic cd4 t cells into wt mice and analyzed their response to immunization. in response to lymphocytic choriomeningitis virus immunization, wt cd4 t cells expanded approximately 100-fold, whereas ifn-ir(0) cd4 t cells expanded <10-fold. however, both wt and ifn-ir(0) cd4 t cells e ...	2006	16517698
soluble mhc-peptide complexes containing long rigid linkers abolish ctl-mediated cytotoxicity.	soluble mhc-peptide (pmhc) complexes induce intracellular calcium mobilization, diverse phosphorylation events, and death of cd8+ ctl, given that they are at least dimeric and co-engage cd8. by testing dimeric, tetrameric, and octameric pmhc complexes containing spacers of different lengths, we show that their ability to activate ctl decreases as the distance between their subunit mhc complexes increases. remarkably, pmhc complexes containing long rigid polyproline spacers (> or =80 a) inhibit t ...	2006	16517703
taking the brake off t cells in chronic viral infection.		2006	16520769
cd69 acts downstream of interferon-alpha/beta to inhibit s1p1 and lymphocyte egress from lymphoid organs.	naive lymphocytes continually enter and exit lymphoid organs in a recirculation process that is essential for immune surveillance. during immune responses, the egress process can be shut down transiently. when this occurs locally it increases lymphocyte numbers in the responding lymphoid organ; when it occurs systemically it can lead to immunosuppression as a result of the depletion of recirculating lymphocytes. several mediators of the innate immune system are known to cause shutdown, including ...	2006	16525420
aicardi-like chorioretinitis and maldevelopment of the corpus callosum in congenital lymphocytic choriomeningitis virus.		2006	16527682
recovery of an arenavirus entirely from rna polymerase i/ii-driven cdna.	the prototypic arenavirus lymphocytic choriomeningitis virus has been a primary workhorse of viral immunologists for almost a century, and it has served as an important model for studying basic principles of arenavirus molecular biology. its negative-stranded bisegmented rna genome has, however, posed a major obstacle to attempts at manipulating the infectious virus by reverse genetic techniques. here, we report the recovery of infectious lymphocytic choriomeningitis virus (the immunosuppressive ...	2006	16537369
cxcl10 is the key ligand for cxcr3 on cd8+ effector t cells involved in immune surveillance of the lymphocytic choriomeningitis virus-infected central nervous system.	ifn-gamma-inducible protein 10/cxcl10 is a chemokine associated with type 1 t cell responses, regulating the migration of activated t cells through binding to the cxcr3 receptor. expression of both cxcl10 and cxcr3 are observed during immunopathological diseases of the cns, and this receptor/ligand pair is thought to play a central role in regulating t cell-mediated inflammation in this organ site. in this report, we investigated the role of cxcl10 in regulating cd8(+) t cell-mediated inflammati ...	2006	16547260
ifn-induced attrition of cd8 t cells in the presence or absence of cognate antigen during the early stages of viral infections.	profound lymphopenia has been observed during many acute viral infections, and our laboratory has previously documented a type i ifn-dependent loss of cd8 t cells immediately preceding the development of the antiviral t cell response. most memory (cd44(high)) and some naive (cd44(low)) cd8 t cells are susceptible to ifn-induced attrition, and we show in this study that the ifn-induced attrition of cd8(+)cd44(high) t cells is associated with elevated activation of caspase-3 and caspase-8. we ques ...	2006	16547266
long-lived memory cd8+ t cells are programmed by prolonged antigen exposure and low levels of cellular activation.	cd8+ t cells play a crucial role in controlling intracellular pathogens. the level of memory cd8+ t cells developing after vaccination or infection influences the degree of t cell-mediated protection after secondary infection. we used defined animal models and infections/immunizations by replicating or non-replicating antigens to define on a molecular and cellular level in vivo the parameters that identify and shape long-lived cd8+ t cell memory. we show that the timing of antigen exposure durin ...	2006	16552716
is there an association of pneumocystis infection with the presence of arena-, hanta-, and poxvirus antibodies in wild mice and shrews in finland?	as part of studies on the nature of the endemic virus infections in natural rodent hosts, the possible association of cyst forms of pneumocystis spp. with the presence of hanta-, cowpox-, and arenavirus antibodies in wild mice (apodemus flavicollis, n=105; apodemus agrarius, n=63; micromys minutus, n=50) and the common shrew (sorex araneus, n=101) was studied in south-central finland. one hantavirus (saaremaa virus, saav) seropositive a. agrarius, and 2 cowpoxvirus (cpxv) seropositive s. araneus ...	2006	16556344
evaluating antigen-specific cytotoxic t lymphocyte responses by a novel mouse granzyme b elispot assay.	we have established novel elisa- and elispot-based assays specific for the detection of a potent cytotoxic mediator, granzyme b (grb), for the assessment of antigen-specific cytotoxic t lymphocyte responses in mice. the sensitivity and specificity of our assays was demonstrated by elisa using purified mouse grb and supernatants and cell lysates of cytotoxic lymphocytes derived from grb-deficient mice. no reactivity was observed by the grb elisa in grb-deficient cells. the mouse grb elispot was s ...	2006	16375915
structural basis of the differential stability and receptor specificity of h-2db in complex with murine versus human beta2-microglobulin.	beta(2)-microglobulin (beta(2)m) is non-covalently linked to the major histocompatibility complex (mhc) class i heavy chain and interacts with cd8 and ly49 receptors. murine mhc class i heavy chains can bind human beta(2)m (hbeta(2)m) and peptide, and such hybrid molecules are often used in structural and functional studies. the replacement of mouse beta(2)m (mbeta(2)m) with hbeta(2)m has several functional consequences for mhc class i complex stability and specificity, but the structural basis ...	2006	16375919
ube1l and protein isgylation are not essential for alpha/beta interferon signaling.	the expression of ubiquitin-like modifier isg15 and its conjugation to target proteins are highly induced by interferon (ifn) stimulation and during viral and bacterial infections. however, the biological significance of this modification has not been clearly understood. to investigate the function of protein modification by isg15, we generated a mouse model deficient in ube1l, an isg15-activating enzyme. ube1l-/- mice did not produce isg15 conjugates but expressed free isg15 normally. isgylatio ...	2006	16382139