Publications

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lassa virus vaccine candidate ml29 generates truncated viral rnas which contribute to interfering activity and attenuation.defective interfering particles (dips) are naturally occurring products during virus replication in infected cells. dips contain defective viral genomes (dvgs) and interfere with replication and propagation of their corresponding standard viral genomes by competing for viral and cellular resources, as well as promoting innate immune antiviral responses. consequently, for many different viruses, including mammarenaviruses, dips play key roles in the outcome of infection. due to their ability to b ...202133573250
identification of potential novel hosts and the risk of infection with lymphocytic choriomeningitis virus in humans in gabon, central africa.lymphocytic choriomeningitis virus (lcmv), a human pathogenic arenavirus, is distributed worldwide. however, no human cases have been reported in africa. this study aimed to investigate the current situation and potential risks of lcmv infection in gabon, central africa.202133667697
protein immunization induces memory cd4+ t cells that lack th lineage commitment.acute viral infection generates lineage-committed th1 and t follicular helper (tfh) memory cells that recall their lineage-specific functions following secondary challenge with virus. however, the lineage commitment of effector and memory th cells in vivo following protein vaccination is poorly understood. in this study, we analyzed effector and memory cd4+ t cell differentiation in mice (mus musculus) following adjuvanted glycoprotein immunization compared with acute lymphocytic choriomeningiti ...202134380649
serological evidence of multiple zoonotic viral infections among wild rodents in barbados.rodents are reservoirs for several zoonotic pathogens that can cause human infectious diseases, including orthohantaviruses, mammarenaviruses and orthopoxviruses. evidence exists for these viruses circulating among rodents and causing human infections in the americas, but much less evidence exists for their presence in wild rodents in the caribbean.202134071689
role of mus musculus in the transmission of several pathogens in poultry farms.this study aimed to analyze the role of mus musculus as a host of leptospira spp., lymphocytic choriomeningitis virus (lcmv) and toxoplasma gondii, in poultry farms of buenos aires province, argentina, and to assess the potential risk of transmission to humans and domestic or breeding animals. samplings were performed between 2009 and 2011 (s1) and during 2016 (s2). in s1, we studied the prevalence of infection for leptospira spp. and lcmv, whereas, in s2, we studied the prevalence of infection ...202133659179
wild red foxes (vulpes vulpes) as sentinels of rodent-borne hantavirus and lymphocytic choriomeningitis virus in the province of soria, northern spain.three hundred and fourteen red foxes (vulpes vulpes) in the province of soria, spain, were examined for hantavirus and lymphocytic choriomeningitis virus (lcmv) infection (and were likely to have been infected by feeding on infected rodents). immunofluorescence and western blot assays confirmed 3.5% (11/314) to have antibodies to hantaviruses, and the immune fluorescence assay showed 2.2% (7/314) to have antibodies to lcmv. the serologic status of the animals showed no statistically significant ...202032011204
seroprevalence of wenzhou virus in china.wenzhou virus (wenv) was first identified in rodents and asian house shrews in wenzhou, zhejiang province, china. however, little is known about the prevalence of wenv infections in humans in china. to determine the threat that wenv may pose to humans, we determine the seroprevalence of wenv in healthy individuals in china in this study. cross-reactivities of nucleoprotein (np) were detected between lymphocytic choriomeningitis virus (lcmv) and wenv using western blot and elisa assy. the prevale ...202032838285
viral diversity of house mice in new york city.the microbiome of wild mus musculus (house mouse), a globally distributed invasive pest that resides in close contact with humans in urban centers, is largely unexplored. here, we report analysis of the fecal virome of house mice in residential buildings in new york city, ny. mice were collected at seven sites in manhattan, queens, brooklyn, and the bronx over a period of 1 year. unbiased high-throughput sequencing of feces revealed 36 viruses from 18 families and 21 genera, including at least 6 ...201829666290
a primate model for viral hemorrhagic fever.lymphocytic choriomeningitis virus strain we (lcmv-we), a risk group 3 virus, causes a disease in rhesus monkeys that closely resembles human infection with lassa fever virus, a risk group 4 agent. three stages of disease progression have been defined and profiled in this model: pre-viremic, viremic, and terminal. the earliest or pre-viremic stage reveals changes in the blood profile predictive of the later stages of disease. in order to identify whether specific changes are pathognomonic, it wa ...201828986843
characterization of akabane virus from domestic bamboo rat, southern china.to identify the causative agents in 3 large-scale outbreaks of encephalitis and death among farmed bamboo rats (rhizomys pruinosus). the routine bacterial culture and identification were performed. there were no significant pathogenic bacteria isolated from the brain, heart, liver, spleen, lung, or kidney of diseased bamboo rats. using pcr-based methods, we excluded the following as causative agent: pox virus, herpesvirus, adenovirus, lymphocytic choriomeningitis virus, rabies virus, and sendai ...201728757035
granzyme k-deficient mice show no evidence of impaired antiviral immunity.the biological role of granzyme k, a serine protease of cytotoxic t lymphocytes (ctl), is controversial. it has been reported to induce perforin-mediated cell death in vitro, but is also reported to be non-cytotoxic and to operate in inflammatory processes. to elucidate the biological role of this protease, we have deleted the granzyme k gene in mice (mutant allele: gzmk(tm1.1pib); mgi:5636646). gzmk (-/-) mice are healthy, anatomically normal, fecund and show normal hematopoietic development. g ...201728428612
[first evidence of lymphocytic choriomeningitis virus (arenavirus) infection in mus musculus rodents captured in the urban area of the municipality of sincelejo, sucre, colombia].the lymphocytic choriomeningitis virus is an old world arenavirus that infects mus musculus, and can cause congenital hydrocephalus, chorioretinitis and multisystemic failure in transplant human recipients. although the disease has not been clinically diagnosed in colombia yet, there have been reports of infection with the pichindé virus in rodents from cauca and valle del cauca departments, and with the guanarito virus in rodents from córdoba department.201728527269
systems-guided forward genetic screen reveals a critical role of the replication stress response protein etaa1 in t cell clonal expansion.t-cell immunity requires extremely rapid clonal proliferation of rare, antigen-specific t lymphocytes to form effector cells. here we identify a critical role for etaa1 in this process by surveying random germ line mutations in mice using exome sequencing and bioinformatic annotation to prioritize mutations in genes of unknown function with potential effects on the immune system, followed by breeding to homozygosity and testing for immune system phenotypes. effector cd8(+) and cd4(+) t-cell form ...201728607084
a map of the arenavirus nucleoprotein-host protein interactome reveals that junín virus selectively impairs the antiviral activity of double-stranded rna-activated protein kinase (pkr).arenaviruses are enveloped negative-strand rna viruses that cause significant human disease. these viruses encode only four proteins to accomplish the viral life cycle, so each arenavirus protein likely plays unappreciated accessory roles during infection. here we used immunoprecipitation and mass spectrometry to identify human proteins that interact with the nucleoproteins (nps) of the old world arenavirus lymphocytic choriomeningitis virus (lcmv) and the new world arenavirus junín virus (junv) ...201728539447
interferon-γ-driven inos: a molecular pathway to terminal shock in arenavirus hemorrhagic fever.arenaviruses such as lassa virus (lasv) cause hemorrhagic fever. terminal shock is associated with a systemic cytokine storm, but the mechanisms are ill defined. here we used hla-a2-expressing mice infected with a monkey-pathogenic strain of lymphocytic choriomeningitis virus (lcmv-we), a close relative of lasv, to investigate the pathophysiology of arenavirus hemorrhagic fever (ahf). ahf manifested as pleural effusions, edematous skin swelling, and serum albumin loss, culminating in hypovolemic ...201728826838
evolutionary analysis of old world arenaviruses reveals a major adaptive contribution of the viral polymerase.the old world (ow) arenavirus complex includes several species of rodent-borne viruses, some of which (i.e., lassa virus, lasv and lymphocytic choriomeningitis virus, lcmv) cause human diseases. most lcmv and lasv infections are caused by rodent-to-human transmissions. thus, viral evolution is largely determined by events that occur in the wildlife reservoirs. we used a set of human- and rodent- derived viral sequences to investigate the evolutionary history underlying ow arenavirus speciation, ...201728779541
type i interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis.the presence of the endogenous leishmania rna virus 1 (lrv1) replicating stably within some parasite species has been associated with the development of more severe forms of leishmaniasis and relapses after drug treatment in humans. here, we show that the disease-exacerbatory role of lrv1 relies on type i ifn (type i ifns) production by macrophages and signaling in vivo. moreover, infecting mice with the lrv1-cured leishmania guyanensis (lgylrv1(-) ) strain of parasites followed by type i ifn tr ...201728439019
recombinant lcmv vectors induce protective immunity following homologous and heterologous vaccinations.successful vaccination against cancer and infectious diseases relies on the induction of adaptive immune responses that induce high-titer antibodies or potent cytoxic t cell responses. in contrast to humoral vaccines, the amplification of cellular immune responses is often hampered by anti-vector immunity that either pre-exists or develops after repeated homologous vaccination. replication-defective lymphocytic choriomeningitis virus (lcmv) vectors represent a novel generation of vaccination vec ...201728803862
cd8(+) memory t-cell inflation renders compromised cd4(+) t-cell-dependent cd8(+) t-cell immunity via naïve t-cell anergy.whether inflation of cd8(+) memory t (mt) cells, which is often derived from repeated prime-boost vaccinations or chronic viral infections in the elderly, would affect late cd8(+) t-cell immunity is a long-standing paradox. we have previously established an animal model with mt-cell inflation by transferring cona-stimulated monoclonal cd8(+) t cells derived from ova-specific t-cell-receptor transgenic oti mice into irradiation-induced lymphopenic b6 mice. in this study, we also established anoth ...201728670575
congenital lymphocytic choriomeningitis virus: a case of prenatal diagnosis. 201728858375
resistance of human plasmacytoid dendritic cal-1 cells to infection with lymphocytic choriomeningitis virus (lcmv) is caused by restricted virus cell entry, which is overcome by contact of cal-1 cells with lcmv-infected cells.plasmacytoid dendritic cells (pdcs), a main source of type i interferon in response to viral infection, are an early cell target during lymphocytic choriomeningitis virus (lcmv) infection, which has been associated with the lcmv's ability to establish chronic infections. human blood-derived pdcs have been reported to be refractory to ex vivo lcmv infection. in the present study we show that human pdc cal-1 cells are refractory to infection with cell-free lcmv, but highly susceptible to infection ...201728843812
microcephaly caused by lymphocytic choriomeningitis virus.we report congenital microencephaly caused by infection with lymphocytic choriomeningitis virus in the fetus of a 29-year-old pregnant women at 23 weeks' gestation. the diagnosis was made by ultrasonography and negative results for other agents and confirmed by a positive pcr result for lymphocytic choriomeningitis virus in an amniotic fluid sample.201728820372
extrinsic protein tyrosine phosphatase non-receptor 22 signals contribute to cd8 t cell exhaustion and promote persistence of chronic lymphocytic choriomeningitis virus infection.a genetic variant of the protein tyrosine phosphatase non-receptor 22 (ptpn22) is associated with a wide range of autoimmune diseases; however, the reasons behind its prevalence in the general population remain not completely understood. recent evidence highlights an important role of autoimmune susceptibility genetic variants in conferring resistance against certain pathogens. in this study, we examined the role of ptpn22 in persistent infection in mice lacking ptpn22 infected with lymphocytic ...201728747914
the impact of illegal waste sites on a transmission of zoonotic viruses.illegal waste disposal impacts public health and causes aesthetic and environmental pollution. waste disposed in places without permitted and controlled facilities can provide a ready source of nutrition and shelter for rodents and thus promote the spread of their ecto- and endoparasites. the presence of two distinct zoonotic viruses, lymphocytic choriomeningitis virus (lcmv) and tick-borne encephalitis virus (tbev), was searched at illegal waste sites. the aim of this study was to determine the ...201728728557
host genetics play a critical role in controlling cd8 t cell function and lethal immunopathology during chronic viral infection.effective cd8 t cell responses are vital for the control of chronic viral infections. many factors of the host immune response contribute to the maintenance of effector cd8 t cell responses versus cd8 t cell exhaustion during chronic infection. specific mhc alleles and the degree of mhc heterogeneity are associated with enhanced cd8 t cell function and viral control during human chronic infection. however, it is currently unclear to what extent host genetics influences the establishment of chron ...201728715493
translation is actively regulated during the differentiation of cd8(+) effector t cells.translation is a critical process in protein synthesis, but translational regulation in antigen-specific t cells in vivo has not been well defined. here we have characterized the translatome of virus-specific cd8(+) effector t cells (teff cells) during acute infection of mice with lymphocytic choriomeningitis virus (lcmv). antigen-specific t cells exerted dynamic translational control of gene expression that correlated with cell proliferation and stimulation via the t cell antigen receptor (tcr) ...201728714979
anti-il-21 monoclonal antibody combined with liraglutide effectively reverses established hyperglycemia in mouse models of type 1 diabetes.immunotherapy for type 1 diabetes (t1d) has previously focused on suppressing the autoimmune response against pancreatic beta cells to preserve endogenous insulin production and regulate glucose levels. with increased attention toward combination therapy strategies, studies indicate the multifunctional cytokine interleukin-21 (il-21) may be a suitable target as an immuno-modulatory arm, while glucagon-like peptide-1 receptor (glp-1r) agonists may be appropriate as a beta cell protective arm in c ...201728711285
unsupervised learning techniques reveal heterogeneity in memory cd8(+) t cell differentiation following acute, chronic and latent viral infections.cd8(+) t lymphocytes are critical for the control of gammaherpesvirus latency. to determine how memory cd8(+) t cells generated during latency differ from those primed during acute or chronic viral infection, we adoptively transferred naive p14 cd8(+) t cells into uninfected recipients, and examined surface proteins, cytokines and transcription factors following infection with the armstrong (acute) or clone 13 (chronic) strains of lymphocytic choriomeningitis virus (lcmv), or murine gammaherpesv ...201728689040
transcutaneous immunization with a novel imiquimod nanoemulsion induces superior t cell responses and virus protection.transcutaneous immunization (tci) is a novel vaccination strategy utilizing the skin associated lymphatic tissue to induce immune responses. tci using a cytotoxic t lymphocyte (ctl) epitope and the toll-like receptor 7 (tlr7) agonist imiquimod mounts strong ctl responses by activation and maturation of skin-derived dendritic cells (dcs) and their migration to lymph nodes. however, tci based on the commercial formulation aldara only induces transient ctl responses that needs further improvement f ...201728655469
immunological phenotype of the murine lrba knockout.biallelic mutations in the human lipopolysaccharide responsive beige-like anchor (lrba) gene lead to a primary immunodeficiency known as lrba deficiency, characterized by a broad range of clinical manifestations including autoimmunity, organomegaly, hypogammaglobulinemia and recurrent infections. considering the phenotypic heterogeneity in patients and the severity of the disease, our aim was to assess the role of lrba in immune cells and to understand the underlying pathomechanisms through the ...201728652580
murine lrba deficiency causes ctla-4 deficiency in tregs without progression to immune dysregulation.inherited mutations in lipopolysaccharide-responsive beige-like anchor (lrba) cause a recessive human immune dysregulation syndrome with memory b-cell and antibody deficiency (common variable immunodeficiency), inflammatory bowel disease, enlarged spleen and lymph nodes, accumulation of activated t cells and multiple autoimmune diseases. to understand the pathogenesis of the syndrome, c57bl/6 mice carrying a homozygous truncating mutation in lrba were produced using crispr/cas9-mediated gene tar ...201728611475
mammalian target of rapamycin complex 1 signalling is essential for germinal centre reaction.the mammalian target of rapamycin (mtor) is a serine-threonine kinase that has been shown to be essential for the differentiation and function of various immune cells. earlier in vitro studies showed that mtor signalling regulates b-cell biology by supporting their activation and proliferation. however, how mtor signalling temporally regulates in vivo germinal centre b (gcb) cell development and differentiation into short-lived plasma cells, long-lived plasma cells and memory cells is still not ...201728557002
replicating viral vector platform exploits alarmin signals for potent cd8(+) t cell-mediated tumour immunotherapy.viral infections lead to alarmin release and elicit potent cytotoxic effector t lymphocyte (ctl(eff)) responses. conversely, the induction of protective tumour-specific ctl(eff) and their recruitment into the tumour remain challenging tasks. here we show that lymphocytic choriomeningitis virus (lcmv) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artlcmv). artlcmv delivers tumour-associated antigens to dendritic cells for efficient ctl priming. unl ...201728548102
the microrna mir-31 inhibits cd8(+) t cell function in chronic viral infection.during infection, antigen-specific t cells undergo tightly regulated developmental transitions controlled by transcriptional and post-transcriptional regulation of gene expression. we found that the microrna mir-31 was strongly induced by activation of the t cell antigen receptor (tcr) in a pathway involving calcium and activation of the transcription factor nfat. during chronic infection with lymphocytic choriomeningitis virus (lcmv) clone 13, mir-31-deficent mice recovered from clinical diseas ...201728530712
in vivo chronic stimulation unveils autoreactive potential of wiskott-aldrich syndrome protein-deficient b cells.wiskott-aldrich syndrome (was) is a primary immunodeficiency caused by mutations in the gene encoding the hematopoietic-specific was protein (wasp). was is frequently associated with autoimmunity, indicating a critical role of wasp in maintenance of tolerance. the role of b cells in the induction of autoreactive immune responses in was has been investigated in several settings, but the mechanisms leading to the development of autoimmune manifestations have been difficult to evaluate in the mouse ...201728512459
high clinical suspicion of donor-derived disease leads to timely recognition and early intervention to treat solid organ transplant-transmitted lymphocytic choriomeningitis virus.despite careful donor screening, unexpected donor-derived infections continue to occur in organ transplant recipients (otrs). lymphocytic choriomeningitis virus (lcmv) is one such transplant-transmitted infection that in previous reports has resulted in a high mortality among the affected otrs. we report a lcmv case cluster that occurred 3 weeks post-transplant in three otrs who received allografts from a common organ donor in march 2013. following confirmation of lcmv infection at centers for d ...201728423464
nkg2d stimulation of cd8(+) t cells during priming promotes their capacity to produce cytokines in response to viral infection in mice.natural killer group 2 member d (nkg2d) is an activating receptor that is expressed on most cytotoxic cells of the immune system, including nk cells, γδ, and cd8(+) t cells. it is still a matter of debate whether and how nkg2d mediates priming of cd8(+) t cells in vivo, due to a lack of studies where nkg2d is eliminated exclusively in these cells. here, we studied the impact of nkg2d on effector cd8(+) t-cell formation. nkg2d deficiency that is restricted to murine cd8(+) t cells did not impair ...201728378389
cd8 t-cell regulation by t regulatory cells and the programmed cell death protein 1 pathway.the primary function of the immune system is to protect the host from infectious microorganisms and cancers. however, a major component of the immune response involves the direct elimination of cells in the body and the induction of systemic inflammation, which may result in life-threatening immunopathology. therefore, the immune system has developed complex mechanisms to regulate itself with a specialized subset of cd4 t lymphocytes (referred to as regulatory t cells) and immune checkpoint path ...201728375543
congenital cytomegalovirus: a "now" problem-no really, now.despite the clear need, progress toward a vaccine for congenital cytomegalovirus (cmv) has been slow. however, recent events have provided new interest, and several vaccine candidates are either in clinical trials or the trials are close to starting. in this issue of clinical and vaccine immunology, schleiss and colleagues show that a nonreplicating lymphocytic choriomeningitis virus (rlcmv)-vectored vaccine expressing cmv glycoprotein b (gb) and/or pp65 induces b and t cells and improves pup su ...201727795304
additive protection against congenital cytomegalovirus conferred by combined glycoprotein b/pp65 vaccination using a lymphocytic choriomeningitis virus vector.subunit vaccines for prevention of congenital cytomegalovirus (cmv) infection based on glycoprotein b (gb) and pp65 are in clinical trials, but it is unclear whether simultaneous vaccination with both antigens enhances protection. we undertook evaluation of a novel bivalent vaccine based on nonreplicating lymphocytic choriomeningitis virus (rlcmv) vectors expressing a cytoplasmic tail-deleted gb [gb(dct)] and full-length pp65 from human cmv in mice. immunization with the gb(dct) vector alone eli ...201727795301
chronic type i ifn is sufficient to promote immunosuppression through accumulation of myeloid-derived suppressor cells.failure of the immune system to eradicate viruses results in chronic viral infections, which are associated with increased susceptibility to secondary infections. pathogenic hiv or lymphocytic choriomeningitis virus chronic infections display a persistent type i ifn signature. in chronic lymphocytic choriomeningitis virus infection, blockade of type i ifn signaling partially restores antiviral responses. in a mouse model, we tested whether chronic administration of type i ifn, at doses mimicking ...201728003378
macrophages and the viral dissemination super highway.monocytes and macrophages are key components of the innate immune system yet they are often the victims of attack by infectious agents. this review examines the significance of viral infection of macrophages. the central hypothesis is that macrophage tropism enhances viral dissemination and persistence, but these changes may come at the cost of reduced replication in cells other than macrophages.201726949751
spatiotemporally restricted arenavirus replication induces immune surveillance and type i interferon-dependent tumour regression.immune-mediated effector molecules can limit cancer growth, but lack of sustained immune activation in the tumour microenvironment restricts antitumour immunity. new therapeutic approaches that induce a strong and prolonged immune activation would represent a major immunotherapeutic advance. here we show that the arenaviruses lymphocytic choriomeningitis virus (lcmv) and the clinically used junin virus vaccine (candid#1) preferentially replicate in tumour cells in a variety of murine and human c ...201728248314
efficient control of chronic lcmv infection by a cd4 t cell epitope-based heterologous prime-boost vaccination in a murine model.cd4(+) t cells are essential for sustaining cd8(+) t cell responses during a chronic infection. the adoptive transfer of virus-specific cd4(+) t cells has been shown to efficiently rescue exhausted cd8(+) t cells. however, the question of whether endogenous virus-specific cd4(+) t cell responses can be enhanced by certain vaccination strategies and subsequently reinvigorate exhausted cd8(+) t cells remains unexplored. in this study, we developed a cd4(+) t cell epitope-based heterologous prime-b ...201728287115
the mouse cortical meninges are the site of immune responses to many different pathogens, and are accessible to intravital imaging.a wide range of viral and microbial infections are known to cause meningitis, and there is evidence that the meninges are the gateway to pathogenic invasion of the brain parenchyma. hence observation of these regions has wide application to understanding host-pathogen interactions. interactions between pathogens and cells of the immune response can be modified by changes in their environment, such as suppression of the flow of blood and lymph, and, particularly in the case of the meninges, with ...201728351758
t regulatory cells are critical for the maintenance, anamnestic expansion, and protection elicited by vaccine-induced cd8 t cells.t regulatory cells (tregs) are critical for preventing autoimmunity and suppressing immune responses during cancer and chronic infection. however, the role of tregs in the generation of vaccine-induced immune memory remains ill-defined. using the mouse model of lymphocytic choriomeningitis virus (lcmv) infection, we demonstrate that transient absence of tregs during effector to memory cd8 t cell transition results in a permanent impairment in the maintenance, function, and recall capacity of cd8 ...201728295248
difference of two new lcmv strains in lethality and viral genome load in tissues.more than 30 strains of lymphocytic choriomeningitis virus (lcmv) have been isolated from mice, hamsters and humans in the united states, europe and japan. experimentally infected mice exhibit different clinical signs and lethality depending on a combination of lcmv epitope peptides and host major histocompatibility complex (mhc) class i molecules. this study examined the pathogenicity, clinical signs and lethality, of two new lcmv strains (brc and oq28) using three inbred mouse strains with dif ...201728260717
presentation of autoantigen in peripheral lymph nodes is sufficient for priming autoreactive cd8(+) t cells.peripheral tolerance is an important mechanism by which the immune system can guarantee a second line of defense against autoreactive t and b cells. one autoimmune disease that is related to a break of peripheral tolerance is diabetes mellitus type 1. using the rip-gp mouse model, we analyzed the role of the spleen and lymph nodes (lns) in priming cd8(+) t cells and breaking peripheral tolerance. we found that diabetes developed in splenectomized mice infected with the lymphocytic choriomeningit ...201728239381
farnesoid x receptor in mice prevents severe liver immunopathology during lymphocytic choriomeningitis virus infection.bile acids (bas) are steroid molecules that are synthesized in the liver. in addition to their important role as a surfactant in solubilizing lipids and promoting the absorption of lipids in the gastrointestinal tract, they act as inflammagens. the role of bas and their receptor farnesoid x receptor (fxr) during viral infection has not been studied in detail.201728214859
cutting edge: chromatin accessibility programs cd8 t cell memory.cd8 t cell memory is characterized by rapid recall of effector function, increased proliferation, and reduced activation requirements. despite the extensive functional characterization, the molecular mechanisms that facilitate these enhanced properties are not well characterized. in this study, the assay for transposase-accessible chromatin sequencing was employed to map the cis-regulatory elements in cd8 t cells responding to acute and chronic lymphocytic choriomeningitis virus infections. inte ...201728179496
armc5 deletion causes developmental defects and compromises t-cell immune responses.armadillo repeat containing 5 (armc5) is a cytosolic protein with no enzymatic activities. little is known about its function and mechanisms of action, except that gene mutations are associated with risks of primary macronodular adrenal gland hyperplasia. here we map armc5 expression by in situ hybridization, and generate armc5 knockout mice, which are small in body size. armc5 knockout mice have compromised t-cell proliferation and differentiation into th1 and th17 cells, increased t-cell apopt ...201728169274
the bcl-2 pro-survival protein a1 is dispensable for t cell homeostasis on viral infection.the physiological role of the pro-survival bcl-2 family member a1 has been debated for a long time. strong mrna induction in t cells on t cell receptor (tcr)-engagement suggested a major role of a1 in the survival of activated t cells. however, the investigation of the physiological roles of a1 was complicated by the quadruplication of the a1 gene locus in mice, making a1 gene targeting very difficult. here, we used the recently generated a1(-/-) mouse model to examine the role of a1 in t cell i ...201728085151
adenovirus serotype 5 vaccination results in suboptimal cd4 t helper 1 responses in mice.adenovirus serotype 5 (ad5) is one of the most widely used viral vectors and is known to generate potent t cell responses. while many previous studies have characterized ad5-induced cd8 t cell responses, there is a relative lack of detailed studies that have analyzed cd4 t cells elicited by ad5 vaccination. here, we immunized mice with ad5 vectors encoding lymphocytic choriomeningitis virus (lcmv) glycoprotein (gp) and examined gp-specific cd4 t cell responses elicited by ad5 vectors and compare ...201728003483
development of novel replication-defective lymphocytic choriomeningitis virus vectors expressing siv antigens.an important focus in vaccine research is the design of vaccine vectors with low seroprevalence and high immunogenicity. replication-incompetent lymphocytic choriomeningitis virus (rlcmv) vectors do not elicit vector-neutralizing antibody responses, and homologous prime-boost regimens with rlcmv vectors induce boostable and protective t cell responses to model antigens in mice. however, cellular and humoral immune responses following homologous rlcmv vaccine regimens have not been rigorously eva ...201727899229
conserved region c functions to regulate pd-1 expression and subsequent cd8 t cell memory.expression of programmed death 1 (pd-1) on cd8 t cells promotes t cell exhaustion during chronic ag exposure. during acute infections, pd-1 is transiently expressed and has the potential to modulate cd8 t cell memory formation. conserved region c (cr-c), a promoter proximal cis-regulatory element that is critical to pd-1 expression in vitro, responds to nfatc1, foxo1, and/or nf-κb signaling pathways. here, a cr-c knockout mouse was established to determine its role on pd-1 expression and the cor ...201727895178
protein tyrosine phosphatase ptpn22 has dual roles in promoting pathogen versus homeostatic-driven cd8 t-cell responses.ptpn22 (protein tyrosine phosphatase non receptor 22) encodes a tyrosine phosphatase that functions as a key regulator of immune homeostasis. in particular, ptpn22 inhibits t-cell receptor signaling and selectively promotes type i interferon responses in myeloid cells. to date, there is little information on the cd8 t-cell-intrinsic role of ptpn22 in response to a viral pathogen. we unexpectedly found that ptpn22-deficient virus-specific cd8 t cells failed to accumulate in wild-type hosts after ...201727725666
cytokine regulation of lung th17 response to airway immunization using lps adjuvant.infections caused by bacteria in the airway preferentially induce a th17 response. however, the mechanisms involved in the regulation of cd4 t-cell responses in the lungs are incompletely understood. here, we have investigated the mechanisms involved in the regulation of th17 differentiation in the lungs in response to immunization with lipopolysaccharide (lps) as an adjuvant. our data show that both myd88 and trif are necessary for th17 induction. this distinctive fate determination can be acco ...201727328989
mtor promotes antiviral humoral immunity by differentially regulating cd4 helper t cell and b cell responses.mtor has important roles in regulation of both innate and adaptive immunity, but whether and how mtor modulates humoral immune responses have yet to be fully understood. to address this issue, we examined the effects of rapamycin, a specific inhibitor of mtor, on b cell and cd4 t cell responses during acute infection with lymphocytic choriomeningitis virus. rapamycin treatment resulted in suppression of virus-specific b cell responses by inhibiting proliferation of germinal center (gc) b cells. ...201727974559
α4 β1 integrin promotes accumulation of tissue-resident memory cd8(+) t cells in salivary glands.the salivary glands (sgs) of virus-immune mice contain substantial numbers of tissue-resident memory cd8(+) t cells (trm cells) that can provide immunity to local infections. integrins regulate entry of activated t cells into nonlymphoid tissues but the molecules that mediate migration of virus-specific cd8(+) t cells to the sgs have not yet been defined. here, we found that polyinosinic-polycytidylic acid (poly(i:c)) strongly promoted the accumulation of p14 tcr-transgenic cd8(+) trm cells in s ...201727861803
development of live-attenuated arenavirus vaccines based on codon deoptimization of the viral glycoprotein.several arenaviruses, chiefly lassa (lasv) in west africa, cause hemorrhagic fever (hf) disease in humans and pose important public health problems in their endemic regions. to date, there are no fda-approved arenavirus vaccines and current anti-arenaviral therapy is limited to the use of ribavirin that has very limited efficacy. in this work we document that a recombinant prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) with a codon deoptimized (cd) surface glycoprotein (gp), rlc ...201727855284
heterologous immunity and persistent murine cytomegalovirus infection.one's history of infections can affect the immune response to unrelated pathogens and influence disease outcome through the process of heterologous immunity. this can occur after acute viral infections, such as infections with lymphocytic choriomeningitis virus (lcmv) and vaccinia virus, where the pathogens are cleared, but it becomes a more complex issue in the context of persistent infections. in this study, murine cytomegalovirus (mcmv) was used as a persistent infection model to study hetero ...201727807227
irreversible splenic atrophy following chronic lcmv infection is associated with compromised immunity in mice.lymphocytic choriomeningitis virus clone 13 (lcmv13) infection of mice is a widely used model for investigating the mechanisms driving persistent viral infection in humans. lcmv13 disrupts splenic architecture early during infection, but this returns to normal within a few weeks. however, the long-term effects of lcmv13 infection on splenic structure have not been reported. here, we report that persistent infection with lcmv13 results in sustained splenic atrophy that persists for at least 500 d ...201727730627
islet-expressed cxcl10 promotes autoimmune destruction of islet isografts in mice with type 1 diabetes.type 1 diabetes (t1d) results from the autoimmune destruction of insulin-producing β-cells in the pancreas. thereby, the chemokine cxc-motif ligand 10 (cxcl10) plays an important role in the recruitment of autoaggressive lymphocytes to the islets of langerhans. transplantation of isolated islets as a promising therapy for t1d has been hampered by early graft rejection. here, we investigated the influence of cxcl10 on the autoimmune destruction of islet isografts using rip-lcmv mice expressing a ...201727797910
impaired subset progression and polyfunctionality of t cells in mice exposed to methamphetamine during chronic lcmv infection.methamphetamine (meth) is a widely used psychostimulant that severely impacts the host's innate and adaptive immune systems and has profound immunological implications. t cells play a critical role in orchestrating immune responses. we have shown recently how chronic exposure to meth affects t cell activation using a murine model of lymphocytic choriomeningitis virus (lcmv) infection. using the tricom (trinary state combinations) feature of gemstone™ to study the polyfunctionality of t cells, we ...201627760221
application of interferon modulators to overcome partial resistance of human ovarian cancers to vsv-gp oncolytic viral therapy.previously, we described an oncolytic vesicular stomatitis virus variant pseudotyped with the nonneurotropic glycoprotein of the lymphocytic choriomeningitis virus, vsv-gp, which was highly effective in glioblastoma. here, we tested its potency for the treatment of ovarian cancer, a leading cause of death from gynecological malignancies. effective oncolytic activity of vsv-gp could be demonstrated in ovarian cancer cell lines and xenografts in mice; however, remission was temporary in most mice. ...201627738655
ptpn22 contributes to exhaustion of t lymphocytes during chronic viral infection.the protein encoded by the autoimmune-associated protein tyrosine phosphatase nonreceptor type 22 gene, ptpn22, has wide-ranging effects in immune cells including suppression of t-cell receptor signaling and promoting efficient production of type i interferons (ifn-i) by myeloid cells. here we show that mice deficient in ptpn22 resist chronic viral infection with lymphocytic choriomeningitis virus clone 13 (lcmv cl13). the numbers and function of viral-specific cd4 t lymphocytes is greatly enhan ...201627799548
too much of a good thing: sustained type 1 interferon signaling limits humoral responses to secondary viral infection.the induction of a pan-immunosuppressive state is a central feature of persistent viral infections. over the past decade, multiple pathways have been identified that contribute to immune suppression. recently, it was revealed that aberrant or sustained type 1 interferon (ifn-i) production or signaling is a central contributor to immune suppression elicited during persistent viral infection. in this issue, honke et al. [eur. j. immunol. 2016. 46: 372-380] identify that ifn-i signaling promotes an ...201626783074
identification of lymphocytic choriomeningitis mammarenavirus in house mouse (mus musculus, rodentia) in french guiana.thirty-seven house mice (mus musculus, rodentia) caught in different localities in french guiana were screened to investigate the presence of lymphocytic choriomeningitis mammarenavirus (lcmv). two animals trapped in an urban area were found positive, hosting a new strain of lcmv, that we tentatively named lcmv "comou". the complete sequence was determined using a metagenomic approach. phylogenetic analyses revealed that this strain is related to genetic lineage i composed of strains inducing se ...201626631809
dampened antiviral immunity to intravaginal exposure to rna viral pathogens allows enhanced viral replication.understanding the host immune response to vaginal exposure to rna viruses is required to combat sexual transmission of this class of pathogens. in this study, using lymphocytic choriomeningitis virus (lcmv) and zika virus (zikv) in wild-type mice, we show that these viruses replicate in the vaginal mucosa with minimal induction of antiviral interferon and inflammatory response, causing dampened innate-mediated control of viral replication and a failure to mature local antigen-presenting cells (a ...201627852793
local cellular and cytokine cues in the spleen regulate in situ t cell receptor affinity, function, and fate of cd8(+) t cells.t cells rapidly undergo contraction upon viral clearance, but how t cell function and fate are determined during this phase is unclear. during the contraction phase of an acute infection with lymphocytic choriomeningitis virus, we found that virus-specific cd8(+) t cells within the splenic red pulp (rp) had higher two-dimensional (2d) effective affinity than those within the white pulp (wp). this increased antigen recognition of rp-derived cd8(+) t cells correlated with more efficient target cel ...201627851926
type i interferon suppresses virus-specific b cell responses by modulating cd8(+) t cell differentiation.studies have established a role for t cells in resolving persistent viral infections, yet emerging evidence indicates that both t and b cells are required to control some viruses. during persistent infection, a marked lag or failure to generate neutralizing antibodies is commonly observed and likely contributes to an inability to control certain pathogens. using lymphocytic choriomeningitis virus (lcmv) as a model, we have examined how a persistent viral infection can suppress neutralizing humor ...201627812556
liver monocytes and kupffer cells remain transcriptionally distinct during chronic viral infection.due to the scarcity of immunocompetent animal models for chronic viral hepatitis, little is known about the role of the innate intrahepatic immune system during viral replication in the liver. these insights are however fundamental for the understanding of the inappropriate adaptive immune responses during the chronic phase of the infection. we apply the lymphocytic choriomenigitis virus (lcmv) clone 13 mouse model to examine chronic virus-host interactions of kupffer cells (kc) and infiltrating ...201627812182
cd40l expression by cd4(+) but not cd8(+) t cells regulates antiviral immune responses in acute lcmv infection in mice.cd40-cd40 ligand (cd40l) signaling plays multiple indispensable roles in cellular and humoral immunity. impaired memory t-cell responses in the absence of cd40l have been well documented, but the requirement of this interaction for efficient priming of cd8(+) t cells especially under inflammatory conditions has been under debate. in contrast to previous publications, we report here that virus-specific cd8(+) t-cell responses as well as viral clearance are affected not only in the memory but also ...201627562840
cd169(+) macrophages regulate pd-l1 expression via type i interferon and thereby prevent severe immunopathology after lcmv infection.upon infection with persistence-prone virus, type i interferon (ifn-i) mediates antiviral activity and also upregulates the expression of programmed death ligand 1 (pd-l1), and this upregulation can lead to cd8(+) t-cell exhaustion. how these very diverse functions are regulated remains unknown. this study, using the lymphocytic choriomeningitis virus, showed that a subset of cd169(+) macrophages in murine spleen and lymph nodes produced high amounts of ifn-i upon infection. absence of cd169(+) ...201627809306
modelling and simulation of the dynamics of the antigen-specific t cell response using variable structure control theory.experimental and mathematical studies in immunology have revealed that the dynamics of the programmed t cell response to vigorous infection can be conveniently modelled using a sigmoidal or a discontinuous immune response function. this paper hypothesizes strong synergies between this existing work and the dynamical behaviour of engineering systems with a variable structure control (vsc) law. these findings motivate the interpretation of the immune system as a variable structure control system. ...201627861537
complement inhibition enables tumor delivery of lcmv glycoprotein pseudotyped viruses in the presence of antiviral antibodies.the systemic delivery of therapeutic viruses, such as oncolytic viruses or vaccines, is limited by the generation of neutralizing antibodies. while pseudotyping of rhabdoviruses with the lymphocytic choriomeningitis virus glycoprotein has previously allowed for multiple rounds of delivery in mice, this strategy has not translated to other animal models. for the first time, we provide experimental evidence that antibodies generated against the lymphocytic choriomeningitis virus glycoprotein media ...201627909702
interleukin-21-dependent modulation of t cell antigen receptor reactivity towards low affinity peptide ligands in autoreactive cd8(+) t lymphocytes.il-21 promotes autoimmune type-1 diabetes (t1d) in nod mice by facilitating cd4(+) t cell help to cd8(+) t cells. il-21 also enables autoreactive cd8(+) t cells to respond to weak tcr ligands and induce t1d. here, we assessed whether il-21 is essential for t1d induction in a mouse model where the disease can occur independently of cd4 help. in this model, which expresses lymphocytic choriomeningitis virus (lcmv) glycoprotein (gp) antigen under the rat insulin promoter (rip-gp), lcmv infection ac ...201627300756
il-4 sensitivity shapes the peripheral cd8+ t cell pool and response to infection.previous studies have revealed that a population of innate memory cd8(+) t cells is generated in response to il-4, first appearing in the thymus and bearing high expression levels of eomesodermin (eomes) but not t-bet. however, the antigen specificity and functional properties of these cells is poorly defined. in this study, we show that il-4 regulates not only the frequency and function of innate memory cd8(+) t cells, but also regulates eomes expression levels and functional reactivity of naiv ...201627298446
alterations in cellular metabolism modulate cd1d-mediated nkt-cell responses.natural killer t (nkt) cells play a critical role in the host's innate immune response. cd1d-mediated presentation of glycolipid antigens to nkt cells has been established; however, the mechanisms by which nkt cells recognize infected or cancerous cells remain unclear. 5(')-amp activated protein kinase (ampk) is a master regulator of lipogenic pathways. we hypothesized that activation of ampk during infection and malignancy could alter the repertoire of antigens presented by cd1d and serve as a ...201627297969
development and application of elisa for the detection of igg antibodies to lymphocytic choriomeningitis virus.lymphocytic choriomeningitis virus (lcmv) is a neglected human pathogen, which can cause severe illnesses in humans. the most vulnerable are the human foetus and immunosuppressed individuals. since there is no commercially available enzyme-linked immunosorbent assay (elisa) for the diagnosis of anti-lcmv antibodies in human sera, we developed a sandwich elisa method detecting anti-nucleoprotein igg antibodies, using a specific monoclonal anti-nucleoprotein antibody and cells persistently infecte ...201627265463
psgl-1 is an immune checkpoint regulator that promotes t cell exhaustion.chronic viruses and cancers thwart immune responses in humans by inducing t cell dysfunction. using a murine chronic virus that models human infections, we investigated the function of the adhesion molecule, p-selectin glycoprotein ligand-1 (psgl-1), that is upregulated on responding t cells. psgl-1-deficient mice cleared the virus due to increased intrinsic survival of multifunctional effector t cells that had downregulated pd-1 as well as other inhibitory receptors. notably, this response resu ...201627192578
cd8 engineered cytotoxic t cells reprogram melanoma tumor environment.cytotoxic t lymphocytes (ctl) from cd8β-deficient mice have powerful fasl-mediated cytotoxicity and ifnγ responses, but ablated ca(2+) and nfat signaling, which can be restored by transduction with cd8β. upon infection with lymphocytic choriomeningitis virus (lcmv), these cells yielded gp33-specific ctl (cd8βr) that exhibited high fasl/fas-mediated cytotoxicity, ifnγ cxcl9 and 10 chemokine responses. transfer of these cells in b16-gp33 tumor bearing mice resulted in (i) massive t cell tumor infi ...201627141342
prenatal brain mri of fetuses with zika virus infection.an outbreak of zika virus was observed in french polynesia in 2013-2014. maternal zika virus infection has been associated with fetal microcephaly and severe cerebral damage.201627090801
generation of lymphocytic choriomeningitis virus based vaccine vectors.vaccination with a recombinant lcmv based vector expressing tumor-associated or viral antigens is a safe and versatile method to induce an immune response against tumors or viral infections. here, we describe the generation of recombinant lcmv vectors in which the gene encoding the viral lcmv-gp was substituted with a gene of interest (vaccine antigen). this renders the vaccine vector propagation-incompetent while it preserves the property of eliciting a strong cytotoxic t cell response.201627076310
enhanced local and systemic anti-melanoma cd8+ t cell responses after memory t cell-based adoptive immunotherapy in mice.adoptive cell transfer (act) melanoma immunotherapy typically employs acutely activated effector cd8+ t cells for their ability to rapidly recognize and clear antigen. we have previously observed that effector cd8+ t cells are highly susceptible to melanoma-induced suppression, whereas memory cd8+ t cells are not. although memory t cells have been presumed to be potentially advantageous for act, the kinetics of local and systemic t cell responses after effector and memory act have not been compa ...201627011014
the lymphocytic choriomeningitis virus matrix protein ppxy late domain drives the production of defective interfering particles.arenaviruses cause severe diseases in humans but establish asymptomatic, lifelong infections in rodent reservoirs. persistently-infected rodents harbor high levels of defective interfering (di) particles, which are thought to be important for establishing persistence and mitigating virus-induced cytopathic effect. little is known about what drives the production of di particles. we show that neither the ppxy late domain encoded within the lymphocytic choriomeningitis virus (lcmv) matrix protein ...201627010636
errata: vol. 65, no. 9.in the report, "notes from the field: lymphocytic choriomeningitis virus meningoencephalitis from a household rodent infestation - minnesota, 2015," on page 248, the first sentence of the fourth paragraph should read, "the family was referred for integrated pest management services through the st. paul-ramsey county department of public health, with assistance from the minnesota department of health healthy homes grant program."201627010589
high frequencies of anti-host reactive cd8+ t cells ignore non-hematopoietic antigen after bone marrow transplantation in a murine model.graft versus host disease (gvhd) occurs in 20% of cases with patients having an mhc i matched bone marrow transplantation (bmt). mechanisms causing this disease remain to be studied.201627007114
lymphocytic choriomeningitis virus: ways to establish and maintain non-cytolytic persistent infection.lymphocytic choriomeningitis virus (lcmv) is a prototype virus of the arenaviridae family that is attracting considerable attention both as an important experimental model system to study acute and persistent viral infections, and as a neglected human pathogen of clinical significance. notably, lcmv is capable of persisting in an infected host, and escaping the immune system. here we describe the strategies used by the virus to establish and maintain long-term infection in vitro and/or persisten ...201626982463
il-10 induces t cell exhaustion during transplantation of virus infected hearts.unexpected transmissions of viral pathogens during solid organ transplantation (sot) can result in severe, life-threatening diseases in transplant recipients. immune activation contributes to disease onset. however mechanisms balancing the immune response against transmitted viral infection through organ transplantation remain unknown. methods &201626963287
il-2 consumption by highly activated cd8 t cells induces regulatory t-cell dysfunction in patients with hemophagocytic lymphohistiocytosis.hemophagocytic lymphohistiocytosis (hlh) is a severe inflammatory condition driven by excessive cd8(+) t-cell activation. hlh occurs as both acquired and familial hemophagocytic lymphohistiocytosis (fhl) forms. in both conditions, a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and life-threatening. recent studies have attributed the key distal event to excessive ifn-γ production; however, the proximal events driving immune dysregulation hav ...201626947179
viral escape mutant epitope maintains tcr affinity for antigen yet curtails cd8 t cell responses.t cells have the remarkable ability to recognize antigen with great specificity and in turn mount an appropriate and robust immune response. critical to this process is the initial t cell antigen recognition and subsequent signal transduction events. this antigen recognition can be modulated at the site of tcr interaction with peptide:major histocompatibility (pmhc) or peptide interaction with the mhc molecule. both events could have a range of effects on t cell fate. though responses to antigen ...201626915099
novel drug discovery approaches for treating arenavirus infections.arenaviruses are enveloped negative stranded viruses endemic in africa, europe and the americas. several arenaviruses cause severe viral hemorrhagic fever with high mortality in humans and pose serious public health threats. so far, there are no fda-approved vaccines and therapeutic options are restricted to the off-label use of ribavirin. the major human pathogenic arenaviruses are classified as category a agents and require biosafety level (bsl)-4 containment.201626882218
polygenic mutations in the cytotoxicity pathway increase susceptibility to develop hlh immunopathology in mice.hemophagocytic lymphohistiocytosis (hlh) is a life-threatening hyperinflammatory disease. inherited forms of hlh are caused by biallelic mutations in several effectors of granule-dependent lymphocyte-mediated cytotoxicity. a small proportion of patients with a so-called "secondary" form of hlh, which develops in the aftermath of infection, autoimmunity, or cancer, carry a monoallelic mutation in one or more hlh-associated genes. although this observation suggests that hlh may have a polygenic mo ...201626864340
mcl-1 regulates effector and memory cd8 t-cell differentiation during acute viral infection.mcl-1, an anti-apoptotic member of bcl-2 family maintains cell viability during clonal expansion of cd8 t cells, but the cell intrinsic role of mcl-1 in contraction of effectors or the number of memory cd8 t cells is unknown. mcl-1 levels decline during the contraction phase but rebound to high levels in memory cd8 t cells. therefore, by overexpressing mcl-1 in cd8 t cells we asked whether limiting levels of mcl-1 promote contraction of effectors and constrain cd8 t-cell memory. mcl-1 overexpres ...201626855329
a context-dependent role for il-21 in modulating the differentiation, distribution, and abundance of effector and memory cd8 t cell subsets.the activation of naive cd8 t cells typically results in the formation of effector cells (te) as well as phenotypically distinct memory cells that are retained over time. memory cd8 t cells can be further subdivided into central memory, effector memory (tem), and tissue-resident memory (trm) subsets, which cooperate to confer immunological protection. using mixed bone marrow chimeras and adoptive transfer studies in which cd8 t cells either do or do not express il-21r, we discovered that under h ...201626826252
janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis.hemophagocytic lymphohistiocytosis (hlh) comprises an emerging spectrum of inherited and noninherited disorders of the immune system characterized by the excessive production of cytokines, including interferon-γ and interleukins 2, 6, and 10 (il-2, il-6, and il-10). the janus kinases (jaks) transduce signals initiated following engagement of specific receptors that bind a broad array of cytokines, including those overproduced in hlh. based on the central role for cytokines in the pathogenesis of ...201626825707
virus-specific antibodies allow viral replication in the marginal zone, thereby promoting cd8(+) t-cell priming and viral control.clinically used human vaccination aims to induce specific antibodies that can guarantee long-term protection against a pathogen. the reasons that other immune components often fail to induce protective immunity are still debated. recently we found that enforced viral replication in secondary lymphoid organs is essential for immune activation. in this study we used the lymphocytic choriomeningitis virus (lcmv) to determine whether enforced virus replication occurs in the presence of virus-specifi ...201626805453
novel model of double transgenic mouse results in autoimmune diabetes in males.identifying the type of diabetogenic cd8(+) t cells that initiate autoimmune diabetes (aid) is a critical step in designing appropriate strategies for the early detection of beta cell-directed autoimmunity and its progression to diabetes. we generated a novel double transgenic (tg) mouse model on the naturally diabetes resistant c57bl/6 background, co-expressing two transgenes including a specific tcr anti-lymphocytic choriomeningitis virus nucleoprotein (lcmv-np) carried by cd8(+) t cells and l ...201627683954
antigen exposure shapes the ratio between antigen-specific tregs and conventional t cells in human peripheral blood.the t-cell receptor (tcr) is required for maturation and function of regulatory t cells (tregs), but the ligand specificities of tregs outside the context of transgenic tcrs are largely unknown. using peptide-mhc tetramers, we isolated rare specific foxp3(+) cells directly ex vivo from adult peripheral blood and defined their frequency and phenotype. we find that a proportion of circulating tregs recognize foreign antigens and the frequency of these cells are similar to that of self-reactive tre ...201627681619
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