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vaccine targeting of subdominant cd8+ t cell epitopes increases the breadth of the t cell response upon viral challenge, but may impair immediate virus control.as a result of the difficulties in making efficient vaccines against genetically unstable viruses such as hiv, it has been suggested that future vaccines should preferentially target subdominant epitopes, the idea being that this should allow a greater breadth of the induced t cell response and, hence, a greater efficiency in controlling escape variants. however, to our knowledge the evidence supporting this concept is limited at best. to improve upon this, we used the murine lymphocytic choriom ...201626873995
type i and type ii interferon coordinately regulate suppressive dendritic cell fate and function during viral persistence.persistent viral infections are simultaneously associated with chronic inflammation and highly potent immunosuppressive programs mediated by il-10 and pdl1 that attenuate antiviral t cell responses. inhibiting these suppressive signals enhances t cell function to control persistent infection; yet, the underlying signals and mechanisms that program immunosuppressive cell fates and functions are not well understood. herein, we use lymphocytic choriomeningitis virus infection (lcmv) to demonstrate ...201626808628
tnfrs and control of chronic lcmv infection: implications for therapy.the control of persistent viral infections requires the immune system to limit the spread of the virus while avoiding immunopathology. recent studies have revealed that members of the tumor necrosis factor receptor (tnfr) superfamily play unique and pivotal roles in control of chronic lymphocytic choriomeningitis virus (lcmv) infection and in some settings can tip the balance between immune control and immune pathology. we review these findings and discuss how our understanding of the role of tn ...201526481667
methamphetamine mediates immune dysregulation in a murine model of chronic viral infection.methamphetamine (meth) is a highly addictive psychostimulant that not only affects the brain and cognitive functions but also greatly impacts the host immune system, rendering the body susceptible to infections and exacerbating the severity of disease. although there is gathering evidence about meth abuse and increased incidence of hiv and other viral infections, not much is known about the effects on the immune system in a chronic viral infection setting. we have used the lymphocytic choriomeni ...201526322025
modulation of siv and hiv dna vaccine immunity by fas-fasl signaling.signaling through the fas/apo-1/cd95 death receptor is known to affect virus-specific cell-mediated immune (cmi) responses. we tested whether modulating the fas-apoptotic pathway can enhance immune responses to dna vaccination or lymphocytic choriomeningitis virus (lcmv) infection. mice were electroporated with plasmids expressing a variety of pro- or anti-apoptotic molecules related to fas signaling and then either lcmv-infected or injected with plasmid dna expressing siv or hiv antigens. where ...201525807052
lymphocytic choriomeningitis virus persistence promotes effector-like memory differentiation and enhances mucosal t cell distribution.vaccines are desired that maintain abundant memory t cells at nonlymphoid sites of microbial exposure, where they may be anatomically positioned for immediate pathogen interception. here, we test the impact of antigen persistence on mouse cd8 and cd4 t cell distribution and differentiation by comparing responses to infections with different strains of lcmv that cause either acute or chronic infections. we used in vivo labeling techniques that discriminate between t cells present within tissues a ...201525395301
decoding the complexity of type i interferon to treat persistent viral infections.type i interferons (ifn-i) are a broad family of cytokines that are central to the innate immune response. these proteins have long been appreciated for the critical roles they play in restraining viral infections and shaping antiviral immune responses. however, in recent years there has been increased awareness of the immunosuppressive actions of these proteins as well. although there are many current therapeutic applications to manipulate ifn-i pathways, we have limited understanding of the me ...201324216022
distinct roles of nk cells in viral immunity during different phases of acute friend retrovirus infection.in many virus infections natural killer (nk) cells are critical for the rapid containment of virus replication. polymorphisms in nk cell receptors as well as viral escape from nk cell responses are associated with pathogenesis and viral loads in hiv-infected individuals, emphasizing their importance in retroviral immunity. in contrast, nk cells of lcmv-infected mice dampened virus-specific t cell responses resulting in impaired virus control. thus, the exact role of nk cells during different pha ...201324182203
interfering with type i interferon: a novel approach to purge persistent viral infection. 201323974094
enhanced t cell function in a mouse model of human glycosylation.clinical evidence for a more active immune response in humans compared with our closest hominid relative, the chimpanzee, includes the progression of hiv infection to aids, hepatitis b- and c-related inflammation, autoimmunity, and unwanted harmful immune responses to viral gene transfer vectors. humans have a unique mutation of the enzyme cmp-n-acetylneuraminic acid hydroxylase (cmah), causing loss of expression of the sialic acid neu5gc. this mutation, occurring 2 million years ago, likely alt ...201323709682
normal development and function but impaired memory phenotype of cd8⁺ t cells in transgenic mice expressing hiv-1 nef in its natural target cells.we studied the impact of hiv nef on cd8(+) t cells in a mouse model of aids, the cd4c/hiv(nef) transgenic (tg) mice. we found that negative and positive thymic selections of cd8(+) t cells proceeded normally in nef tg mice bred respectively with hy or ot-1 tcr tg mice. tg peripheral cd8(+) t cells showed an activated phenotype and enhanced cell division in vivo and proliferated efficiently when stimulated in vitro with antigenic peptide. when challenged with lcmv(armstrong), nef tg mice develope ...201323433958
alternative serotype adenovirus vaccine vectors elicit memory t cells with enhanced anamnestic capacity compared to ad5 vectors.the failure of the adenovirus serotype 5 (ad5) vector-based human immunodeficiency virus type 1 (hiv-1) vaccine in the step study has led to the development of adenovirus vectors derived from alternative serotypes, such as ad26, ad35, and ad48. we have recently demonstrated that vaccines using alternative-serotype ad vectors confer partial protection against stringent simian immunodeficiency virus (siv) challenges in rhesus monkeys. however, phenotypic differences between the t cell responses el ...201323152535
chronic hiv infection affects the expression of the 2 transcription factors required for cd8 t-cell differentiation into cytolytic effectors.cd8 t cells lose the capacity to control hiv infection, but the extent of the impairment of cd8 t-cell functions and the mechanisms that underlie it remain controversial. here we report an extensive ex vivo analysis of hiv-specific cd8 t cells, covering the expression of 16 different molecules involved in cd8 function or differentiation. this approach gave remarkably homogeneous readouts in different donors and showed that cd8 dysfunction in chronic hiv infection was much more severe than descri ...201222490682
acute viral respiratory infection rapidly induces a cd8+ t cell exhaustion-like phenotype.acute viral infections typically generate functional effector cd8(+) t cells (tcd8) that aid in pathogen clearance. however, during acute viral lower respiratory infection, lung tcd8 are functionally impaired and do not optimally control viral replication. t cells also become unresponsive to ag during chronic infections and cancer via signaling by inhibitory receptors such as programmed cell death-1 (pd-1). pd-1 also contributes to tcd8 impairment during viral lower respiratory infection, but ho ...201526401005
the role of virus infection in deregulating the cytokine response to secondary bacterial infection.proinflammatory cytokines are produced by macrophages and dendritic cells (dcs) after infection to stimulate t helper (th) cells, linking innate and adaptive immunity. virus infections can deregulate the proinflammatory cytokine response like tumor necrosis factor-α and interleukin (il)-2, making the host more susceptible to secondary bacterial infections. studies using various viruses such as lymphocytic choriomeningitis virus, influenza a virus, and human immunodeficiency virus have revealed s ...201526308503
the pulmonary localization of virus-specific t lymphocytes is governed by the tissue tropism of infection.the migration of pathogen-specific t cells into nonlymphoid tissues, such as the lung, is critical to control peripheral infections. use of in vivo intravascular labeling of leukocytes has allowed for improved discrimination between cells located in the blood from cells present within peripheral tissues, such as the lung. this is particularly important in the lung, which is comprised of an intricate network of blood vessels that harbors a large proportion of the total blood volume at any given t ...201424899187
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
the pi3k/akt pathway contributes to arenavirus budding.several arenaviruses, chiefly lassa virus (lasv), cause hemorrhagic fever (hf) disease in humans and pose a significant public health concern in regions where they are endemic. on the other hand, evidence indicates that the globally distributed prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) is a neglected human pathogen. the phosphatidylinositol 3-kinase (pi3k)/akt pathway participates in many cellular processes, including cell survival and differentiation, and also has been sho ...201222345463
high-resolution structure of the n-terminal endonuclease domain of the lassa virus l polymerase in complex with magnesium ions.lassa virus (lasv) causes deadly hemorrhagic fever disease for which there are no vaccines and limited treatments. lasv-encoded l polymerase is required for viral rna replication and transcription. the functional domains of l-a large protein of 2218 amino acid residues-are largely undefined, except for the centrally located rna-dependent rna polymerase (rdrp) motif. recent structural and functional analyses of the n-terminal region of the l protein from lymphocytic choriomeningitis virus (lcmv), ...201424516554
residues k465 and g467 within the cytoplasmic domain of gp2 play a critical role in the persistence of lymphocytic choriomeningitis virus in mice.several arenaviruses, chiefly lassa virus (lasv), cause hemorrhagic fever disease in humans and pose serious public health concerns in their regions of endemicity. moreover, mounting evidence indicates that the worldwide-distributed prototypic arenavirus, lymphocytic choriomeningitis virus (lcmv), is a neglected human pathogen of clinical significance. we have documented that a recombinant lcmv containing the glycoprotein (gpc) gene of lasv within the backbone of the immunosuppressive clone 13 ( ...201627581982
lassa virus cell entry via dystroglycan involves an unusual pathway of macropinocytosis.the pathogenic old world arenavirus lassa virus (lasv) causes a severe hemorrhagic fever with a high rate of mortality in humans. several lasv receptors, including dystroglycan (dg), tam receptor tyrosine kinases, and c-type lectins, have been identified, suggesting complex receptor use. upon receptor binding, lasv enters the host cell via an unknown clathrin- and dynamin-independent pathway that delivers the virus to late endosomes, where fusion occurs. here we investigated the mechanisms under ...201627147735
the high degree of sequence plasticity of the arenavirus noncoding intergenic region (igr) enables the use of a nonviral universal synthetic igr to attenuate arenaviruses.hemorrhagic fever arenaviruses (hfas) pose important public health problems in regions where they are endemic. concerns about human-pathogenic arenaviruses are exacerbated because of the lack of fda-licensed arenavirus vaccines and because current antiarenaviral therapy is limited to an off-label use of ribavirin that is only partially effective. we have recently shown that the noncoding intergenic region (igr) present in each arenavirus genome segment, the s and l segments (s-igr and l-igr, res ...201626739049
general molecular strategy for development of arenavirus live-attenuated vaccines.hemorrhagic fever arenaviruses (hfa) pose important public health problems in regions where they are endemic. thus, lassa virus (lasv) infects several hundred thousand individuals yearly in west africa, causing a large number of lassa fever cases associated with high morbidity and mortality. concerns about human-pathogenic arenaviruses are exacerbated because of the lack of fda-licensed arenavirus vaccines and because current antiarenaviral therapy is limited to an off-label use of ribavirin tha ...201526401045
international external quality assessment study for molecular detection of lassa virus.lassa virus (lasv) is a causative agent of hemorrhagic fever in west africa. in recent years, it has been imported several times to europe and north america. the method of choice for early detection of lasv in blood is rt-pcr. therefore, the european network for diagnostics of 'imported' viral diseases (enivd) performed an external quality assessment (eqa) study for molecular detection of lasv. a proficiency panel of 13 samples containing various concentrations of inactivated lasv strains josiah ...201525996783
evolution of recombinant lymphocytic choriomeningitis virus/lassa virus in vivo highlights the importance of the gpc cytosolic tail in viral fitness.a key characteristic of arenaviruses is their ability to establish persistent infection in their natural host. different factors like host age, viral dose strain, and route of infection may contribute to the establishment of persistence. however, the molecular mechanisms governing persistence are not fully understood. here, we describe gain-of-function mutations of lymphocytic choriomeningitis virus (lcmv) expressing lassa virus (lasv) gp, which can prolong viremia in mice depending on the seque ...201424829355
pathogenesis of lassa fever virus infection: i. susceptibility of mice to recombinant lassa gp/lcmv chimeric virus.lassa virus (lasv) is a bsl-4 restricted agent. to allow study of infection by lasv under bsl-2 conditions, we generated a recombinant virus in which the lasv glycoprotein (gp) was placed on the backbone of lymphocytic choriomeningitis virus (lcmv) cl13 nucleoprotein, z and polymerase genes (rlcmv cl13/lasv gp). the recombinant virus displayed high tropism for dendritic cells following in vitro or in vivo infection. inoculation of immunocompetent adults resulted in an acute infection, generation ...201323684417
targeting virulence mechanisms for the prevention and therapy of arenaviral hemorrhagic fever.a number of arenaviruses are pathogenic for humans, but they differ significantly in virulence. lassa virus, found in west africa, causes severe hemorrhagic fever (hf), while the other principal old world arenavirus, lymphocytic choriomeningitis virus, causes mild illness in persons with normal immune function, and poses a threat only to immunocompromised individuals. the new world agents, including junin, machupo and sabia virus, are highly pathogenic for humans. arenaviral hf is characterized ...201323261843
the role of proteolytic processing and the stable signal peptide in expression of the old world arenavirus envelope glycoprotein ectodomain.maturation of the arenavirus gp precursor (gpc) involves proteolytic processing by cellular signal peptidase and the proprotein convertase subtilisin kexin isozyme 1 (ski-1)/site 1 protease (s1p), yielding a tripartite complex comprised of a stable signal peptide (ssp), the receptor-binding gp1, and the fusion-active transmembrane gp2. here we investigated the roles of ski-1/s1p processing and ssp in the biosynthesis of the recombinant gp ectodomains of lymphocytic choriomeningitis virus (lcmv) ...201323218200
plasmacytoid dendritic cells are productively infected and activated through tlr-7 early after arenavirus infection.the antiviral response is largely mediated by dendritic cells (dcs), including conventional (c) dcs that function as antigen-presenting cells, and plasmacytoid (p) dcs that produce type i interferons, making them an attractive target for viruses. we find that the old world arenaviruses lymphocytic choriomeningitis virus clone 13 (lcmv cl13) and lassa virus bind pdcs to a greater extent than cdcs. consistently, lcmv cl13 targets pdcs early after in vivo infection of its natural murine host and es ...201222704622
cell surface molecules involved in infection mediated by lymphocytic choriomeningitis virus glycoprotein.the glycoprotein (gp) of lymphocytic choriomeningitis virus (lcmv), the prototype arenavirus, is a promising envelope protein of lentiviral pseudotype vectors for gene therapy. the distribution of dystroglycan, a known receptor for lcmv, cannot explain the narrow tropism of lcmv-gp-pseudotypes. here, we examined whether infection of lcmv-gp-pseudotypes was affected by the expression of four cell surface molecules-axl and tyro3 (from the tam family) and dc-sign and lsectin (from the c-type lectin ...201222673088
pathogenic old world arenaviruses inhibit tlr2/mal-dependent proinflammatory cytokines in vitro.lymphocytic choriomeningitis virus (lcmv), the prototype arenavirus, and lassa virus (lasv), the causative agent of lassa fever (lf), have extensive strain diversity and significant variations in pathogenicity for humans and experimental animals. the we strain of lcmv (lcmv-we), but not the armstrong (arm) strain, induces a fatal lf-like disease in rhesus macaques. we also demonstrated that lasv infection of human macrophages and endothelial cells resulted in reduced levels of proinflammatory cy ...201222532679
molecular characterization of the processing of arenavirus envelope glycoprotein precursors by subtilisin kexin isozyme-1/site-1 protease.a crucial step in the life cycle of arenaviruses is the biosynthesis of the mature fusion-active viral envelope glycoprotein (gp) that is essential for virus-host cell attachment and entry. the maturation of the arenavirus gp precursor (gpc) critically depends on proteolytic processing by the cellular proprotein convertase (pc) subtilisin kexin isozyme-1 (ski-1)/site-1 protease (s1p). here we undertook a molecular characterization of the ski-1/s1p processing of the gpcs of the prototypic arenavi ...201222357276
self-association of lymphocytic choriomeningitis virus nucleoprotein is mediated by its n-terminal region and is not required for its anti-interferon function.arenaviruses have a bisegmented, negative-strand rna genome. both the large (l) and small (s) genome segments use an ambisense coding strategy to direct the synthesis of two viral proteins. the l segment encodes the virus polymerase (l protein) and the matrix z protein, whereas the s segment encodes the nucleoprotein (np) and the glycoprotein precursor (gpc). nps are the most abundant viral protein in infected cells and virions and encapsidate genomic rna species to form an np-rna complex that, ...201222258244
lymphocytic choriomeningitis virus expands a population of nkg2d+cd8+ t cells that exacerbates disease in mice coinfected with leishmania major.leishmaniasis is a significant neglected tropical disease that is associated with a wide range of clinical presentations and a lifelong persistent infection. because of the chronic nature of the disease, there is a high risk for coinfection occurring in patients, and how coinfections influence the outcome of leishmaniasis is poorly understood. to address this issue, we infected mice with leishmania major and 2 wk later with lymphocytic choriomeningitis virus (lcmv) and then monitored the course ...201526290604
t cell lipid peroxidation induces ferroptosis and prevents immunity to infection.the selenoenzyme glutathione peroxidase 4 (gpx4) is a major scavenger of phospholipid hydroperoxides. although gpx4 represents a key component of the reactive oxygen species-scavenging network, its relevance in the immune system is yet to be defined. here, we investigated the importance of gpx4 for physiological t cell responses by using t cell-specific gpx4-deficient mice. our results revealed that, despite normal thymic t cell development, cd8(+) t cells from t(δgpx4/δgpx4) mice had an intrins ...201525824823
engagement of nkg2d on bystander memory cd8 t cells promotes increased immunopathology following leishmania major infection.one of the hallmarks of adaptive immunity is the development of a long-term pathogen specific memory response. while persistent memory t cells certainly impact the immune response during a secondary challenge, their role in unrelated infections is less clear. to address this issue, we utilized lymphocytic choriomeningitis virus (lcmv) and listeria monocytogenes immune mice to investigate whether bystander memory t cells influence leishmania major infection. despite similar parasite burdens, lcmv ...201424586170
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
type i interferons in infectious disease.type i interferons (ifns) have diverse effects on innate and adaptive immune cells during infection with viruses, bacteria, parasites and fungi, directly and/or indirectly through the induction of other mediators. type i ifns are important for host defence against viruses. however, recently, they have been shown to cause immunopathology in some acute viral infections, such as influenza virus infection. conversely, they can lead to immunosuppression during chronic viral infections, such as lympho ...201525614319
dynamic functional modulation of cd4+ t cell recall responses is dependent on the inflammatory environment of the secondary stimulus.the parameters that modulate the functional capacity of secondary th1 effector cells are poorly understood. in this study, we employ a serial adoptive transfer model system to show that the functional differentiation and secondary memory potential of secondary cd4+ effector t cells are dependent on the inflammatory environment of the secondary challenge. adoptive transfer of tcr transgenic lymphocytic choriomeningitis virus (lcmv) glycoprotein-specific smarta memory cells into lcmv-immune hosts, ...201424854337
vsv-gp: a potent viral vaccine vector that boosts the immune response upon repeated applications.antivector immunity limits the response to homologous boosting for viral vector vaccines. here, we describe a new, potent vaccine vector based on replication-competent vesicular stomatitis virus pseudotyped with the glycoprotein of the lymphocytic choriomeningitis virus (vsv-gp), which we previously showed to be safe in mice. in mice, vsv and vsv-gp encoding ovalbumin (ova) as a model antigen (vsv-ova and vsv-gp-ova) induced equal levels of ova-specific humoral and cellular immune responses upon ...201424554655
adenovirus-based vaccine against listeria monocytogenes: extending the concept of invariant chain linkage.the use of replication-deficient adenoviruses as vehicles for transfer of foreign genes offers many advantages in a vaccine setting, eliciting strong cellular immune responses involving both cd8(+) and cd4(+) t cells. further improving the immunogenicity, tethering of the inserted target ag to mhc class ii-associated invariant chain (ii) greatly enhances both the presentation of most target ags, as well as overall protection against viral infection, such as lymphocytic choriomeningitis virus (lc ...201324043891
homeostatic division is not necessary for antigen-specific cd4+ memory t cell persistence.cd4(+) memory t cells are generated in response to infection or vaccination, provide protection to the host against reinfection, and persist through a combination of enhanced survival and slow homeostatic turnover. we used timed deletion of the tcr-signaling adaptor molecule src homology 2 domain-containing phosphoprotein of 76 kda (slp-76) with mhc:peptide tetramers to study the requirements for tonic tcr signals in the maintenance of polyclonal ag-specific cd4(+) memory t cells. slp-76-deficie ...201222956580
lymphocytic choriomeningitis, ljungan and orthopoxvirus seroconversions in patients hospitalized due to acute puumala hantavirus infection.the emergence and re-emergence of zoonotic and vector-borne diseases are increasing in europe. prominent rodent-borne zoonotic viruses include puumala hantavirus (puuv; the causative agent of nephropathia epidemica, ne), lymphocytic choriomeningitis virus (lcmv), and orthopoxviruses (opv). in addition, ljungan virus (lv) is considered a potentially zoonotic virus.201627721109
serological survey of rodent-borne viruses in finnish field voles.in northern europe, rodent populations display cyclic density fluctuations that can be correlated with the human incidence of zoonotic diseases they spread. during density peaks, field voles (microtus agrestis) become one of the most abundant rodent species in northern europe, yet little is known of the viruses they host. we screened 709 field voles, trapped from 14 sites over 3 years, for antibodies against four rodent-borne, potentially zoonotic viruses or virus groups-hantaviruses, lymphocyti ...201424689532
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
cd4 t helper cells instruct lymphopenia-induced memory-like cd8 t cells for control of acute lcmv infection.lymphopenic conditions lead to expansion of memory-like t cells (tml), which develop from naïve t cells by spontaneous proliferation. tml cells are often increased in the elderly population, aids patients, and patients recovering from radio- or chemotherapy. at present, it is unclear whether tml cells can efficiently respond to foreign antigen and participate in antiviral immunity. to address this question, we analyzed the immune response during acute low-dose infection with lymphocytic choriome ...201628066432
the tcf1-bcl6 axis counteracts type i interferon to repress exhaustion and maintain t cell stemness.during chronic viral infections and in cancer, t cells become dysfunctional, a state known as t cell exhaustion. although it is well recognized that memory cd8 t cells account for the persistence of cd8 t cell immunity after acute infection, how exhausted t cells persist remains less clear. using chronic infection with lymphocytic choriomeningitis virus clone 13 and tumor samples, we demonstrate that cd8 t cells differentiate into a less exhausted tcf1(high) and a more exhausted tcf1(low) popula ...201628018990
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
type i interferon impairs specific antibody responses early during establishment of lcmv infection.elicitation of type i interferon (ifn-i) has been shown to both enhance and impair cell-mediated immune responses in acute and persistent viral infections, respectively. here, we show that, in addition to its effect on t cells, ifn-i drives impairment of specific antibody responses through interaction with b cells in the acute phase of lymphocytic choriomeningitis virus (lcmv) infection. this impairment was limited to the t cell-dependent b cell response and was associated with disruption of b c ...201627994594
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
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
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
interferon-driven deletion of antiviral b cells at the onset of chronic infection.inadequate antibody responses and perturbed b cell compartments represent hallmarks of persistent microbial infections, but the mechanisms whereby persisting pathogens suppress humoral immunity remain poorly defined. using adoptive transfer experiments in the context of a chronic lymphocytic choriomeningitis virus (lcmv) infection of mice, we have documented rapid depletion of virus-specific b cells that coincided with the early type i interferon response to infection. we found that the loss of ...201627872905
inflammatory monocytes hinder antiviral b cell responses.antibodies are critical for protection against viral infections. however, several viruses, such as lymphocytic choriomeningitis virus (lcmv), avoid the induction of early protective antibody responses by poorly understood mechanisms. here we analyzed the spatiotemporal dynamics of b cell activation to show that, upon subcutaneous infection, lcmv-specific b cells readily relocate to the interfollicular and t cell areas of the draining lymph node where they extensively interact with cd11b(+)ly6c(h ...201627868108
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
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
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
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
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
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
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
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
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
t-cells underlie some but not all of the cerebellar pathology in a neonatal rat model of congenital lymphocytic choriomeningitis virus infection.lymphocytic choriomeningitis virus (lcmv) infection during pregnancy injures the human fetal brain. neonatal rats inoculated with lcmv are an excellent model of congenital lcmv infection because they develop cerebellar injuries similar to those in humans. to evaluate the role of t-lymphocytes in lcmv-induced cerebellar pathology, congenitally athymic rats, deficient in t-lymphocytes were compared with euthymic rats. peak viral titers and cellular targets of infection were similar, but viral clea ...201627667772
t-cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases.during acute viral infection cd8 t cells rapidly expand before contracting down to a persistent memory population that confers long-lasting immunity. however when the antigen persists, such as during chronic viral infection, a dysfunctional process termed 'exhaustion' limits the antiviral response, facilitating ongoing viraemia and poor clinical outcome. cd8 t-cell exhaustion was originally identified in lymphocytic choriomeningitis virus infection of mice; however, new evidence has shown that e ...201627577866
tcr independent suppression of cd8(+) t cell cytokine production mediated by ifnγ in vivo.cd8(+) memory t cells produce ifnγ within hours of secondary infection, but this is quickly terminated in vivo despite the presence of stimulatory viral antigen, suggesting that active suppression occurs. herein, we investigated the in vivo effector function of cd8(+) memory t cells during successive encounters with viral antigen. cd8(+) t cells in immune mice receiving prior viral or peptide challenge failed to reproduce ifnγ during lcmv rechallenge. surprisingly, this refractory state was indu ...201627564543
dendritic cells are dispensable for t cell priming and control of acute lymphocytic choriomeningitis virus infection.dendritic cells (dcs) are considered to be the major apcs with potent activity for priming of naive cd4 and cd8 t cells. however, t cell priming can also be achieved by other apcs including macrophages, b cells, or even nonhematopoietic cell types. systemic low-dose infection of mice with lymphocytic choriomeningitis virus (lcmv) results in massive expansion of virus-specific cd4 and cd8 t cells. to determine the role of dcs as apcs and source of type i ifns in this infection model, we used δdc ...201627549169
t cell factor 1-expressing memory-like cd8(+) t cells sustain the immune response to chronic viral infections.chronic infections promote the terminal differentiation (or "exhaustion") of t cells and are thought to preclude the formation of memory t cells. in contrast, we discovered a small subpopulation of virus-specific cd8(+) t cells that sustained the t cell response during chronic infections. these cells were defined by, and depended on, the expression of the transcription factor tcf1. transcriptome analysis revealed that this population shared key characteristics of central memory cells but lacked ...201627533016
defining cd8+ t cells that provide the proliferative burst after pd-1 therapy.chronic viral infections are characterized by a state of cd8(+) t-cell dysfunction that is associated with expression of the programmed cell death 1 (pd-1) inhibitory receptor. a better understanding of the mechanisms that regulate cd8(+) t-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted cd8(+) t cells. here we identify a population of virus-specific cd8(+) t cells that proliferate after blockade of the pd-1 inhibitory pathway in ...201627501248
bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor pd-1 are an early driver of cd8(+) t cell exhaustion.dynamic reprogramming of metabolism is essential for t cell effector function and memory formation. however, the regulation of metabolism in exhausted cd8(+) t (tex) cells is poorly understood. we found that during the first week of chronic lymphocytic choriomeningitis virus (lcmv) infection, before severe dysfunction develops, virus-specific cd8(+) t cells were already unable to match the bioenergetics of effector t cells generated during acute infection. suppression of t cell bioenergetics inv ...201627496729
high level of perforin expression is required for effective correction of hemophagocytic lymphohistiocytosis.perforin-1 mutations result in a potentially fatal hemophagocytic lymphohistiocytosis (hlh) with heightened immune activation, hypercytokinemia, pancytopenia, and end-organ damage. at present, hematopoietic stem cell (hsc) transplantation is curative, but limited by donor availability and associated mortality, making gene therapy an attractive alternative approach for hlh. we reported that perforin expression driven by cellular promoters in lentiviral (lv) vectors resulted in significant, albeit ...201627471778
demethylation of the pd-1 promoter is imprinted during the effector phase of cd8 t cell exhaustion.pd-1 is an inhibitory receptor that has a major role in t cell dysfunction during chronic infections and cancer. while demethylation of the pd-1 promoter dna is observed in exhausted t cells isolated from chronically infected individuals, little is known about when this stable demethylation of pd-1 promoter dna is programmed during the course of a chronic infection. to assess if pd-1 promoter dna demethylation is impacted by prolonged stimulation during effector phase of chronic infection, we ad ...201627466420
targeting t cell bioenergetics by modulating p-glycoprotein selectively depletes alloreactive t cells to prevent graft-versus-host disease.t lymphocytes play a central role in many human immunologic disorders, including autoimmune and alloimmune diseases. in hematopoietic stem cell transplantation, acute graft-versus-host-disease (gvhd) is caused by an attack on the recipient's tissues from donor allogeneic t cells. selectively depleting gvhd-causing cells prior to transplant may prevent gvhd. in this study, we evaluated 24 chalcogenorhodamine photosensitizers for their ability to selectively deplete reactive t lymphocytes and iden ...201627456485
high antigen levels induce an exhausted phenotype in a chronic infection without impairing t cell expansion and survival.chronic infections induce t cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as pd-1. what determines the acquisition of this chronic phenotype and how it impacts t cell function remain vaguely understood. using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (lcmv) strains, we uncovered that t cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the freque ...201627455951
a novel phosphoserine motif in the lcmv matrix protein z regulates the release of infectious virus and defective interfering particles.we report that the lymphocytic choriomeningitis virus (lcmv) matrix protein, which drives viral budding, is phosphorylated at serine 41 (s41). a recombinant (r)lcmv bearing a phosphomimetic mutation (s41d) was impaired in infectious and defective interfering (di) particle release, while a non-phosphorylatable mutant (s41a) was not. the s41d mutant was disproportionately impaired in its ability to release di particles relative to infectious particles. thus, di particle production by lcmv may be d ...201627421645
phenotypic and functional analysis of activated regulatory t cells isolated from chronic lymphocytic choriomeningitis virus-infected mice.regulatory t (treg) cells, which express foxp3 as a transcription factor, are subsets of cd4(+) t cells. treg cells play crucial roles in immune tolerance and homeostasis maintenance by regulating the immune response. the primary role of treg cells is to suppress the proliferation of effector t (teff) cells and the production of cytokines such as ifn-γ, tnf-α, and il-2. it has been demonstrated that treg cells' ability to inhibit the function of teff cells is enhanced during persistent pathogen ...201627404802
il-10 regulates memory t cell development and the balance between th1 and follicular th cell responses during an acute viral infection.t cells provide protective immunity against infections by differentiating into effector cells that contribute to rapid pathogen control and by forming memory populations that survive over time and confer long-term protection. thus, understanding the factors that regulate the development of effective t cell responses is beneficial for the design of vaccines and immune-based therapies against infectious diseases. cytokines play important roles in shaping t cell responses, and il-10 has been shown ...201627402701
ccr7 expression alters memory cd8 t-cell homeostasis by regulating occupancy in il-7- and il-15-dependent niches.c-c receptor 7 (ccr7) is important to allow t cells and dendritic cells to migrate toward ccl19- and ccl21-producing cells in the t-cell zone of the spleen and lymph nodes. the role of this chemokine receptor in regulating the homeostasis of effector and memory t cells during acute viral infection is poorly defined, however. in this study, we show that ccr7 expression alters memory cd8 t-cell homeostasis following lymphocytic choriomeningitis virus infection. greater numbers of ccr7-deficient me ...201627385825
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
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
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