Publications

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in vivo conversion of bm plasmacytoid dc into cd11b+ conventional dc during virus infection.dc are a highly heterogeneous population that plays a critical role in host defense. we previously demonstrated that virus infection induces bm plasmacytoid dc (pdc) differentiation into cd11b(+) conventional dc (cdc) upon in vitro culture with fms-like tyrosine kinase 3 ligand (flt3l). here we use immunoglobulin d-j rearrangements and pdc adoptive transfer to provide definitive proof supporting bm pdc conversion into cd11b(+) cdc during in vivo viral infection. we show that in vivo bm pdc conve ...200818979509
a griscelli syndrome type 2 murine model of hemophagocytic lymphohistiocytosis (hlh).griscelli syndrome type 2 is caused by mutations in the rab27a gene and is a rare and potentially fatal immune disorder associated with hemophagocytic lymphohistiocytosis (hlh). animal models could provide assistance for better understanding the mechanisms and finding new treatments. rab27a-deficient (ashen) mice do not spontaneously develop hlh. when injected with lymphocytic choriomeningitis virus (lcmv) strain we, rab27a-deficient c57bl/6 mice developed wasting disease, hypothermia, splenomeg ...200818991284
thymus leukemia antigen controls intraepithelial lymphocyte function and inflammatory bowel disease.intestinal intraepithelial lymphocytes (iel) bear a partially activated phenotype that permits them to rapidly respond to antigenic insults. however, this phenotype also implies that iel must be highly controlled to prevent misdirected immune reactions. it has been suggested that iel are regulated through the interaction of the cd8alpha alpha homodimer with the thymus leukemia (tl) antigen expressed by intestinal epithelial cells. we have generated and characterized mice genetically-deficient in ...200819004778
efficacy of il-2- versus il-15-stimulated cd8 t cells in adoptive immunotherapy.we determined the efficacy of in vitro expanded p14 tcr transgenic cd8 t cells to mediate tumor cell elimination and to protect against viral infection in mice. contrary to previous studies, an adoptive transfer model without lymphodepletion, vaccination or cytokine treatment was used. antigen-activated p14 t cells cultured in il-2-containing medium for 7 days (p14il-2) exhibited potent effector cell functions in vitro but did not confer protection against melanoma growth or viral infection. in ...200818825743
lymphocytic choriomeningitis virus infection yields overlapping cd4+ and cd8+ t-cell responses.activation of cd4(+) t cells helps establish and sustain other immune responses. we have previously shown that responses against a broad set of nine cd4(+) t-cell epitopes were present in the setting of lymphocytic choriomeningitis virus (lcmv) armstrong infection in the context of h-2(d). this is quite disparate to the h-2(b) setting, where only two epitopes have been identified. we were interested in determining whether a broad set of responses was unique to h-2(d) or whether additional cd4(+) ...200818829752
persistent virus infection inhibits type i interferon production by plasmacytoid dendritic cells to facilitate opportunistic infections.emerging studies indicate an association between virus-induced impairment in type i interferon (ifn-i) production and enhanced susceptibility to opportunistic infections, which represent a major health problem. here, we provide in vivo evidence that lymphocytic choriomeningitis virus (lcmv) infection of its natural murine host dramatically diminishes the unique capacity of plasmacytoid dendritic cells (pdcs) to secrete high levels of systemic ifn-i. while both acute and persistent lcmv infection ...200818854241
a cell-based luciferase assay amenable to high-throughput screening of inhibitors of arenavirus budding.several arenaviruses cause hemorrhagic fever (hf) disease in humans for which there are no licensed vaccines, and current therapy is limited to the use of ribavirin (rib) that is only partially effective and associated with significant side effects. in addition, compelling evidence indicates that the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) is a neglected human pathogen of clinical significance. therefore, it is important to develop novel and effective anti-arenaviral drug ...200818929379
post-translational modification of {alpha}-dystroglycan is not critical for lymphocytic choriomeningitis virus receptor function in vivo.alpha-dystroglycan (alpha-dg) is a ubiquitously expressed molecule that has been identified as a cellular receptor for lymphocytic choriomeningitis virus (lcmv) and other arenaviruses. recently, it was demonstrated that lcmv receptor function is critically dependent on post-translational modifications, namely glycosylation. in particular, it was shown that o-mannosylation, a rare type of mammalian o-linked glycosylation, is important in determining the binding of lcmv to its cellular receptor. a ...200818931067
cd4 memory t cells divide poorly in response to antigen because of their cytokine profile.immunological memory is a hallmark of adaptive immunity, and understanding t cell memory will be central to the development of effective cell-mediated vaccines. the characteristics and functions of cd4 memory cells have not been well defined. here we demonstrate that the increased size of the secondary response is solely a consequence of the increased antigen-specific precursor frequency within the memory pool. memory cells proliferated less than primary responding cells, even within the same ho ...200818787120
selective expansion of a subset of exhausted cd8 t cells by alphapd-l1 blockade.programmed death-1 (pd-1) regulates t cell exhaustion during chronic infections. blocking the pd-1:pd-ligand (pd-l) pathway reinvigorates exhausted cd8 t cells. exactly how blocking pd-1:pd-l interactions improves t cell immunity, however, remains unclear. pd-1:pd-l blockade could reprogram all exhausted t cells to become antiviral effectors. alternatively, this blockade might selectively expand a subset of exhausted t cells. we have identified two subpopulations of exhausted cd8 t cells during ...200818809920
estimating in vivo death rates of targets due to cd8 t-cell-mediated killing.despite recent advances in immunology, several key parameters determining virus dynamics in infected hosts remain largely unknown. for example, the rate at which specific effector and memory cd8 t cells clear virus-infected cells in vivo is hardly known for any viral infection. we propose a framework to quantify t-cell-mediated killing of infected or peptide-pulsed target cells using the widely used in vivo cytotoxicity assay. we have reanalyzed recently published data on killing of peptide-puls ...200818815293
unaltered neurological disease and mortality in cxcr3-deficient mice infected intracranially with lymphocytic choriomeningitis virus-armstrong.intracranial infection of mice with lymphocytic choriomeningitis virus (lcmv) results in a lethal neurological disease termed lymphocytic choriomeningitis (lcm) that is mediated by antiviral cd8(+) t cells. previous studies have implicated the chemokine receptor cxcr3 and its ligand cxcl10 in cd8(+) t cell trafficking in the brain and in the lethal disease following intracranial infection of mice with the lcmv-traub strain. here we investigated the role of cxcr3 in lcm following intracranial inf ...200819115931
tcr down-regulation controls virus-specific cd8+ t cell responses.the cd3gamma di-leucine-based motif plays a central role in tcr down-regulation. however, little is understood about the role of the cd3gamma di-leucine-based motif in physiological t cell responses. in this study, we show that the expansion in numbers of virus-specific cd8(+) t cells is impaired in mice with a mutated cd3gamma di-leucine-based motif. the cd3gamma mutation did not impair early tcr signaling, nor did it compromise recruitment or proliferation of virus-specific t cells, but it inc ...200819017968
ox40 drives protective vaccinia virus-specific cd8 t cells.vaccinia virus (vacv) affords long-lasting protection against variola virus, the agent of smallpox. vacv-reactive cd8 t cells contribute to protection but their molecular control is unknown. we show that the tnfr molecule ox40 (cd134) controls primary vacv-specific cd8 t cell expansion and antiviral cytokine production and dictates development of strong memory to both dominant and subdominant vacv epitopes. using adoptive transfer of ox40-deficient cd8 tcr-transgenic t cells responding to ag in ...200819017988
emerging viruses in transplantation: there is more to infection after transplant than cmv and ebv.transplant physicians and surgeons are familiar with the risks, clinical behavior, and management of cytomegalovirus in transplant recipients. donor-transmitted viral infections are uncommon but in recent years have brought to light the clinical manifestations of rabies, west nile virus, and lymphocytic choriomeningitis virus in the early posttransplant period. later posttransplant, infection with viruses circulating in the community can occur with a number of pathogens, including some vaccine-p ...200819033999
quantitative pcr technique for detecting lymphocytic choriomeningitis virus in vivo.quantitative pcr (qpcr, or real time pcr (rtpcr)) has emerged as a powerful virologic technique for measuring viral replication and viral loads in humans and animal models. we have developed a qpcr assay to accurately quantify lymphocytic choriomeningitis virus (lcmv) in infected mice. we first validated this assay using plasmid dna and lcmv viral stocks. we then demonstrated that the lcmv qpcr assay can detect lcmv in serum and tissues of chronically infected mice (lcmv-clone 13), with greater ...200817920702
generation and maintenance of listeria-specific cd8+ t cell responses in perforin-deficient mice chronically infected with lcmv.disruption of the perforin gene results in primary immunodeficiency and an increased susceptibility to opportunistic pathogens. perforin-deficient (pko) mice fail to clear primary lymphocytic choriomeningitis virus (lcmv) armstrong, resulting in persistent infection and functional exhaustion of virus-specific cd8+ t cells. cd8+ t cell responses to listeria monocytogenes (lm) challenge within the first week after lcmv infection were diminished in both wt and pko mice, and correlated with enhanced ...200817936870
lymphocytoid choriomeningitis virus activates plasmacytoid dendritic cells and induces a cytotoxic t-cell response via myd88.toll-like receptors (tlrs) and retinoic acid-inducible gene i-like helicases (rlhs) are two major machineries recognizing rna virus infection of innate immune cells. intracellular signaling for tlrs and rlhs is mediated by their cytoplasmic adaptors, i.e., myd88 or trif and ips-1, respectively. in the present study, we investigated the contributions of tlrs and rlhs to the cytotoxic t-lymphocyte (ctl) response by using lymphocytoid choriomeningitis virus (lcmv) as a model virus. the generation o ...200817942529
novel plant virus-based vaccine induces protective cytotoxic t-lymphocyte-mediated antiviral immunity through dendritic cell maturation.currently used vaccines protect mainly through the production of neutralizing antibodies. however, antibodies confer little or no protection for a majority of chronic viral infections that require active involvement of cytotoxic t lymphocytes (ctls). virus-like particles (vlps) have been shown to be efficient inducers of cell-mediated immune responses, but administration of an adjuvant is generally required. we recently reported the generation of a novel vlp system exploiting the self-assembly p ...200817989184
cellular entry of lymphocytic choriomeningitis virus.in contrast to most enveloped viruses that enter the host cell via clathrin-dependent endocytosis, the old world arenavirus lymphocytic choriomeningitis virus (lcmv) enters cells via noncoated vesicles that deliver the virus to endosomes, where ph-dependent membrane fusion occurs. here, we investigated the initial steps of lcmv infection. we found that the attachment of lcmv to its cellular receptor alpha-dystroglycan occurs rapidly and is not dependent on membrane cholesterol. however, subseque ...200818045945
inhibition of cellular entry of lymphocytic choriomeningitis virus by amphipathic dna polymers.the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) represents a powerful experimental model for the study of the basic virology and pathogenesis of arenaviruses. in the present study, we used the lcmv model to evaluate the anti-viral potential of phosphorothioate oligonucleotides against arenaviruses. our findings indicate that amphipathic dna polymers (aps) are potent inhibitors of infection with a series of lcmv isolates with ic(50) in the low nanomolar range. aps target the s ...200818022208
hematopoiesis and immunity of hoxb4-transduced embryonic stem cell-derived hematopoietic progenitor cells.the ability of embryonic stem (es) cells to form cells and tissues from all 3 germ layers can be exploited to generate cells that can be used to treat diseases. in particular, successful generation of hematopoietic cells from es cells could provide safer and less immunogenic cells than bone marrow cells, which require severe host preconditioning when transplanted across major histocompatibility complex barriers. here, we exploited the self-renewal properties of ectopically expressed hoxb4, a hom ...200818056836
efficient induction of mucosal and systemic immune responses by virus-like particles administered intranasally: implications for vaccine design.intranasal (i.n.) immunization aims to induce local as well as systemic immune responses. in the present study, we assessed a vaccine platform based on virus-like particles (vlp) derived from the rna phage qbeta for i.n. immunization. we found that both i.n. and subcutaneous (s.c.) administration of qbeta-vlp elicited strong and comparable specific igg responses in serum and lung. surprisingly, both routes also induced high levels of specific iga in serum. in contrast, only i.n. administration o ...200818081037
rip2 contributes to nod signaling but is not essential for t cell proliferation, t helper differentiation or tlr responses.receptor-interacting protein 2 (rip2), also known as cardiak and rick, has been reported to play a role in both adaptive t cell responses and innate immunity as a mediator in tlr signaling and nucleotide-binding oligomerization domain (nod) signaling. because initial reports remain controversial, we have further examined both innate and adaptive immune responses in rip2-deficient mice on the c57bl/6 background. despite the up-regulation of rip2 after t cell activation, we could not detect any de ...200818085666
differential microenvironment localization of effector and memory cd8 t cells.cd8 t cells are critical for the clearance of intracellular pathogens. upon infection, naive cd8 t cells differentiate into effector cells that target and eliminate infected cells. following clearance of the pathogen, most effector cells die, although a small fraction survives to establish a memory population. subsequent exposure to the same pathogen induces a rapid response of memory t cells and efficient elimination of the pathogen. although much is known about the cd8 t cell response, the pre ...200818097030
cell entry by human pathogenic arenaviruses.the arenaviruses lassa virus (lasv) in africa and machupo (macv), guanarito (gtov) and junin viruses (junv) in south america cause severe haemorrhagic fevers in humans with fatality rates of 15-35%. the present review focuses on the first steps of infection with human pathogenic arenaviruses, the interaction with their cellular receptor molecules and subsequent entry into the host cell. while similarities exist in genomic organization, structure and clinical disease caused by pathogenic old worl ...200818182084
platelets prevent ifn-alpha/beta-induced lethal hemorrhage promoting ctl-dependent clearance of lymphocytic choriomeningitis virus.we found that mice infected with different isolates of lymphocytic choriomeningitis virus (lcmv) develop a mild hemorrhagic anemia, which becomes severe and eventually lethal in animals depleted of platelets or lacking integrin beta3. lethal hemorrhagic anemia is mediated by virus-induced ifn-alpha/beta that causes platelet dysfunction, mucocutaneous blood loss and suppression of erythropoiesis. in addition to the life-threatening hemorrhagic anemia, platelet-depleted mice fail to mount an effic ...200818184798
control of virus-specific cd8+ t-cell exhaustion and immune-mediated pathology by e3 ubiquitin ligase cbl-b during chronic viral infection.a characteristic feature in the immune response to many persistent viral infections is the dysfunction or deletion of antigen-specific t cells (exhaustion). this down-regulation of virus-specific t-cell response represents a critical control mechanism that exists within t-cell activation pathways to prevent lethal disease by inappropriate responses against disseminating virus infections. however, the molecular mechanisms by which the immune system determines whether to mount a full response to s ...200818199651
viruses and other infections in stillbirth: what is the evidence and what should we be doing?in australia, as in other developed countries, approximately 40-50% of stillbirths are of unknown aetiology. emerging evidence suggests stillbirths are often multifactorial. the absence of a known cause leads to uncertainty regarding the risk of recurrence, which can cause extreme anguish for parents that may manifest as guilt, anger or bewilderment. further, clinical endeavours to prevent recurrences in future pregnancies are impaired by lack of a defined aetiology. therefore, efforts to provid ...200818203037
kinetic and mechanistic requirements for helping cd8 t cells.the requirements for the generation of fully competent long-lived memory cd8 t cells and in particular the role and the mechanisms of help from cd4 t cells remain ill-defined. memory cd8 t cells generated in the absence of cd4 t cell help often have an impaired recall proliferation and are thus unable to confer protection against certain pathogens. however, the timing and the mechanisms involved in the delivery of help are still unclear and differ between various experimental systems. in this st ...200818209047
regulation of immune response and inflammatory reactions against viral infection by vcam-1.the migration of activated antigen-specific immune cells to the target tissues of virus replication is controlled by the expression of adhesion molecules on the vascular endothelium that bind to ligands on circulating lymphocytes. here, we demonstrate that the adhesion pathway mediated by vascular cell adhesion molecule 1 (vcam-1) plays a role in regulating t-cell-mediated inflammation and pathology in nonlymphoid tissues, including the central nervous system (cns) during viral infection. the ab ...200818216105
effects of il-7 on memory cd8 t cell homeostasis are influenced by the timing of therapy in mice.il-7 is integral to the generation and maintenance of cd8(+) t cell memory, and insufficient il-7 is believed to limit survival and the persistence of memory cd8(+) t cells. here, we show that during the mouse t cell response to lymphocytic choriomeningitis virus, il-7 enhanced the number of memory cd8(+) t cells when its administration was restricted to the contraction phase of the response. likewise, il-7 administration during the contraction phase of the mouse t cell response to vaccinia viru ...200818246202
a new arenavirus in a cluster of fatal transplant-associated diseases.three patients who received visceral-organ transplants from a single donor on the same day died of a febrile illness 4 to 6 weeks after transplantation. culture, polymerase-chain-reaction (pcr) and serologic assays, and oligonucleotide microarray analysis for a wide range of infectious agents were not informative.200818256387
apoptosis regulators bim and fas function concurrently to control autoimmunity and cd8+ t cell contraction.throughout most of adult life, lymphocyte number remains constant because of a balance of proliferation and apoptosis. mutation of bim, a proapoptotic protein in the intrinsic death pathway, or fas, a tumor necrosis factor receptor (tnfr) superfamily member of the extrinsic pathway, results in late-onset autoimmunity and increased antigen-specific cd8(+) t cell responses during viral infection. however, virus-specific immune responses eventually return to amounts comparable to those for nonmutan ...200818275832
irak-4 kinase activity is required for irak-4-dependent innate and adaptive immune responses.interleukin-1 receptor-associated kinase (irak)-4 is a serine-threonine kinase that plays an important role in innate and adaptive immune responses. while the requirement of irak-4 kinase activity has been studied in the context of il-1r signaling, it is not clear whether irak-4 requires its kinase function for all of its roles in the immune system. irak-4 kinase-dead knock-in (irak-4kd/kd) mice were generated to further elucidate whether irak-4 kinase activity is required for irak-4 to induce c ...200818286567
absence of ctl responses to early viral antigens facilitates viral persistence.cd8+ t cells are crucial for the control of intracellular pathogens such as viruses and some bacteria. using lymphocytic choriomeningitis virus (lcmv) infection of mice--the prototypic arenavirus evolutionarily closely related to human lassa fever and south american hemorrhagic fever viruses, we have shown previously that the kinetics of ag presentation determine immunodominance of the lcmv-specific ctl response due to progressive exhaustion of lcmv nucleoprotein (np)-specific ctl upon increasin ...200818292534
mhc class ii-associated invariant chain linkage of antigen dramatically improves cell-mediated immunity induced by adenovirus vaccines.the ideal vaccine induces a potent protective immune response, which should be rapidly induced, long-standing, and of broad specificity. recombinant adenoviral vectors induce potent ab and cd8+ t cell responses against transgenic ags within weeks of administration, and they are among the most potent and versatile ag delivery vehicles available. however, the impact of chronic infections like hiv and hepatitis c virus underscore the need for further improvements. in this study, we show that the pr ...200818292559
lymphocytic choriomeningitis virus (lcmv) infection of cns glial cells results in tlr2-myd88/mal-dependent inflammatory responses.in response to invading pathogens, toll-like receptors (tlr) play a critical role in the initiation of the innate immune response, which can be either beneficial or detrimental to the host. in the present study, we demonstrated that central nervous system (cns) glial cells are activated by lymphocytic choriomeningitis virus (lcmv) in a tlr2-myd88/mal-dependent manner. specifically, in response to lcmv, both astrocytes and microglial cells isolated from wild-type (wt) mice produced chemokines, su ...200818295350
functional and genomic profiling of effector cd8 t cell subsets with distinct memory fates.an important question in memory development is understanding the differences between effector cd8 t cells that die versus effector cells that survive and give rise to memory cells. in this study, we provide a comprehensive phenotypic, functional, and genomic profiling of terminal effectors and memory precursors. using killer cell lectin-like receptor g1 as a marker to distinguish these effector subsets, we found that despite their diverse cell fates, both subsets possessed remarkably similar gen ...200818316415
il-10 blockade facilitates dna vaccine-induced t cell responses and enhances clearance of persistent virus infection.therapeutic vaccination is a potentially powerful strategy to establish immune control and eradicate persistent viral infections. large and multifunctional antiviral t cell responses are associated with control of viral persistence; however, for reasons that were mostly unclear, current therapeutic vaccination approaches to restore t cell immunity and control viral infection have been ineffective. herein, we confirmed that neutralization of the immunosuppressive factor interleukin (il)-10 stimul ...200818332180
enhancing therapeutic vaccination by blocking pd-1-mediated inhibitory signals during chronic infection.therapeutic vaccination is a potentially promising strategy to enhance t cell immunity and viral control in chronically infected individuals. however, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral t cell responses has not always been observed. one of the principal reasons for the limited success of therapeutic vaccination is that virus-specific t cells become functionally exhausted during chronic infections. we now provide a novel strat ...200818332181
eye manifestations of intrauterine infections and their impact on childhood blindness.intrauterine infections are important causes of childhood blindness in both developed and developing countries. chorioretinal scars are the most characteristic eye manifestation of a congenital or prenatal infection. the various ocular manifestations of congenital infections, summarized by the mnemonic torch, and recent additions to the "other" category (lymphocytic choriomeningitis virus and west nile virus) are discussed.200818348876
il-15 transpresentation augments cd8+ t cell activation and is required for optimal recall responses by central memory cd8+ t cells.although the adaptive immune system has a remarkable ability to mount rapid recall responses to previously encountered pathogens, the cellular and molecular signals necessary for memory cd8(+) t cell reactivation are poorly defined. il-15 plays a critical role in memory cd8(+) t cell survival; however, whether il-15 is also involved in memory cd8(+) t cell reactivation is presently unclear. using artificial ag-presenting surfaces prepared on cell-sized microspheres, we specifically addressed the ...200818354159
rapid culling of the cd4+ t cell repertoire in the transition from effector to memory.requirements for cd4+ t cell memory differentiation were analyzed with adoptively transferred smarta t cell receptor (tcr) transgenic cells specific for alymphocytic choriomeningitis virus (lcmv) epitope. lcmv-induced effector and memory differentiation of smarta cells mimicked the endogenous cd4+ t cell response. in contrast, infection with a recombinant listeria expressing the lcmv epitope, although resulting initially in massive smarta expansion, led to loss of effector function and rapid cel ...200818356084
diminished primary cd8 t cell response to viral infection during protein energy malnutrition in mice is due to changes in microenvironment and low numbers of viral-specific cd8 t cell precursors.protein energy malnutrition (pem) increases the incidence and severity of infection, causing morbidity and mortality in malnourished populations. viral-specific cells are an important component of protective immunity. we hypothesized that reduction in the expansion of viral-specific cells and the microenvironment of the pem host leads to increased incidence and severity of infections. we tested this hypothesis using a mouse model of lymphocytic choriomeningitis virus (lcmv) infection and an adop ...200818356339
formation of il-7ralphahigh and il-7ralphalow cd8 t cells during infection is regulated by the opposing functions of gabpalpha and gfi-1.il-7 is essential for the survival of naive and memory t cells, and il-7 receptor alpha-chain (il-7ralpha) expression is dynamically regulated in activated cd8 t cells during acute viral and bacterial infections. most virus-specific cd8 t cells become il-7ralpha(low) and are relatively short-lived, but some escape il-7ralpha repression (referred to as il-7ralpha(high) memory precursor effector cells) and preferentially enter the memory cd8 t cell pool. how antiviral effector cd8 t cells regulate ...200818390712
protein kinase c-theta critically regulates the proliferation and survival of pathogen-specific t cells in murine listeriosis.protein kinase c-theta (pkc-theta) is essential for the activation of t cells in autoimmune disorders, but not in viral infections. to study the role of pkc-theta in bacterial infections, pkc-theta(-/-) and wild-type mice were infected with listeria monocytogenes (lm). in primary and secondary listeriosis, the numbers of lm-specific cd8 and cd4 t cells were drastically reduced in pkc-theta(-/-) mice, resulting in increased cfus in spleen and liver of both pkc-theta(-/-) c57bl/6 and balb/c mice. ...200818390745
effective t-cell immune responses in the absence of the serine/threonine kinase rip2.the serine/threonine kinase rip2 has been reported to be essential for nod1 and nod2 mediated cell activation, and has been suggested to play a role in the signaling cascade downstream of the t-cell receptor. we sought to ascertain the exact role of rip2 in t-helper cell differentiation and cd8+ t-cell effector function in vivo and in vitro. in contrast to previous reports, we found that rip2-deficient t cells did not exhibit impaired proliferation upon tcr engagement in vitro, and differentiati ...200818403232
tentative t cells: memory cells are quick to respond, but slow to divide.t cell memory is a cornerstone of protective immunity, and is the key element in successful vaccination. upon encountering the relevant pathogen, memory t cells are thought to initiate cell division much more rapidly than their naïve counterparts, and this is thought to confer a significant biological advantage upon an immune host. here, we use traceable tcr-transgenic t cells to evaluate this proposed characteristic in cd4+ and cd8+ memory t cells. we find that, even in the presence of abundant ...200818404208
fusogenicity of membranes: the impact of acid sphingomyelinase on innate immune responses.acid sphingomyelinase (asmase) has been implemented in cellular signaling mainly because its reaction product, ceramide, has been assumed to be a mediator within signaling pathways. our studies of three independent infection systems show that asmase is required for phago-lysosomal fusion in macrophages infected with listeria monocytogenes, for exocytosis of secretory lysosomes by lymphocytic choriomeningitis virus-specific cytotoxic t cells, and for generation of multinucleated giant cells in gr ...200818406376
genetic mimics of congenital lymphocytic choriomeningitis virus encephalitis. 200818409198
dendritic cells are preferentially targeted among hematolymphocytes by modified vaccinia virus ankara and play a key role in the induction of virus-specific t cell responses in vivo.modified vaccinia ankara (mva) is a highly attenuated strain of vaccinia virus (vv) that has lost approximately 15% of the vv genome, along with the ability to replicate in most mammalian cells. it has demonstrated impressive safety and immunogenicity profile in both preclinical and clinical studies, and is being actively explored as a promising vaccine vector for a number of infectious diseases and malignancies. however, little is known about how mva interacts with the host immune system consti ...200818412969
basolateral entry and release of new and old world arenaviruses from human airway epithelia.transmission of arenaviruses from rodent hosts to humans is generally thought to occur through inhalation or ingestion of dust or droplets containing viral particles. here we demonstrate that two identified arenavirus receptors, alpha-dystroglycan (alpha-dg) and transferrin receptor 1 (tfr1), are expressed in polarized human airway epithelia. lymphocytic choriomeningitis virus strains with high or low alpha-dg affinity and junin virus, which binds tfr1, efficiently infected polarized epithelia o ...200818417570
conversion of tyrosine to the inflammation-associated analog 3'-nitrotyrosine at either tcr- or mhc-contact positions can profoundly affect recognition of the mhc class i-restricted epitope of lymphocytic choriomeningitis virus glycoprotein 33 by cd8 t cells.immunohistochemical detection of increased levels of protein-associated nitrotyrosine has become widely used as a surrogate marker of in situ inflammation. however, the potential consequences of protein-associated nitrotyrosine formation in terms of cellular immune recognition has received surprisingly little attention. using a well-defined i-e(k)-restricted epitope of pigeon cytochrome c, we previously demonstrated that conversion of a single tyrosine residue to nitrotyrosine can have a profoun ...200818424715
restoration of lymphoid organ integrity through the interaction of lymphoid tissue-inducer cells with stroma of the t cell zone.the generation of lymphoid microenvironments in early life depends on the interaction of lymphoid tissue-inducer cells with stromal lymphoid tissue-organizer cells. whether this cellular interface stays operational in adult secondary lymphoid organs has remained elusive. we show here that during acute infection with lymphocytic choriomeningitis virus, antiviral cytotoxic t cells destroyed infected t cell zone stromal cells, which led to profound disruption of secondary lymphoid organ integrity. ...200818425132
increasing the cd4+ t cell precursor frequency leads to competition for ifn-gamma thereby degrading memory cell quantity and quality.the precursor frequency of naive cd4(+) t cells shows an inverse relationship with the number of memory cells generated after exposure to cognate ag. using the lymphocytic choriomeningitis virus (lcmv) model, we show here that only when the initial number of naive virus-specific cd4(+) t cell precursors is low (< or =10(4) per spleen) do they give rise to abundant and homogeneous memory cells that are cd62l(low), il-7r(high), and imbued with an enhanced capacity to produce cytokine, proliferate, ...200818453598
[preparation of h-2db tetramer and its application in enumerating the cd8+ t cells specific for lymphocytic choriomeningitis virus].major histocompatibility complex (mhc) tetramer technology offers a powerful means to study specific t cell populations of interest. to investigate the immune response of h-2db-restricted cd8+ t cells in immunotherapy, we prepared the h-2db tetramer and verified its effectiveness in enumerating the cd8+ t cells specific for the lymphocytic choriomeningitis virus (lcmv). first, the cdna encoding h-2db heavy chain was cloned by rt-pcr from the spleen of a c57bl/6 mouse. the expression vector for h ...200818464613
rescue of cytotoxic function in the cd8alpha knockout mouse by removal of mhc class ii.cd8 plays an important role in the activity of cytolytic t cells (ctl). however, whether or not cd8 is required for the development of ctl has not been clearly determined. cytotoxic activity in the cd8alpha knockout mouse is difficult to induce, and has only been demonstrated against allogenic mhc targets. the lack of cytotoxicity may result from impaired lineage commitment of ctl in the absence of cd8, or diminished competitiveness during selection against (unimpaired) development of cd4(+) t c ...200818465769
genomic and biological characterization of aggressive and docile strains of lymphocytic choriomeningitis virus rescued from a plasmid-based reverse-genetics system.arenaviruses include several causative agents of haemorrhagic fever disease in humans. in addition, the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) is a superb model for the study of virus-host interactions, including the basis of viral persistence and associated diseases. there is little understanding about the molecular mechanisms concerning the regulation and specific role of viral proteins in modulating arenavirus-host cell interactions either associated with an acute or ...200818474558
overexpression of lymphotoxin in t cells induces fulminant thymic involution.activated lymphocytes and lymphoid-tissue inducer cells express lymphotoxins (lts), which are essential for the organogenesis and maintenance of lymphoreticular microenvironments. here we describe that t-cell-restricted overexpression of lt induces fulminant thymic involution. this phenotype was prevented by ablation of the lt receptors tumor necrosis factor receptor (tnfr) 1 or lt beta receptor (ltbetar), representing two non-redundant pathways. multiple lines of transgenic ltalphabeta and ltal ...200818483211
molecular characterization of the genes coding for glycoprotein and l protein of lymphocytic choriomeningitis virus strain mx.lymphocytic choriomeningitis virus (lcmv) is the prototype arenavirus with ambisense coding strategy. we have previously described a new mx strain lcmv and determined the primary structure of the genes coding for the nucleoprotein and ring finger z protein. in this report, we describe amplification and sequencing of the entire coding sequences of additional mx genes, the glycoprotein precursor (gpc) and l protein. the obtained mx gpc cdna sequence was 1,615 nucleotides long and contained an orf, ...200818493846
cd4+ t cell help improves cd8+ t cell memory by retained cd27 expression.cd4+ t cell help during the priming of cd8+ t lymphocytes imprints the capacity for optimal secondary expansion upon re-encounter with antigen. helped memory cd8+ t cells rapidly expand in response to a secondary antigen exposure, even in the absence of t cell help and, are most efficient in protection against a re-infection. in contrast, helpless memory ctl can mediate effector function, but secondary expansion is reduced. how cd4+ t cells instruct cd8+ memory t cells during priming to undergo ...200818506879
lymphocytic choriomeningitis infection of the central nervous system.viral infection of the central nervous system (cns) can result in a multitude of responses including pathology, persistence or immune clearance. lymphocytic choriomeningitis virus (lcmv) is a powerful model system to explore these potential outcomes of cns infection due to the diversity of responses that can be achieved after viral inoculation. several factors including tropism, timing, dose and variant of lcmv in combination with the development or suppression of the corresponding immune respon ...200818508527
different mechanisms of cell entry by human-pathogenic old world and new world arenaviruses.the old world arenavirus lassa virus (lasv) is the causative agent of severe viral hemorrhagic fever (vhf) in humans and is the most prevalent human pathogen among arenaviruses. the present study investigated the largely unknown mechanisms of cell entry of lasv, a process know to be mediated solely by the virus envelope glycoprotein (gp). to circumvent biosafety restrictions associated with the use of live lasv, we used reverse genetics to generate a recombinant variant of the prototypic arenavi ...200818508885
immune system derived from homeostatic proliferation generates normal cd8 t-cell memory but altered repertoires and diminished heterologous immune responses.the host responds to lymphopenic environments by acute homeostatic proliferation of t lymphocytes, which acquire phenotypes similar to memory cells. using t-cell knockout (ko) mice adoptively reconstituted with splenocytes from immunologically naive mice, we examined the immune responses of an immune system derived from homeostatically proliferating (hp) t cells. hp cells mounted relatively normal acute cd8 t-cell responses to lymphocytic choriomeningitis virus (lcmv), but with altered t-cell re ...200818509089
pd-1 expression and il-2 loss of cytomegalovirus- specific t cells correlates with viremia and reversible functional anergy.cytomegalovirus (cmv) represents a major cause of infectious complications after transplantation. recently, chronic infections with lymphocyte choriomeningitis virus (lcmv), hiv or hcv were shown to be associated with functionally exhausted t cells characterized by high expression of the programmed death (pd)-1 molecule and altered cytokine expression patterns. we therefore hypothesized that functional exhaustion of cmv-specific cd4 t cells may determine impaired cmv control in patients after re ...200818510628
optimized lentiviral transduction of mouse bone marrow-derived mesenchymal stem cells.mesenchymal stem cells (mscs) have attracted much attention as potential platforms for transgene delivery and cell-based therapy for human disease. mscs have the capability to self-renew and retain multipotency after extensive expansion in vitro, making them attractive targets for ex vivo modification and autologous transplantation. viral vectors, including lentiviral vectors, provide an efficient means for transgene delivery into human mscs. in contrast, mouse mscs have proven more difficult to ...200818513160
aggravation of viral hepatitis by platelet-derived serotonin.more than 500 million people worldwide are persistently infected with hepatitis b virus or hepatitis c virus. although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. virus-specific t cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also ...200818516052
donor-derived infection: old problem, new solutions? 200818522543
a new arenavirus in transplantation. 200818550879
lymphocytic choriomeningitis virus uses a novel endocytic pathway for infectious entry via late endosomes.the endocytic entry of lymphocytic choriomeningitis virus (lcmv) into host cells was compared to the entry of viruses known to exploit clathrin or caveolae/raft-dependent pathways. pharmacological inhibitors, expression of pathway-specific dominant-negative constructs, and sirna silencing of clathrin together with electron and light microscopy provided evidence that although a minority population followed a classical clathrin-mediated mechanism of entry, the majority of these enveloped rna virus ...200818554681
natural antibodies target virus-antibody complexes to organized lymphoid tissue.natural antibodies (na) specific for infectious pathogens are found at low titer (usually <1:40) in the serum of healthy, non-immunized, individuals. therefore, na are part of the first line of defence against blood borne microorganisms. they directly neutralize viral infections or lyse pathogens by activating the complement cascade. in addition, recent studies highlighted their role in the pooling of infectious pathogens and other antigens to the spleen. this prevents infection of vital target ...200818558366
no evidence of selection for mutational robustness during lethal mutagenesis of lymphocytic choriomeningitis virus.lethal mutagenesis is a transition towards virus extinction mediated by enhanced mutation rates during viral genome replication. theoretical studies suggest that viruses can evolve towards regions of their fitness landscapes at which they display resistance to the deleterious effects of mutations. it has been suggested that such mutational robustness could jeopardize lethal mutagenesis. we have used the arenavirus lymphocytic choriomeningitis virus (lcmv) to explore whether treatment with the mu ...200818572218
local not systemic modulation of dendritic cell s1p receptors in lung blunts virus-specific immune responses to influenza.the mechanism by which locally delivered sphingosine analogs regulate host response to localized viral infection has never been addressed. in this report, we show that intratracheal delivery of the chiral sphingosine analog (r)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol (aal-r) or its phosphate ester inhibits the t-cell response to influenza virus infection. in contrast, neither intraperitoneal delivery of aal-r nor intratracheal instillation of the non-phosphorylatable stereoisomer aal-s sup ...200818577684
increasing entrapment of peptides within poly(alkyl cyanoacrylate) nanoparticles prepared from water-in-oil microemulsions by copolymerization.low molecular hydrophilic actives such as peptides are typically poorly encapsulated within poly(alkyl cyanoacrylate) nanoparticles when prepared from micellar or microemulsion templates. the aim of the present study was to investigate whether the entrapment of peptides within poly(alkyl cyanoacrylate) nanoparticles could be increased by functionalizing the peptide so that it could copolymerize with the alkyl cyanoacrylate monomer. peptide and acryloyl functionalized peptide representing the ant ...200818598746
delayed contraction of the cd8+ t cell response toward lymphocytic choriomeningitis virus infection in mice lacking serglycin.we previously reported that the lack of serglycin proteoglycan affects secretory granule morphology and granzyme b (grb) storage in in vitro generated ctls. in this study, the role of serglycin during viral infection was studied by infecting wild-type (wt) mice and serglycin-deficient (sg(-/-)) mice with lymphocytic choriomeningitis virus (lcmv). wt and sg(-/-) mice cleared 10(3) pfu of highly invasive lcmv with the same kinetics, and the cd8(+) t lymphocytes from wt and sg(-/-) animals did not ...200818606656
a novel virus carrier state to evaluate immunotherapeutic regimens: regulatory t cells modulate the pathogenicity of antiviral memory cells.restrictions in the diversity of an adaptive immune repertoire can facilitate viral persistence. because a host afflicted with an immune deficiency is not likely to purge a persistent infection using endogenous mechanisms, it is important to explore adoptive therapies to supplement the host with a functional immune defense. in this study, we describe a virus carrier state that results from introducing lymphocytic choriomeningitis virus (lcmv) into adult mice possessing a restricted t cell repert ...200818606669
detection of the antibody to lymphocytic choriomeningitis virus in sera of laboratory rodents infected with viruses of laboratory and newly isolated strains by elisa using purified recombinant nucleoprotein.an enzyme-linked immunosorbent assay (elisa) was developed to detect the antibody against lymphocytic choriomeningitis virus (lcmv) in sera of laboratory animals. in this elisa system, lcmv-nucleoprotein (np) expressed by recombinant baculovirus and purified with high molar urea was used as the antigen. sera from laboratory animals experimentally infected with the armstrong strain or the newly isolated m1 strain of lcmv were examined to detect anti-lcmv antibody by the elisa system, and the reac ...200818633158
anomalous type 17 response to viral infection by cd8+ t cells lacking t-bet and eomesodermin.when intracellular pathogens invade mammalian hosts, naïve cd8+ t cells differentiate into cytotoxic killers, which lyse infected target cells and secrete cytokines that activate intracellular microbicides. we show that cd8+ t cells deficient in the transcription factors t-bet and eomesodermin (eomes) fail to differentiate into functional killers required for defense against lymphocytic choriomeningitis virus. instead, virus-specific cd8+ t cells lacking both t-bet and eomes differentiate into a ...200818635804
naive precursor frequencies and mhc binding rather than the degree of epitope diversity shape cd8+ t cell immunodominance.the primary cd8(+) t cell response of c57bl/6j mice against the 28 known epitopes of lymphocytic choriomeningitis virus (lcmv) is associated with a clear immunodominance hierarchy whose mechanism has yet to be defined. to evaluate the role of epitope competition in immunodominance, we manipulated the number of cd8(+) t cell epitopes that could be recognized during lcmv infection. decreasing epitope numbers, using a viral variant lacking dominant epitopes or c57bl/6j mice lacking h-2k(b), resulte ...200818641351
brief report: lymphocytic choriomeningitis virus transmitted through solid organ transplantation--massachusetts, 2008.lymphocytic choriomeningitis virus (lcmv) is a rodent-borne arenavirus found worldwide. house mice (mus musculus) are the natural reservoir, but lcmv also can infect other wild, pet, and laboratory rodents (e.g., rats, mice, guinea pigs, and hamsters). humans can be infected through exposure to rodent excreta. person-to-person transmission has occurred only through maternal-fetal transmission and solid organ transplantation. lcmv infection in humans can be asymptomatic or cause a spectrum of ill ...200818650788
mutation of a self-processing site in caspase-8 compromises its apoptotic but not its nonapoptotic functions in bacterial artificial chromosome-transgenic mice.caspase-8, the proximal enzyme in the death-induction pathway of the tnf/nerve growth factor receptor family, is activated upon juxtaposition of its molecules within the receptor complexes and is then self-processed. caspase-8 also contributes to the regulation of cell survival and growth, but little is known about the similarities or the differences between the mechanisms of these nonapoptotic functions and of the enzyme's apoptotic activity. in this study, we report that in bacterial artificia ...200818684943
transforming growth factor-beta suppresses the activation of cd8+ t-cells when naive but promotes their survival and function once antigen experienced: a two-faced impact on autoimmunity.transforming growth factor-beta (tgf-beta) can exhibit strong immune suppression but has also been shown to promote t-cell growth. we investigated the differential effect of this cytokine on cd8(+) t-cells in autoimmunity and antiviral immunity.200818689691
the requirement of reactive oxygen intermediates for lymphocytic choriomeningitis virus binding and growth.multiple viruses induce reactive oxygen intermediate (roi) generation during infection that plays an important role in growth. we have examined the importance of roi during lymphocytic choriomeningitis virus (lcmv) infection of immortalized bhk-21 cells and murine peritoneal macrophages. within 15 min of virus addition, intracellular roi levels increased. to examine the contribution of roi to lcmv infection, cells were pretreated with antioxidant prior to virus addition. antioxidant treatment in ...200818691729
immunology: surprising side effects. 200818704076
transient fty720 treatment promotes immune-mediated clearance of a chronic viral infection.for a wide variety of microbial pathogens, the outcome of the infection is indeterminate. in some individuals the microbe is cleared, but in others it establishes a chronic infection, and the factors that tip this balance are often unknown. in a widely used model of chronic viral infection, c57bl/6 mice clear the armstrong strain of lymphocytic choriomeningitis virus (lcmv), but the clone 13 strain persists. here we show that the armstrong strain induces a profound lymphopenia at days 1-3 after ...200818704087
[zoonoses transmitted by mouse and rat maintained as laboratory or pet animals].large numbers of mice (mus spp.) and rats (rattus spp.) are maintained for scientific reasons and as pet animals in germany. while laboratory animals are monitored for pathogenic agents, the hygienic status of pet animals is usually completely unknown. despite great efforts, zoonotic infections were reported even in laboratory settings, e.g. with hantavirus (seoul virus), streptobacillus moniliformis, and trichphyton mentagrophytes. however, in current reports, zoonotic infections were transmitt ...200818712260
identification of a broad-spectrum arenavirus entry inhibitor.several arenaviruses, including lassa virus (lasv), are causative agents of hemorrhagic fever, for which effective therapeutic options are lacking. the lasv envelope glycoprotein (gp) gene was used to generate lentiviral pseudotypes to identify small-molecule inhibitors of viral entry. a benzimidazole derivative with potent antiviral activity was identified from a high-throughput screen utilizing this strategy. subsequent lead optimization for antiviral activity identified a modified structure, ...200818715909
serological evidence of viruses naturally associated with the montane water vole (arvicola scherman) in eastern france.we surveyed 12 populations of the montane water vole (arvicola scherman), previously known as the fossorial form of the water vole a. terrestris, in eastern france for antibodies (immunoglobulin g) to puumala virus (puuv), lymphocytic choriomeningitis virus (lcmv), and cowpox virus (cpxv). antibodies to puuv were found in 9 (5.5%) of 164 voles from 7 populations, antibodies to lcmv were found in 13 (26.0%) of 50 voles from 2 populations, and antibodies to cpxv were found in 66 (41.8%) of 158 vol ...200818752422
host range and genetic diversity of arenaviruses in rodents, united kingdom.during a study to extend our knowledge of the host range and genetic diversity of arenaviruses in great britain, 66 of 1,147 rodent blood samples tested for antibody, and 127 of 482 tested by pcr, were found positive. all sequences most closely resembled those of previously identified lymphocytic choriomeningitis virus.200818760019
myd88 plays a critical t cell-intrinsic role in supporting cd8 t cell expansion during acute lymphocytic choriomeningitis virus infection.during acute lymphocytic choriomeningitis virus (lcmv) infection, cd8 t cells rapidly expand and differentiate into effectors that are required for viral clearance. the accumulation of activated t cells is greatly reduced in mice lacking the adaptor molecule myd88. although myd88 has generally been considered to indirectly regulate adaptive immune responses by controlling inflammatory cytokine production and ag presentation in innate immune cells, in this study, we identify an unappreciated cell ...200818768833
lymphocytic choriomeningitis virus (lcmv): propagation, quantitation, and storage.lymphocytic choriomeningitis virus (lcmv) is an enveloped, ambisense rna virus and the prototypic virus of the arenavirus group. it can cause viral meningitis and other ailments in humans, but its natural host is the mouse. the lcmv/mouse model has been useful for examining mechanisms of viral persistence and the basic concepts of virus-induced immunity and immunopathology. this unit discusses strain differences and biosafety containment issues for lcmv. recommendations are made for techniques f ...200818770534
reverse genetics approaches to combat pathogenic arenaviruses.several arenaviruses cause hemorrhagic fever (hf) in humans, and evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) is a neglected human pathogen of clinical significance. moreover, arenaviruses pose a biodefense threat. no licensed anti-arenavirus vaccines are available, and current anti-arenavirus therapy is limited to the use of ribavirin, which is only partially effective and is associated with anemia and other side effects. ther ...200818782590
lymphocytic choriomeningitis in a pet store worker in romania. 200818784339
revisiting estimates of ctl killing rates in vivo.recent experimental advances have allowed the estimation of the in vivo rates of killing of infected target cells by cytotoxic t lymphocytes (ctl). we present several refinements to a method applied previously to quantify killing of targets in the spleen using a dynamical model. we reanalyse data previously used to estimate killing rates of ctl specific for two epitopes of lymphocytic choriomeningitis virus (lcmv) in mice and show that, contrary to previous estimates the "killing rate" of effect ...200718074025
cbl-b regulates antigen-induced tcr down-regulation and ifn-gamma production by effector cd8 t cells without affecting functional avidity.the e3 ubiquitin ligase cbl-b is a negative regulator of tcr signaling that: 1) sets the activation threshold for t cells; 2) is induced in anergic t cells; and 3) protects against autoimmunity. however, the role of cbl-b in regulating cd8 t cell activation and functions during physiological t cell responses has not been systematically examined. using the lymphocytic choriomeningitis virus infection model, we show that cbl-b deficiency did not significantly affect the clonal expansion of virus-s ...200718025165
nonimmunosuppressive chemotherapy: em011-treated mice mount normal t-cell responses to an acute lymphocytic choriomeningitis virus infection.myelosuppression and associated immunosuppression are major problems in cancer chemotherapy. thus, infection remains a significant source of morbidity and mortality during chemotherapy of cancer patients. viral infections, particularly herpes simplex virus, varicella zoster virus, and cytomegalovirus, result either due to reactivation of latent viruses or new infections as sequelae of chemotherapy and debilitated cell-mediated immunity. ultimately, the resolution of these infections can only be ...200718025274
[behavior of argentine lymphocytic choriomeningitis virus strains in rodents].the activity of lcm virus was first reported in argentina at the beginning of the seventies and only five strains have been isolated from rodents mus domesticus and two from humans. the objective of this paper was to find differential biological characteristics of argentine strains of lcm virus comparing them in relation to the historical strains we and armstrong. regarding the results obtained in tissue culture, when l 929 cells were used, plaque forming units (pfu) were obtained with human and ...200718051229
congenital viral infections of the brain: lessons learned from lymphocytic choriomeningitis virus in the neonatal rat.the fetal brain is highly vulnerable to teratogens, including many infectious agents. as a consequence of prenatal infection, many children suffer severe and permanent brain injury and dysfunction. because most animal models of congenital brain infection do not strongly mirror human disease, the models are highly limited in their abilities to shed light on the pathogenesis of these diseases. the animal model for congenital lymphocytic choriomeningitis virus (lcmv) infection, however, does not su ...200718052527
systemic and mucosal infection program protective memory cd8 t cells in the vaginal mucosa.whether mucosal immunization is required for optimal protective cd8 t cell memory at mucosal surfaces is controversial. in this study, using an adoptive transfer system, we compare the efficacy of two routes of acute lymphocytic choriomeningitis viral infection on the generation, maintenance, and localization of ag-specific cd8 t cells in tissues, including the vaginal mucosa. surprisingly, at day 8, i.p. infection results in higher numbers of ag-specific cd8 t cells in the vaginal mucosa and il ...200718056354
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