| memory t cells: total recall or just a sense of déjà vu? | | 2001 | 11685219 |
| role of cd28-b7 interactions in generation and maintenance of cd8 t cell memory. | although the role of cd28-b7 interaction in the activation of naive t cells is well established, its importance in the generation and maintenance of t cell memory is not well understood. in this study, we examined the requirement for cd28-b7 interactions in primary t cell activation and immune memory. ag-specific cd8 t cell responses were compared between wild-type (+/+) and cd28-deficient (cd28(-/-)) mice following an acute infection with lymphocytic choriomeningitis virus (lcmv). during the pr ... | 2001 | 11698427 |
| viral escape mechanisms--escapology taught by viruses. | viruses have 'studied' immunology over millions of years of coevolution with their hosts. during this ongoing education they have developed countless mechanisms to escape from the host's immune system. to illustrate the most common strategies of viral immune escape we have focused on two murine models of persistent infection, lymphocytic choriomeningitis virus (lcmv) and murine cytomegalovirus (mcmv). lcmv is a fast replicating small rna virus with a genome prone to mutations. therefore, lcmv es ... | 2001 | 11703537 |
| eye manifestations of intrauterine infections. | the eye finding most characteristic of a prenatal, and therefore, congenital infection is a chorioretinal scar or an active chorioretinitis as can be seen in congenital toxoplasmosis, cmv, hsv, lymphocytic choriomeningitis virus, or varicella zoster infections. congenital cataracts are suggestive, but less specific for congenital infection. they may be a relatively isolated finding in rubella, syphilis, varicella zoster, and epstein-barr virus infections. when they are present in congenital toxo ... | 2001 | 11705152 |
| dna-based immunisation against rabies and rabies-related viruses: towards multivalent vaccines. | prototypes of multivalent dna vaccines against lyssaviruses (lv: rabies and rabies-related viruses) and other viruses were developed using chimaeric lv glycoprotein (clvg) dna and clvg dna carrying foreign epitopes. clvg is composed of the n-terminal half of an lv genotype (gt) containing antigenic site ii, the c-terminal half of gt containing antigenic site iii, as well as the transmembrane and cytoplasmic domains of the same or a different gt. both antigenic sites induced virus neutralizing an ... | 2000 | 11713814 |
| cd8+ t lymphocytes in double alpha beta tcr transgenic mice. i. tcr expression and thymus selection in the absence or in the presence of self-antigen. | we derived rag2-deficient mice bearing two rearranged alphabeta tcr transgenes, one specific for the hy male ag and the second specific for the gp33-41 peptide of lymphocytic choriomeningitis virus, both restricted to the mhc h-2d(b) class i molecule. we found that, in female double transgenic (dtg) mice, most cd8 t cells express only the tcrbeta chain from the ahy transgene. by comparing the mrna species for both beta-chains, we observed that in t cells from dtg mice the ahy tcrbeta chain trans ... | 2001 | 11714774 |
| protection from type 1 diabetes in the face of high levels of activated autoaggressive lymphocytes in a viral transgenic mouse model crossed to the sv129 strain. | in comparing the incidence of virally induced type 1 diabetes in f(1) crosses of rip-lcmv mice to three different mouse strains identical at the major histocompatibility complex h-2d(b) locus, we surprisingly found that disease development was reduced by 80% in f(1) crosses to the sv129 genetic background and by 60% after eight backcrosses to the original c57bl/6 rip-lcmv mice. in this model, diabetes is strongly dependent on a virally induced h-2d(b)-restricted cytotoxic t-cell (ctl) response. ... | 2001 | 11723052 |
| t cells down-modulate peptide-mhc complexes on apcs in vivo. | t cells compete in the response to antigen in vivo and this competition may drive the affinity maturation of a secondary t cell response. here we show that high-affinity t cells out-competed lower affinity t cells during a response to antigenic challenge in vivo. although competition between t cells specific for different peptide-major histocompatibility complexes (mhc) occurred, it was less efficient than competition between t cells of the same peptide-mhc specificity. in addition, high-affinit ... | 2002 | 11731800 |
| immunoproteasomes largely replace constitutive proteasomes during an antiviral and antibacterial immune response in the liver. | the proteasome is critically involved in the production of mhc class i-restricted t cell epitopes. proteasome activity and epitope production are altered by ifn-gamma treatment, which leads to a gradual replacement of constitutive proteasomes by immunoproteasomes in vitro. however, a quantitative analysis of changes in the steady state subunit composition of proteasomes during an immune response against viruses or bacteria in vivo has not been reported. here we show that the infection of mice wi ... | 2001 | 11739503 |
| cd8(+)-t-cell response to secreted and nonsecreted antigens delivered by recombinant listeria monocytogenes during secondary infection. | understanding how existing antivector immunity impacts live vaccine delivery systems is critical when the same vector system may be used to deliver different antigens. we addressed the impact of antivector immunity, elicited by immunization with attenuated acta-deficient listeria monocytogenes, on the cd8(+)-t-cell response to a well-characterized lymphocytic choriomeningitis virus epitope, np118-126, delivered by infection with recombinant l. monocytogenes. challenges of immune mice with acta-d ... | 2002 | 11748177 |
| constitutive beta cell expression of il-12 does not perturb self-tolerance but intensifies established autoimmune diabetes. | to analyze the function of the th1-promoting cytokine il-12 in vivo, we generated transgenic (tg) mice (rip-il12 mice) whose pancreatic beta cells constitutively express bioactive il-12 or one of its components, p35 or p40. in contrast to non-tg littermates or single-tg rip-p35 and rip-p40 mice, rip-il12 mice developed a marked pancreatic infiltration of lymphocytes and macrophages, mainly around islets. expression of bioactive il-12 primarily upregulated transcript levels of ifn-inducible prote ... | 2001 | 11748258 |
| critical role for perforin-, fas/fasl-, and tnfr1-mediated cytotoxic pathways in down-regulation of antigen-specific t cells during persistent viral infection. | viral persistence following infection with invasive strains of lymphocytic choriomeningitis virus (lcmv) can be achieved by selective down-regulation of virus-specific t lymphocytes. high viral burden in the onset of infection drives responding cells into functional unresponsiveness (anergy) that can be followed by their physical elimination. in this report, we studied down-regulation of the virus-specific cd8(+)-t-cell response during persistent infection of adult mice with lcmv, with emphasis ... | 2002 | 11752172 |
| endogenous expression levels of autoantigens influence success or failure of dna immunizations to prevent type 1 diabetes: addition of il-4 increases safety. | administration of autoantigens through dna immunizations or via the oral route can prevent progression of islet destruction and lower the incidence of type 1 diabetes in animal models. this beneficial effect is mediated by autoreactive regulatory cd4 lymphocytes, and it is known that their induction depends on the precise dose and route of antigen administration. however, it is not clear which endogenous factors determine when such immunizations lead to activation of regulatory versus aggressive ... | 2002 | 11754351 |
| oncoretrovirus and lentivirus vectors pseudotyped with lymphocytic choriomeningitis virus glycoprotein: generation, concentration, and broad host range. | lymphocytic choriomeningitis virus (lcmv) is a noncytopathic arenavirus shown to infect a broad range of different cell types. here, we combined the beneficial characteristics of the lcmv glycoprotein (lcmv-gp) and those of retroviral vectors to generate a new, safe, and efficient gene transfer system. these lcmv-gp pseudotypes were systematically compared with vectors containing the widely used amphotropic murine leukemia virus envelope (a-mlvenv) or the vesicular stomatitis virus g protein (vs ... | 2002 | 11773421 |
| nonmitogenic cd3 antibody reverses virally induced (rat insulin promoter-lymphocytic choriomeningitis virus) autoimmune diabetes without impeding viral clearance. | treatment with nonmitogenic cd3 ab reverses established autoimmune diabetes in nonobese diabetic mice by restoring self-tolerance, and is currently under clinical evaluation in patients presenting recent onset type i diabetes. due to the immunosuppressive potential of this strategy, it was relevant to explore how this treatment would influence the outcome of concomitant viral infections. in this study, we used a transgenic model of virally induced autoimmune diabetes (rat insulin promoter-lympho ... | 2002 | 11777992 |
| self-assembly properties of a model ring domain. | ring domains act in a variety of essential cellular processes but have no general function ascribed to them. here, we observe that purified arenaviral protein z, constituted almost entirely by its ring domain, self-assembles in vitro into spherical structures that resemble functional bodies formed by z in infected cells. by using a variety of biophysical methods we provide a thermodynamic and kinetic framework for the ring-dependent self-assembly of z. assembly appears coupled to substantial con ... | 2002 | 11792829 |
| [isolation of lymphocytic choriomeningitis virus from human individuals]. | the activity of lymphocytic choriomeningitis virus (lcmv) in argentina has been previously reported on the basis of serological evidence in rodents and humans and the isolation of only one strain of lcmv from a mus domesticus captured in the province of córdoba. the aim of this paper was to register patients with serological diagnosis of lcm, to isolate and to identify human strains of lcmv in argentina. during the last 19 years, 15 cases were diagnosed as lcm by immunoflourescent indirect assay ... | 2001 | 11808424 |
| exhaustion of cytotoxic t cells during adoptive immunotherapy of virus carrier mice can be prevented by b cells or cd4+ t cells. | rapid disappearance of antiviral ctl after transfusion into persistently infected individuals is a serious limitation of adoptive immunotherapy protocols. in the mouse model of persistent infection with lymphocytic choriomeningitis virus (lcmv) naive or immune virus-specific donor cd8+ t cells are exhausted after transfusion into carrier recipients with similar kinetics. here we show that cotransfusion of immune cd4+ t cells prevents exhaustion of immune cd8+ t cells. interestingly, cotransfer o ... | 2002 | 11813156 |
| induction of protective antiviral cytotoxic t cells by a tubular structure capable of carrying large foreign sequences. | bluetongue virus (btv) produces large numbers of tubules during infection which are formed by a single virus coded non-structural protein, ns1. the ns1 protein has been fused with full length green fluorescent protein (gfp) and was shown to retain the capacity to form tubules when expressed in heterologous expression systems. moreover, recombinant purified chimeric tubules were demonstrated to be internalized by macrophages and dendritic cells. the ability of such chimeric tubules to induce prot ... | 2002 | 11818155 |
| the role of cc chemokine receptor 5 in antiviral immunity. | the cc chemokine receptor ccr5 is an important coreceptor for human immunodeficiency virus (hiv), and there is a major thrust to develop anti-ccr5-based therapies for hiv-1. however, it is not known whether ccr5 is critical for a normal antiviral t-cell response. this study investigated the immune response to lymphocytic choriomeningitis virus in mice lacking ccr5 (ccr5(-/-) mice). this infection is a classical model for studying antiviral immunity, and influx of ccr5-expressing cd8(+) t cells a ... | 2002 | 11830471 |
| [neutralization test for lymphocytic choriomeningitis virus for distinguishing between two arenavirus infections in argentina]. | the active coexistence of two pathogenic arenaviruses, junin (junv) and lymphocytic choriomeningitis (lcmv), in the same region of argentina, has been known since the early 70's, and records of clinical and subclinical human infections by one and/or the other agent have been continuously produced for the last 25 years. anti-lcmv antibody is currently searched only by indirect immunofluorescence, a test that shows cross reactions among a number of arenaviruses yielding, in the cases of lcmv and j ... | 2001 | 11833256 |
| role of an intact splenic microarchitecture in early lymphocytic choriomeningitis virus production. | an acute infection with lymphocytic choriomeningitis virus (lcmv) is efficiently controlled by the cytotoxic-t-cell (ctl) response of the host, and lcmv titers in the spleen and peripheral solid organs usually fall sharply after day 4 to 6 postinfection. surprisingly, infection of immunodeficient recombination-activating gene 2-deficient (rag2-/-) mice with 5 x 10(2) pfu of lcmv-we causes about 80-fold-lower lcmv titers in the spleen on day 4 postinfection compared with c57bl/6 control mice. thi ... | 2002 | 11836415 |
| interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. | interferon (ifn)-alpha/beta and interleukin (il)-12 are cytokines critical in defense against viruses, but their cellular sources and mechanisms of regulation for in vivo expression remain poorly characterized. the studies presented here identified a novel subset of dendritic cells (dcs) as major producers of the cytokines during murine cytomegalovirus (mcmv) but not lymphocytic choriomeningitis virus (lcmv) infections. these dcs differed from those activated by toxoplasma antigen but were relat ... | 2002 | 11854364 |
| fucosyltransferase vii-deficient mice with defective e-, p-, and l-selectin ligands show impaired cd4+ and cd8+ t cell migration into the skin, but normal extravasation into visceral organs. | the first step of leukocyte extravasation, leukocyte rolling, is mediated by e-, p-, and l-selectins. mice deficient for alpha-1,3-fucosyltransferase vii (fuctvii)(-/-) are characterized by deficiency of e-, p-, and l-selectin ligand activity. this model system was used to evaluate the role of the interactions of selectins with their ligands in t and b cell responses. in the present study, fuctvii(-/-) mice showed reduced cd4+ t cell-mediated contact hypersensitivity reactions of the ears to fit ... | 2002 | 11859099 |
| cross-presentation of virus-like particles by skin-derived cd8(-) dendritic cells: a dispensable role for tap. | virus-like particles (vlp) induce efficient ctl responses although they do not carry any genetic information. here, we analyzed mhc class i associated presentation of vlp-derived ctl-epitopes in vivo. after intradermal injection of vlp containing the immunodominant epitope (p33) of lymphocytic choriomeningitis virus (p33-vlp), presentation of peptide p33 in draining lymph nodes was largely restricted to cd8(-) skin-derived dendritic cells (dc). surprisingly, and in contrast to findings with tumo ... | 2002 | 11870626 |
| enhanced t cell responses contribute to the genetic predisposition of cd8-mediated spontaneous autoimmunity. | a number of factors have been demonstrated to influence the induction of pathogenic autoimmune responses, including the loss of regulatory t cells. to assess the contribution of regulatory t cells in cd8(+) t cell-mediated autoimmunity, rip-gp/p14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (lcmv) glycoprotein (gp) on pancreatic beta-islet cells, together with t cells expressing an lcmv-gp-specific t cell receptor (tcr), were crossed to rag 2-deficient mice. the loss ... | 2002 | 11870633 |
| estimating the precursor frequency of naive antigen-specific cd8 t cells. | the constraint of fitting a diverse repertoire of antigen specificities in a limited total population of lymphocytes results in the frequency of naive cells specific for any given antigen (defined as the precursor frequency) being below the limit of detection by direct measurement. we have estimated this precursor frequency by titrating a known quantity of antigen-specific cells into naive recipients. adoptive transfer of naive antigen-specific t cell receptor transgenic cells into syngeneic non ... | 2002 | 11877489 |
| critical role for activation of antigen-presenting cells in priming of cytotoxic t cell responses after vaccination with virus-like particles. | virus-like particles (vlps) are known to induce strong ab responses in the absence of adjuvants. in addition, vlps are able to prime ctl responses in vivo. to study the efficiency of this latter process, we fused peptide p33 derived from lymphocytic choriomeningitis virus to the hepatitis b core ag, which spontaneously assembles into vlps (p33-vlps). these p33-vlps were efficiently processed in vitro and in vivo for mhc class i presentation. nevertheless, p33-vlps induced weak ctl responses that ... | 2002 | 11884458 |
| recombinant vaccinia virus-induced t-cell immunity: quantitation of the response to the virus vector and the foreign epitope. | recombinant vaccinia viruses (rvv) have been extensively used as vaccines, but there is little information about the total magnitude of the vv-specific t-cell response and how this compares to the immune response to the foreign gene(s) expressed by the rvv. to address this issue, we quantitated the t-cell responses to both the viral vector and the insert following the infection of mice with vv expressing a cytotoxic t lymphocyte (ctl) epitope (np118-126) from lymphocytic choriomeningitis virus ( ... | 2002 | 11884558 |
| effects of promyelocytic leukemia protein on virus-host balance. | the cellular promyelocytic leukemia protein (pml) associates with the proteins of several viruses and in some cases reduces viral propagation in cell culture. to examine the role of pml in vivo, we compared immune responses and virus loads of pml-deficient and control mice infected with lymphocytic choriomeningitis virus (lcmv) and vesicular stomatitis virus (vsv). pml(-/-) mice exhibited accelerated primary footpad swelling reactions to very-low-dose lcmv, higher swelling peaks upon high-dose i ... | 2002 | 11907221 |
| role of lymphotoxin alpha in t-cell responses during an acute viral infection. | the importance of lymphotoxin alpha (ltalpha) in lymphoid organogenesis is well established. although ltalpha has been implicated in the pathogenesis of t-cell-mediated immunopathologies, the requirement for ltalpha in t-cell activation and effector function in vivo is not well understood. to determine the role of ltalpha in t-cell activation in vivo, we compared the generation of antigen-specific t-cell responses between wild type (+/+) and ltalpha-deficient (ltalpha(-/-)) mice during an acute ... | 2002 | 11907234 |
| cd40l blockade prevents autoimmune diabetes by induction of bitypic nk/dc regulatory cells. | systemic treatment with antibody to cd40 ligand (acd40l) can prevent autoimmunity and transplant rejection in several animal models and is currently under evaluation in clinical trials. while it is known that acd40l administration inhibits expansion and effector functions of aggressive t cells, it is still unclear whether additional regulatory mechanisms are operative. here we demonstrate that a single episode of cd40l blockade during development of the autoaggressive immune response completely ... | 2002 | 11911825 |
| the importance of lytic and nonlytic immune responses in viral infections. | antiviral immune effector mechanisms can be divided broadly into lytic and nonlytic components. we use mathematical models to investigate the fundamental question of which type of response is required to combat different types of viral infection. according to our model, the relative roles of the two types of component depend on the cytopathicity of the virus relative to its rate of replication. if the viral cytopathicity is low relative to the rate of viral replication, the model predicts that a ... | 2002 | 11923114 |
| severe impairment of interleukin-1 and toll-like receptor signalling in mice lacking irak-4. | toll-like receptors (tlrs), which recognize pathogen-associated molecular patterns, and members of the pro-inflammatory interleukin-1 receptor (il-1r) family, share homologies in their cytoplasmic domains called toll/il-1r/plant r gene homology (tir) domains. intracellular signalling mechanisms mediated by tirs are similar, with myd88 (refs 5-8) and traf6 (refs 9, 10) having critical roles. signal transduction between myd88 and traf6 is known to involve the serine-threonine kinase il-1 receptor- ... | 2002 | 11923871 |
| c-jun nh(2)-terminal kinase (jnk)1 and jnk2 signaling pathways have divergent roles in cd8(+) t cell-mediated antiviral immunity. | c-jun nh(2)-terminal kinases (jnk) play important roles in t helper cell (th) proliferation, differentiation, and maintenance of th1/th2 polarization. to determine whether jnks are involved in antiviral t cell immunity, and whether jnk1 and jnk2 bear biological differences, we investigated the immune responses of jnk1-deficient and jnk2-deficient mice to lymphocytic choriomeningitis virus (lcmv). after lcmv infection, wild-type (jnk(+/+)) mice had a 5- to 10-fold increase in splenic cd8(+) t cel ... | 2002 | 11927625 |
| immunodominance in virus-induced cd8(+) t-cell responses is dramatically modified by dna immunization and is regulated by gamma interferon. | the phenomenon whereby the host immune system responds to only a few of the many possible epitopes in a foreign protein is termed immunodominance. immunodominance occurs not only during microbial infection but also following vaccination, and clarification of the underlying mechanism may permit the rational design of vaccines which can circumvent immunodominance, thereby inducing responses to all epitopes, dominant and subdominant. here, we show that immunodominance affects dna vaccines and that ... | 2002 | 11932390 |
| promotion of alpha/beta interferon induction during in vivo viral infection through alpha/beta interferon receptor/stat1 system-dependent and -independent pathways. | viruses and viral components can be potent inducers of alpha/beta interferons (ifn-alpha/beta). in culture, ifn-alpha/beta prime for their own expression, in response to viruses, through interferon regulatory factor 7 (irf-7) induction. the studies presented here evaluated the requirements for functional ifn receptors and the ifn signaling molecule stat1 in ifn-alpha/beta induction during infections of mice with lymphocytic choriomeningitis virus (lcmv). at 24 h after infection, levels of induce ... | 2002 | 11932417 |
| tumor immunity within the central nervous system stimulated by recombinant listeria monocytogenes vaccination. | tumors arising within the central nervous system (cns) present the immune system with a challenging target, given the heterogeneous nature of these neoplasms and their location within an "immunologically privileged" site. we used the lymphocytic choriomeningitis virus nucleoprotein (lcmv-np) as a pseudotumor antigen to investigate recombinant listeria monocytogenes as a tumor vaccine against s.c. and intracerebral challenges with a np-expressing glioma, 9l-np. using fischer 344 rats, we demonstr ... | 2002 | 11956085 |
| predominant role of t cell receptor (tcr)-alpha chain in forming preimmune tcr repertoire revealed by clonal tcr reconstitution system. | the cdr3 regions of t cell receptor (tcr)-alpha and -beta chains play central roles in the recognition of antigen (ag)-mhc complex. tcr repertoire is created on the basis of ag recognition specificity by cdr3s. to analyze the potential spectrum of tcr-alpha and -beta to exhibit ag specificity and generate tcr repertoire, we established hundreds of tcr transfectants bearing a single tcr-alpha or -beta chain derived from a cytotoxic t cell (ctl) clone, rt-1, specific for hivgp160 peptide, and rand ... | 2002 | 11956290 |
| new world arenavirus clade c, but not clade a and b viruses, utilizes alpha-dystroglycan as its major receptor. | alpha-dystroglycan (alpha-dg) has been identified as a major receptor for lymphocytic choriomeningitis virus (lcmv) and lassa virus, two old world arenaviruses. the situation with new world arenaviruses is less clear: previous studies demonstrated that oliveros virus also exhibited high-affinity binding to alpha-dg but that guanarito virus did not. to extend these initial studies, several additional old and new world arenaviruses were screened for entry into mouse embryonic stem cells possessing ... | 2002 | 11967329 |
| calcineurin aalpha plays an exclusive role in tcr signaling in mature but not in immature t cells. | calcineurin has been demonstrated as one of the key enzymes in tcr-mediated signaling cascades that lead to the transcription of a variety of cytokines including il-2. in this study, we addressed the role of calcineurin in lymphocyte development and peripheral t cell responses using the lymphocytic choriomeningitis virus glycoprotein peptide p33-specific, tcr (p14)-transgenic t cells that were deficient in calcineurin subunit a alpha-isoform (cnaalpha(-/-)). fetal thymic organ culture of p14/cna ... | 2002 | 11981809 |
| immunity, immunopathology and vaccines against hiv? | immunity and immunopathology of hiv infections leading to aids are reviewed from an evolutionary point of view. accordingly infectious agents and host defences have co-evolved to reach balanced states where virus and host survive. while hiv has not quite yet reached an optimal balance, tuberculosis (tb), leprosy, hbv, hcv in humans or lymphocytic choriomeningitis virus (lcmv) in mice have successfully established persistence. these non- or poorly-cytopathic infections infect the next host usuall ... | 2002 | 11983244 |
| reverse genetics of arenaviruses. | | 2002 | 11987806 |
| lymphocytic choriomeningitis virus and immunology. | | 2002 | 11987811 |
| contribution of lcmv transgenic models to understanding t lymphocyte development, activation, tolerance, and autoimmunity. | | 2002 | 11987812 |
| regulation of virally induced autoimmunity and immunopathology: contribution of lcmv transgenic models to understanding autoimmune insulin-dependent diabetes mellitus. | | 2002 | 11987813 |
| lcmv and the central nervous system: uncovering basic principles of cns physiology and virus-induced disease. | | 2002 | 11987814 |
| contribution of lcmv towards deciphering biology of quasispecies in vivo. | | 2002 | 11987815 |
| bystander t cell activation and attrition. | | 2002 | 11987818 |
| immunocytotherapy. | | 2002 | 11987819 |
| mechanisms of humoral immunity explored through studies of lcmv infection. | | 2002 | 11987820 |
| innate immune responses to lcmv infections: natural killer cells and cytokines. | although much remains to be learned, the study of early responses to lcmv infections of mice has contributed to the basic understanding of the regulation of a variety of important innate immune responses. major discoveries have included the appreciation of the levels of type 1 ifns induced during endogenous responses to viral infections, the importance of ifn-alpha/beta for induction of nk cell cytotoxicity, and the roles for ifn-alpha/beta in regulating the expression of other innate cytokines, ... | 2002 | 11987821 |
| biology and pathogenesis of lymphocytic choriomeningitis virus infection. | | 2002 | 11987822 |
| targeted transduction patterns in the mouse brain by lentivirus vectors pseudotyped with vsv, ebola, mokola, lcmv, or mulv envelope proteins. | lentiviral vectors have proven to be promising tools for transduction of central nervous system (cns) cells in vivo and in vitro. in this study, cns transduction patterns of lentiviral vectors pseudotyped with envelope glycoproteins from ebola virus, murine leukemia virus (mulv), lymphocytic choriomeningitis virus (lcmv), or the rabies-related mokola virus were compared to a vector pseudotyped with the vesicular stomatitis virus glycoprotein (vsv-g). mokola-, lcmv-, and vsv-g-pseudotyped vectors ... | 2002 | 11991743 |
| hemorrhagic fever occurs after intravenous, but not after intragastric, inoculation of rhesus macaques with lymphocytic choriomeningitis virus. | arenaviruses can cause hemorrhagic fever and death in primates and guinea pigs, but these viruses are not highly pathogenic for most rodent carriers. in the united states, arenaviruses precipitated outbreaks of hepatitis in captive monkeys, and they present an emerging health threat in the tropical areas of africa and south america. we describe infection of rhesus macaques with the prototype arenavirus, lymphocytic choriomeningitis virus (lcmv), using the we strain that has been known to cause b ... | 2002 | 11992578 |
| cd40 ligation in the presence of self-reactive cd8 t cells leads to severe immunopathology. | previous work has shown that stimulation of apcs via cd40 strongly influences the outcome of a cd8 t cell response. in this study, we examined the effect of cd40 ligation on peripheral tolerance induction of self-reactive cd8 t cells in an adoptive transfer model. naive cd8 t cells from tcr-transgenic (tg) mice specific for the gp33 epitope of lymphocytic choriomeningitis virus were tolerized when transferred into h8-tg mice expressing the gp33 epitope under the control of a mhc class i promoter ... | 2002 | 11994466 |
| serological evidence of murine pathogens in wild grey squirrels (sciurus carolinensis) in north wales. | wild grey squirrels in north wales were examined for their serological response to a range of laboratory mouse pathogens. nineteen squirrels were tested against 14 organisms and a high seroprevalence was found to several, including murine cytomegalovirus, mouse adenovirus, reovirus 3, rotavirus and sendai virus. four of the squirrels were seropositive for lymphocytic choriomeningitis virus, a zoonotic pathogen. none of the infections has previously been reported in squirrels. | 2002 | 12019534 |
| antiinfection immunity and autoimmunity. | this review summarizes findings that indicate that immune reactions of t and b cells depend on thresholds of the binding avidity of the receptor, on antigen amounts, on the time period during which antigen is available in secondary lymphatic tissues, as well as on the detection methods used. usually immunologically ignored, strictly extralymphatic host cells or their antigens may be released by infection or immunopathology to reach lymphatic organs and induce autoimmune diseases. if we know the ... | 2002 | 12021079 |
| viruses and diabetes. | insulin-dependent diabetes mellitus (iddm) is a multifactorial disease. besides a genetic predisposition environmental factors have been implicated in the pathogenesis of beta cell destruction. among these environmental factors viruses have been the focus of many studies. some viruses are diabetogenic in animals, and others have been implicated as triggers in human iddm by temporal and geographical association between iddm and viral infections, serological evidence of infection in recently diagn ... | 2002 | 12021080 |
| apoptosis of autoreactive cd8 lymphocytes as a potential mechanism for the abrogation of type 1 diabetes by islet-specific tnf-alpha expression at a time when the autoimmune process is already ongoing. | the role of tnf-alpha in type 1 diabetes pathogenesis is controversial. using double transgenic mice expressing (i) the glycoprotein (gp) of lymphocytic choriomeningitis virus (lcmv) as an islet self-antigen and (ii) tnf-alpha under control of a tetracycline-regulated promotor system (tta) in the pancreatic beta cells, we could previously demonstrate a differential effect of tnf-alpha on the incidence of type 1 diabetes. most interestingly, late expression of tnf-alpha resulted in a reversion of ... | 2002 | 12021099 |
| identification of the lymphocytic choriomeningitis virus (lcmv) proteins required to rescue lcmv rna analogs into lcmv-like particles. | we have used a reverse genetic approach to identify the viral proteins required for packaging and assembly of the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv). plasmids encoding individual lcmv proteins under the control of an rna polymerase ii promoter were cotransfected with a plasmid containing an lcmv minigenome (mg). intracellular synthesis of the lcmv mg was driven by t7 rna polymerase whose expression was also mediated by a pol ii promoter. the supernatant from transfec ... | 2002 | 12021374 |
| cutting edge: competition for apc by ctls of different specificities is not functionally important during induction of antiviral responses. | the hypothesis that t cell competition for access to apc influences priming of ctl responses is a controversial issue. a recent study using ova as a model ag supports this hypothesis and received considerable attention. however, using a comparable approach, we reached a different conclusion. we analyzed whether tcr transgenic t cells specific for lymphocytic choriomeningitis virus gp33-41/d(b) could inhibit the priming of endogenous responses against gp33-41 and against two other lymphocytic cho ... | 2002 | 12023329 |
| critical role for glial cells in the propagation and spread of lymphocytic choriomeningitis virus in the developing rat brain. | inoculation of the neonatal rat with lymphocytic choriomeningitis virus (lcmv) results in the selective infection of several neuronal populations and in focal pathological changes. however, the pathway by which lcmv reaches the susceptible neurons has not been described, and the nature and time course of the pathological changes induced by the infection are largely unknown. this study examined the sequential migration of lcmv in the developing rat brain and compared the pathological changes amon ... | 2002 | 12050375 |
| characterization of the arenavirus ring finger z protein regions required for z-mediated inhibition of viral rna synthesis. | the prototypic arenavirus lymphocytic choriomeningitis virus (lcmv) is an enveloped virus with a bisegmented negative-strand rna genome whose proteomic capability is limited to four polypeptides, namely, nucleoprotein; surface glycoprotein (gp), which is proteolytically processed into gp1 and gp2; polymerase (l); and a small (11-kda) ring finger protein (z). using a reverse genetic system based on the arm strain of lcmv, we have previously shown that z has a strong inhibitory activity on lcmv mi ... | 2002 | 12050381 |
| dynamic regulation of t cell immunity by cd43. | during a viral response, ag-specific effector t cells show dramatically increased binding by the mab 1b11 and the lectin peanut agglutinin (pna). we investigated the contribution of cd43 expression to 1b11 and pna binding as well as its role in generation and maintenance of a cd8 t cell response. analysis of cd43(-/-) mice revealed no increased 1b11 binding and reduced pna binding on virus-specific cd8 t cells from -/- mice compared with +/+ mice. furthermore, we examined the role of cd43 in the ... | 2002 | 12055210 |
| antiviral immune responses in the absence of organized lymphoid t cell zones in plt/plt mice. | the paucity of lymph node (ln) t cells (plt) mutation in mice results in strongly reduced t cell numbers in lns and homing defects of both dendritic cells (dcs) and naive t cells. in this study, we investigated the functional significance of the plt phenotype for the generation of antiviral immune responses against cytopathic and noncytopathic viruses. we found that dc-cd8(+) t cell contacts and the initial priming of virus-specific t cells in plt/plt mice occurred mainly in the marginal zone of ... | 2002 | 12055211 |
| viral abrogation of stem cell transplantation tolerance causes graft rejection and host death by different mechanisms. | tolerance-based stem cell transplantation using sublethal conditioning is being considered for the treatment of human disease, but safety and efficacy remain to be established. we have shown that mouse bone marrow recipients treated with sublethal irradiation plus transient blockade of the cd40-cd154 costimulatory pathway develop permanent hematopoietic chimerism across allogeneic barriers. we now report that infection with lymphocytic choriomeningitis virus at the time of transplantation preven ... | 2002 | 12055213 |
| programmed contraction of cd8(+) t cells after infection. | the extent of infection and rate of pathogen clearance are thought to determine both the magnitude of antigen-specific cd8(+) t cell expansion and the ensuing contraction to a stable number of memory cells. we show that cd8(+) t cell expansion after listeria monocytogenes infection was primarily dependent on the initial infection dose or amount of antigen displayed, and was also influenced by the rate of pathogen clearance. however, the onset and kinetics of cd8(+) t cell contraction after l. mo ... | 2002 | 12055624 |
| t cell immunodominance and maintenance of memory regulated by unexpectedly cross-reactive pathogens. | we show here that t cell cross-reactivity between heterologous viruses influences the immunodominance of virus-specific cd8(+) t cells by two mechanisms. first, t cells specific for cross-reactive epitopes dominate acute responses to viral infections; second, within the memory pool, t cells specific for cross-reactive epitopes are maintained while those specific for non-cross-reactive epitopes are selectively lost. these findings suggest an immunological paradigm in which viral infections shape ... | 2002 | 12055626 |
| transduction of dendritic cells by antigen-encoding lentiviral vectors permits antigen processing and mhc class i-dependent presentation. | because antigen-presenting dendritic cells (dcs) play a major role in the polarization of t cells, including t(h)2 cells involved in allergy, strategies to modify dcs genetically are required. | 2002 | 12063529 |
| interleukin 15 is required for proliferative renewal of virus-specific memory cd8 t cells. | the generation and efficient maintenance of antigen-specific memory t cells is essential for long-lasting immunological protection. in this study, we examined the role of interleukin (il)-15 in the generation and maintenance of virus-specific memory cd8 t cells using mice deficient in either il-15 or the il-15 receptor alpha chain. both cytokine- and receptor-deficient mice made potent primary cd8 t cell responses to infection with lymphocytic choriomeningitis virus (lcmv), effectively cleared t ... | 2002 | 12070282 |
| dynamics of memory t cell proliferation under conditions of heterologous immunity and bystander stimulation. | by examining adoptively transferred csfe-labeled lymphocytic choriomeningitis virus (lcmv)-immune donor t cells in thy-1 congenic hosts inoculated with viruses or with the cytokine inducer poly(i:c), strikingly different responses of bona fide memory t cells were found in response to different stimuli. poly(i:c) (cytokine) stimulation caused a limited synchronized division of memory cd8 t cells specific to each of five lcmv epitopes, with no increase and sometimes a loss in number, and no change ... | 2002 | 12077233 |
| exogenous peptides delivered by ricin require processing by signal peptidase for transporter associated with antigen processing-independent mhc class i-restricted presentation. | in this study we demonstrate that a disarmed version of the cytotoxin ricin can deliver exogenous cd8(+) t cell epitopes into the mhc class i-restricted pathway by a tap-independent, signal peptidase-dependent pathway. defined viral peptide epitopes genetically fused to the n terminus of an attenuated ricin a subunit (rta) that was reassociated with its partner b subunit were able to reach the early secretory pathway of sensitive cells, including tap-deficient cells. successful processing and pr ... | 2002 | 12077234 |
| the role of proinflammatory cytokines in wasting disease during lymphocytic choriomeningitis virus infection. | infection with pathogens often leads to loss of body weight, but the cause of weight loss during infection is poorly understood. we used the infection of mice with lymphocytic choriomeningitis virus (lcmv) as a model to study how pathogens induce weight loss. if lcmv is introduced into the cns of ctl-deficient mice, the immune response against the virus leads to a severe weight loss called wasting disease. we planned to determine what components of this antiviral immune response mediate wasting ... | 2002 | 12077263 |
| cd8(+) t cell responses: it's all downhill after their prime. | | 2002 | 12087413 |
| role of cd28 co-stimulation in generation and maintenance of virus-specific t cells. | efficient induction of t cell responses is normally assumed to require both tcr-mediated signaling and engagement of co-stimulatory molecules, in particular cd28. however, the importance of cd28 co-stimulation in induction and maintenance of antiviral t cell responses is not clearly established. for this reason antiviral cd4(+) and cd8(+) t cell responses in cd28-deficient mice were studied using two different viruses [vesicular stomatitis virus and lymphocytic choriomeningitis virus (lcmv)]. in ... | 2002 | 12096029 |
| cutting edge: ccr7+ and ccr7- memory t cells do not differ in immediate effector cell function. | it has been proposed that expression of the chemokine receptor ccr7 represents a defining factor for nonpolarized central (ccr7(+)) and polarized effector memory (ccr7(-)) t cells. in this study, we have tested this hypothesis using in vivo-activated t cells from p14 and smarta tcr-transgenic (tg) mice specific for mhc class i- and ii-restricted epitopes of the lymphocytic choriomeningitis virus (lcmv) glycoprotein. ccr7 cell surface expression on tcr-tg cells was monitored with a cc chemokine l ... | 2002 | 12097363 |
| cd94/nkg2 expression does not inhibit cytotoxic function of lymphocytic choriomeningitis virus-specific cd8+ t cells. | murine ag-specific cd8(+) t cells express various nk markers and nk inhibitory receptors that have been proposed to modulate immune responses. following acute infection of c57bl/6 and balb/cj mice with lymphocytic choriomeningitis virus (lcmv), we observed that ag-specific cd8(+) t cells expressed cd94/nkg2. only slight expression of ly49a and ly49c receptors was observed on np396-specific t cells, while all np396-specific t cells expressed the nkt cell marker u5a2-13 ag. expression of cd94/nkg2 ... | 2002 | 12097371 |
| pharmacological cyclin-dependent kinase inhibitors inhibit replication of wild-type and drug-resistant strains of herpes simplex virus and human immunodeficiency virus type 1 by targeting cellular, not viral, proteins. | pharmacological cyclin-dependent kinase (cdk) inhibitors (pcis) block replication of several viruses, including herpes simplex virus type 1 (hsv-1) and human immunodeficiency virus type 1 (hiv-1). yet, these antiviral effects could result from inhibition of either cellular cdks or viral enzymes. for example, in addition to cellular cdks, pcis could inhibit any of the herpesvirus-encoded kinases, dna replication proteins, or proteins involved in nucleotide metabolism. to address this issue, we as ... | 2002 | 12097601 |
| new glioma vaccine in pipeline. | | 2002 | 12107010 |
| the differential contribution of granzyme a and granzyme b in cytotoxic t lymphocyte-mediated apoptosis is determined by the quality of target cells. | complementary approaches with purified molecules or transfected cytolytic effector cells have suggested that both, granzyme a (gzma) and granzyme b (gzmb), similarly contribute to ctl-mediatedand perforin (perf)-dependent apoptotic nuclear damage (dna fragmentation) in target cells. studies employing gzma or gzmb single-knockout mice on the other hand indicated that gzmb is the prominent ctl effector molecule for the rapid induction of dna fragmentation, with gzma playing only a minor part. we h ... | 2002 | 12115618 |
| t cell receptor transgenic mice recognizing the immunodominant epitope of the torpedo californica acetylcholine receptor. | myasthenia gravis (mg) is an autoimmune disease caused by t cell-dependent antibody-mediated reduction of acetylcholine receptors (achr) at the neuromuscular junction. immunization of animals with torpedo californica achr (tachr) results in an experimental model of mg. we used the variable regions of alpha and beta t cell receptor (tcr) genes recognizing an immunodominant peptide containing amino acids 146-162 from the alpha subunit of tachr presented in the context of i-a(b) to generate tcr-tra ... | 2002 | 12115627 |
| defective generation but normal maintenance of memory t cells in old mice. | the ability to maintain memory after encounter with antigen is one of the central features of the immune system. immune memory generated during young age can be maintained well into old age. however, we know little about maintenance of immune memory generated during old age. in this study, we compared generation and maintenance of memory cd8 t cells in young (2-3-month-old) and aged (22-24-month-old) mice following acute lymphocytic choriomeningitis virus infection. we found that young mice made ... | 2002 | 12115639 |
| lentiviral vectors pseudotyped with a modified rd114 envelope glycoprotein show increased stability in sera and augmented transduction of primary lymphocytes and cd34+ cells derived from human and nonhuman primates. | generating lentiviral vectors pseudotyped with different viral glycoproteins (gps) may modulate the physicochemical properties of the vectors, their interaction with the host immune system, and their host range. we have investigated the capacity of a panel of gps of both retroviral (amphotropic murine leukemia virus [mlv-a]; gibbon ape leukemia virus [galv]; rd114, feline endogenous virus) and nonretroviral (fowl plague virus [fpv]; ebola virus [ebov]; vesicular stomatitis virus [vsv]; lymphocyt ... | 2002 | 12130492 |
| viral and bacterial infections induce expression of multiple nk cell receptors in responding cd8(+) t cells. | nk cells express several families of receptors that play central roles in target cell recognition. these nk cell receptors are also expressed by certain memory phenotype cd8(+) t cells, and in some cases are up-regulated in t cells responding to viral infection. to determine how the profile of nk receptor expression changes in murine cd8(+) t cells as they respond to intracellular pathogens, we used class i tetramer reagents to directly examine ag-specific t cells during lymphocytic choriomening ... | 2002 | 12133970 |
| marginal zone macrophages and immune responses against viruses. | the effective establishment of antiviral protection requires a coordinated interplay between the innate and adaptive immune system. using osteopetrotic (op(-/-)) mice, this study investigated the influence of marginal zone macrophages in controlling and initiating a protective immune response against a cytopathic vs a non- or low-cytopathic virus. despite the generation of potent adaptive immune responses, antiviral protection against cytopathic vesicular stomatitis virus critically depended on ... | 2002 | 12133971 |
| elevated generation of reactive oxygen/nitrogen species in hantavirus cardiopulmonary syndrome. | hantavirus cardiopulmonary syndrome (hcps) is a life-threatening respiratory disease characterized by profound pulmonary edema and myocardial depression. most cases of hcps in north america are caused by sin nombre virus (snv), which is carried asymptomatically by deer mice (peromyscus maniculatus). the underlying pathophysiology of hcps is poorly understood. we hypothesized that pathogenic snv infection results in increased generation of reactive oxygen/nitrogen species (rons), which contribute ... | 2002 | 12134039 |
| high numbers of il-2-producing cd8+ t cells during viral infection: correlation with stable memory development. | using infections with lymphocytic choriomeningitis virus (lcmv) and vesicular stomatitis virus in mice as model systems, we have investigated the ability of antigen-primed cd8+ t cells generated in the context of viral infections to produce il-2. our results indicate that acute immunizing infection normally leads to generation of high numbers of il-2-producing antigen-specific cd8+ t cells. by costaining for il-2 and ifn-gamma intracellularly, we found that il-2-producing cells predominantly con ... | 2002 | 12185265 |
| travels along the viral-immunobiology highway. | michael oldstone began his biomedical research career over three decades ago, showing contrary to established scientific dogma, the host was not tolerant but made a specific antiviral immune response during persistent virus infections. further, the immune response to the virus actually caused tissue damage and disease, the first observation that several manifestations ordinarily accompanying infections were due to the host's antiviral immune response. these observations made originally with lymp ... | 2002 | 12190922 |
| antigen-induced cell death of t effector cells in vitro proceeds via the fas pathway, requires endogenous interferon-gamma and is independent of perforin and granzymes. | activation of resting t cells usually leads to their proliferation and differentiation into effector cells and a subsequent decline following elimination of the antigen. a situation of excessive antigen density may result in t cell receptor (tcr)-induced deletion of t effector cells, a process termed antigen-induced cell death (agicd). previous studies indicate that agicd of cytotoxic t cells may be induced by either of the two key cytotoxic processes, granule exocytosis, including perforin and ... | 2002 | 12207333 |
| molecular indetermination in the transition to error catastrophe: systematic elimination of lymphocytic choriomeningitis virus through mutagenesis does not correlate linearly with large increases in mutant spectrum complexity. | studies with several rna viruses have shown that enhanced mutagenesis resulted in decreases of infectivity or virus extinction, as predicted from virus entry into error catastrophe. here we report that lymphocytic choriomeningitis virus, the prototype arenavirus, is extremely susceptible to extinction mutagenesis by the base analog 5-fluorouracil. virus elimination was preceded by increases in complexity of the mutant spectra of treated populations. however, careful molecular comparison of the m ... | 2002 | 12215495 |
| peptidic termini play a significant role in tcr recognition. | tcr recognition of class i mhc is dependent on the composition of the antigenic peptide and the mhc. single amino acid substitutions in either the mhc or the peptide may dramatically alter recognition. while the major interactions between tcr and the peptide/mhc complex appear to be focused on the complementarity-determining region (cdr)3, it is also clear from the cocrystal structure of class i mhc and tcr that the amino and carboxyl ends of the peptide may play a role through interactions with ... | 2002 | 12218131 |
| critical role for stat4 activation by type 1 interferons in the interferon-gamma response to viral infection. | interferons (ifns) are essential for host defense. although the antiviral effects of the type 1 ifns ifn-alpha and ifn-beta (ifn-alpha/beta) have been established, their immunoregulatory functions, especially their ability to regulate ifn-gamma production, are poorly understood. here we show that ifn-alpha/beta activate stat4 directly (stat, signal transducers and activators of transcription) and that this is required for ifn-gamma production during viral infections of mice, in concert with t ce ... | 2002 | 12242445 |
| differential sensitivity of naive and memory cd8+ t cells to apoptosis in vivo. | apoptosis is a critical regulator of homeostasis in the immune system. in this study we demonstrate that memory cd8(+) t cells are more resistant to apoptosis than naive cells. after whole body irradiation of mice, both naive and memory cd8(+) t cells decreased in number, but the reduction in the number of naive cells was 8-fold greater than that in memory cd8(+) t cells. in addition to examining radiation-induced apoptosis, we analyzed the expansion and contraction of naive and memory cd8(+) t ... | 2002 | 12244170 |
| molecular anatomy of antigen-specific cd8(+) t cell engagement and synapse formation in vivo. | antigen-specific cd8(+) t cells are required for the clearance of most viral infections and several cancers. however, it is not clear in vivo whether cd8(+) t cells can engage multiple targets simultaneously, engagement results in the formation of an immunologic synapse or molecules involved in cd8 function are redistributed to the synapse. we used here high-resolution microscopy to visualize interactions between virus-specific effectors and target cells in vivo. using either in situ tetramer st ... | 2002 | 12352968 |
| five recombinant simian immunodeficiency virus pseudotypes lead to exclusive transduction of retinal pigmented epithelium in rat. | the purpose of our study was to evaluate lentiviral vector-mediated rat retinal transduction using simian immunodeficiency virus (siv) pseudotyped with envelope proteins from vesicular stomatitis virus g glycoprotein (vsv-g), mokola virus g protein (mk-g), amphotropic murine leukemia virus envelope (4070a-env), influenza a virus hemagglutinin (ha), lymphocytic choriomeningitis virus g protein (lcmv-g), and rd114 retrovirus envelope (rd114-env). the six pseudotyped lentivirus vectors carried cmv- ... | 2002 | 12377185 |
| antagonistic variant virus prevents wild-type virus-induced lethal immunopathology. | altered peptide ligands (apls) and their antagonistic or partial agonistic character-influencing t cell activation have mainly been studied in vitro some studies have shown apls as a viral escape mechanism from cytotoxic cd8(+) t cell responses in vivo. however, whether infection or superinfection with a virus displaying an antagonistic t cell epitope can alter virus-host relationships via inhibiting t cell-mediated immunopathology is unclear. here, we evaluated a recently described cd4(+) t cel ... | 2002 | 12391015 |
| reduction of antiviral cd8 lymphocytes in vivo with dendritic cells expressing fas ligand-increased survival of viral (lymphocytic choriomeningitis virus) central nervous system infection. | in vivo administration of apc expressing fas ligand (fas-l(+) dendritic cells (dcs)) has shown promise in dampening allergic reactions and transplant rejection. since the effect in these studies was mainly on cd4 lymphocytes, our goal was to evaluate the ability of such killer dcs to eliminate antiviral cd8 lymphocytes and in this way ameliorate viral immunopathology or, conversely, impede viral clearance. intravenous administration of fas-l(+) dcs resulted in a 50% reduction of lytic cd8 precur ... | 2002 | 12391197 |
| dna vaccination breaks tolerance for a neo-self antigen in liver: a transgenic murine model of autoimmune hepatitis. | understanding the pathogenesis of autoimmune hepatitis requires an animal model in which chronic progressive immune injury develops spontaneously or with minimal manipulations. the new transgenic mouse model proposed in this study is based on the hypothesis that infectious agents have the potential to initiate autoreactivity through molecular mimicry. a transgenic mouse expressing lymphocytic choriomeningitis virus nucleoprotein (np) in a h-2(b) background developed liver injury when vaccinated ... | 2002 | 12391200 |
| quantitation of cd8+ t cell expansion, memory, and protective immunity after immunization with peptide-coated dendritic cells. | dendritic cells (dcs) are potent apcs for naive cd8(+) t cells and are being investigated as vaccine delivery vehicles. in this study, we examine the cd8(+) t cell response to defined peptides from listeria monocytogenes (lm), lymphocytic choriomeningitis virus, and murine cmv coated singly and in combination onto mature bone marrow-derived dcs (bmdcs). we show that immunization of mice with 2 x 10(5) mature bmdcs coated with multiple mhc class i peptides generates a significant ag-specific cd8( ... | 2002 | 12391206 |