bluuebunny/crossref_metadata_2025_split huggingface dataset:
Massive mammary gland infection and pregnancy‐dependent mammary tumor development in mice infected neonatally with mouse mammary tumor virus (SW) but not in mice infected as adults, despite a dramatic local response
Authors: Papiernik Martine , Waché Anne‐Claude , Pontoux Christiane , Nabarra Bernadette 
Published: March 2007

AbstractMouse mammary tumor virus (MMTV) (SW) caused a high incidence (65%) of pregnancy‐dependent adenocarcinomas in BALB/c(SW) mice infected as new‐borns by suckling their mothers' milk. These tumors were type B adenocarcinomas which developed early, at about 1 year of age. Uninfected breeding females and those infected at an age of 8 weeks by injection of virus had the same low incidence of malignant tumors (13%), and the tumors developed later (at approx. 23–24 months). The low incidence of tumors in adult‐infected mice was correlated with partial infection of the mammary glands, and delayed transmission of MMTV(SW) to the offspring. Although the virus was rapidly disseminated in both types of infection, the responses of neonatally infected and adult‐infected mice to MMTV(SW) infection and viral superantigen (vSAG) presentation were different. Activation by and presentation of the vSAG was impaired in mice infected neonatally, and tolerance induction by clonal deletion was delayed. Local activation was dramatic in mice infected as adults and clonal deletion followed rapidly. Although interaction between B and T cells is needed for completion of the virus life cycle and viral amplification, the strong local immune response to MMTV(SW) in adult‐infected mice limits mammary gland infection, and protects them against mammary tumor development.
Peptide‐induced T cell receptor down‐regulation on naive T cells predicts agonist/partial agonist properties and strictly correlates with T cell activation
Authors: Bachmann Martin F. , Oxenius Annette , Speiser Daniel E. , Mariathasan Sanjeev , Hengartner Hans , Zinkernagel Rolf M. , Ohashi Pamela S. 
Published: March 2007

AbstractRecent experiments defining T cell agonists, partial agonists and antagonists have suggested that the T cell can discriminate between subtle differences in interactions leading to T cell activation. To further understand the complexities of T cell activation, we have analyzed the requirements for the induction of a variety of effector functions using naive T cells and a variety of altered peptide ligands. Using a strong agonist peptide, massive T cell receptor (TCR) down‐regulation correlated with a wide range of effector functions that were all induced above the same threshold peptide concentration. Interestingly, the kinetics of TCR down‐regulation correlated with the concentration of the peptide, whereas the maximal degree of TCR down‐regulation correlated with the induction of all monitored effector functions. A selected group of altered peptide ligands was also examined that were able to render target cells susceptible for lysis by effector cytotoxic T lymphocytes. The extent of TCR down‐regulation induced by these peptides corresponded to the induction of a subset of effector functions. These studies have shown that the extent of TCR down‐regulation defines the strength of TCR‐mediated “signal 1” which correlates with the spectrum of effector functions activated within the T cell. Thus, activation of different T cell functions requires the triggering of distinct numbers of TCR. The different parameters that influence TCR down‐regulation define important distinctions between our results and previously reported findings with T cell clones and may outline decisive parameters for the consequences of T cell activation in vivo.
T cell repertoire in patients with multiple myeloma and monoclonal gammopathy of undetermined significance: Clonal CD8+ T cell expansions are found preferentially in patients with a low tumor burden
Authors: Halapi Eva , Werner Åsa , Wahlström Jan , Österborg Anders , Jeddi‐Tehrani Mahmood , Yi Qing , Janson Carl Harald , Wigzell Hans , Grunewald Johan , Mellstedt Håkan 
Published: March 2007

AbstractThe T cell receptor (TCR) variable (V) gene repertoire was analyzed in patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 17), multiple myeloma (MM) stage I (n = 16), MM stages II/III (n = 31) and agematched controls (n = 27) by immunofluorescence and flow cytometry using a panel of mouse monoclonal antibodies (mAb) (n = 10) against TCR Vα and Vβ gene products. T cell expansion was defined as a value ⩾ thrice the normal median value for each respective TCR V mAb. Fifty‐three percent of all patients displayed CD8+ expansion(s) as compared to 30% of age‐matched controls (p = 0.001). Within the CD4 subset, 18% of the patients displayed T cell expansion(s) in comparison to 11% of the controls (not significant). Interestingly, the CD8+ expansion(s) were more frequently noted in patients with a low tumor burden (MGUS/MMI) (73%) as compared to those with advanced disease (MM II/III) (32% and control donors (30%) (p < 0.01). Likewise, multiple CD8+ expansions (two or more) were more common in MGUS/MM I patients than in MM II/III and controls (p = 0.01). The T cell expansions were stable over time in patients with a stable disease. A high degree of clonality of the expansions was detected by TCR CDR3 fragment length analysis, determination of Jβ gene usage and nucleotide sequencing. The frequent finding of oligoclonal CD8+ T cell expansions in patients with a low tumor mass, but not in patients with advanced disease justifies further work in order to identify the relevance of expanded CD8+ T cells. In one patient with T cell reactivity against the autologous myeloma idiotype, two expansions within the CD8 population (Vβ3 and Vβ5.2 respectively) displayed no reactivity against the idiotype. Instead, idiotype recognition was confined to a CD8 non‐expanded Vβ22+ T cell population, with a highly restricted TCR usage (CDR3 fragment length analysis).
Nephritogenic T cells use granzyme C as a cytotoxic mediator
Authors: Bailey Naila Celesta , Kelly Carolyn J. 
Published: March 2007

AbstractCytoplasmic granules of cytotoxic T lymphocytes contain several proteins that may be involved in cell‐mediated cytotoxicity. We have previously described nephritogenic T cell clones that are cytotoxic to cultured renal proximal tubular epithelial cells (MCT). One of these clones, M52.34.1, expresses perforin, a cytotoxic mediator. We investigated the expression of other granule‐associated proteases of M52.34.1. Granzymes A and B have been extensively studied in T cell‐mediated cytotoxicity, and associated with tissue destruction in models of transplantation. However, the activity of other granzymes has not been as extensively investigated. We focused our studies on granzyme C. Northern blots showed very high levels of granzymes B and C mRNA expression in M52.34.1 cells 3 days following T cell activation. There was no expression of granzyme A mRNA. An antisense oligonucleotide made from the 5′‐upstream region of the murine granzyme C exon 1 inhibited granzyme C mRNA expression in M52.34.1 when added at a concentration of 50 μM to the culture medium for 2 days. There was no inhibition of granzyme C mRNA expression with the sense oligonucleotide. The granzyme C antisense oligonucleotide inhibited M52.34.1 cytotoxicity to MCT at effector: target ratios of 20:1 and 40:1. M52.34.1 cells mediate inflammatory interstitial nephritis following adoptive transfer. If T cells were resuspended in 200 μM of the antisense oligonucleotide prior to subcapsular transfer, the recipient kidneys showed markedly diminished tubular cell destruction, suggesting that granzyme C can also be an important mediator of cytotoxicity in vivo.
Antigen‐specific CD8+ T cell subset distribution in lymph nodes draining the site of herpes simplex virus infection
Authors: Cose Stephen C. , Jones Claeroen M. , Wallace Morgan E. , Heath William R. , Carbone Francis R. 
Published: March 2007

AbstractInoculation with replicating virus leads to an increase in T cell numbers within lymph nodes that drain the site of infection. This increase has been associated with a nonspecific proliferation of bystander cells, with only a minority thought to be directed to the infectious agent. Such an assumption is largely based on precursor cytotoxic T lymphocyte (CTL) estimations using limiting dilution analysis. Recently, studies using more advanced molecular approaches have suggested that such functionally derived precursor frequencies considerably underestimate the proportion of T cells specific for the antigen under investigation. We have defined T cell receptor sequences characteristic of CTL populations directed to a dominant determinant of the herpes simplex virus (HSV) glycoprotein B (gB). In this investigation, we used this receptor signature as a probe to directly monitor changes occurring within lymph nodes draining the sites of active infection with HSV. We found that although lymph node CD8+ T cell numbers increase as a consequence of HSV infection, the majority of these cells are small resting cells that are not enriched for gB‐specific receptors. In contrast, a significant proportion of activated T cells are highly enriched for CTL bearing gB‐specific receptors. Our results are therefore consistent with a nonspecific migration of CTL precursors into the lymph nodes draining the site of infection, followed by the activation and proliferation of the antigen‐specific subset that normally makes up a small proportion of the naive T cell repertoire.
Phenotypic and functional analysis of CD4+ NKRP1A+ human T lymphocytes. Direct evidence that the NKRP1A molecule is involved in transendothelial migration
Authors: Poggi Alessandro , Costa Paola , Zocchi Maria Raffaella , Moretta Lorenzo 
Published: March 2007

AbstractIn this report, we show that among human CD4+ T lymphocytes 5–20% express the C‐type lectin molecule NKRP1A. This lymphocyte subset displays a slightly more limited T cell receptor Vβ repertoire than the CD4+ NKRP1A− counterpart. CD4+ NKRP1A+ T lymphocytes are characterized by a high expression of β1 and β2 integrins, thus representing a T lymphocyte subset that can possibly adhere and migrate through vascular endothelium. Indeed, resting CD4+ NKRP1A+ lymphocytes, differently from the CD4+ NKRP1A− subset, migrated across endothelial cell monolayers in a Transwell chamber system. Pre‐treatment of CD4+ NKRP1A+ T lymphocytes with an anti‐NKRP1A monoclonal antibody (mAb) strongly reduced transendothelial migration, suggesting the involvement of the NKRP1A molecule in the transmigration process. Furthermore, cells of the NKRP1A− Jurkat CD4+ T cell line stably transfected with NKRP1A cDNA migrated more rapidly and efficiently than either untransfected or mock‐transfected Jurkat cells. Finally, mAb‐mediated cross‐linking of NKRP1A molecules in CD4+ T lymphocytes induced the up‐regulation of the lymphocyte function‐associated antigen 1 Mg2+‐binding site as well as β1 and β2 integrin chains. Altogether, these findings suggest that the NKRP1A molecule is involved in transendothelial migration of resting CD4+ T lymphocytes.
Glucocorticoids inhibit human antigen‐specific and enhance total IgE and IgG4 production due to differential effects on T and B cells in vitro
Authors: Akdis Cezmi A. , Blesken Thorsten , Akdis Mübeccel , Alkan Sefik S. , Heusser Christoph H. , Blaser Kurt 
Published: March 2007

AbstractAlthough anti‐inflammatory properties of glucocorticoids (GC) are well documented, their activity in allergic diseases is still controversial. Recently, it has been reported that GC can increase, both in vivo and in vitro, the polyclonal production of total IgE. In this study we investigated the effects of GC on the antigen (Ag)‐specific IgE response in a human in vitro system with peripheral blood mononuclear cells or B cells of bee venom‐sensitized individuals that allows the production of bee venom phospholipase A2 (PLA)‐specific IgE and IgG4 antibodies (Ab). PLA‐specific Ab were induced by simultaneously activating T cells and B cells specifically with allergen and polyclonally with anti‐CD2 and soluble CD40 ligand (sCD40L) in the presence of interleukin (IL)‐4. Indeed, dexamethasone and prednisolone enhanced the formation of total IgE and IgG4 in PBMC, while the production of PLA‐specific IgE and IgG4 Ab was selectively inhibited in a dose‐dependent manner. The suppressive effect of GC was mediated during Ag‐specific stimulation and T cell‐B cell interaction. This was due to GC suppressing specific T cell proliferation and cytokine production, whereas neither allergen‐specific nor total IgE and IgG4 production by sCD40L/IL‐4‐stimulated pure B cells was affected. In contrast to GC, cyclosporine A inhibited both total and PLA‐specific IgE and IgG4 secretion in peripheral blood mononuclear cells and B cell cultures. Further experiments showed that increase in nonspecific total isotype response resulted from inhibition of IL‐4 uptake by cells other than B cells and sufficient availability of IL‐4 to B cells for isotype switch and synthesis. Furthermore, demonstration of opposite regulatory effects of GC on specific and total isotype formation in vitro, including the inhibition of allergy‐relevant Ag‐specific IgE response, may contribute to a better understanding of apparently controversial observations, and explain why most allergic patients benefit from GC therapy.
Ligation of the T cell co‐stimulatory receptor CD28 activates the serine‐threonine protein kinase protein kinase B
Authors: Parry Richard V. , Reif Karin , Smith Graham , Sansom David M. , Hemmings Brian A. , Ward Stephen G. 
Published: March 2007

AbstractThe intracellular signaling pathways activated upon ligation of the co‐stimulatory receptor CD28 remain relatively ill‐defined, although CD28 ligation does result in the strong association with, and activation of, phosphatidylinositol (PI) 3‐kinase. The downstream effector targets of the CD28‐activated PI 3‐kinase‐dependent signaling pathway remain poorly defined, but recent evidence from other systems has shown that Akt/protein kinase B (PKB) is a major target of PI 3‐kinase and have indicated that a major function of PKB is the regulation of cell survival events. Given the strong coupling of CD28 to PI 3‐kinase and the known protective effects of both CD28 and PI 3‐kinase against apoptosis in different cell models, we investigated the effects of CD28 on PKB activation. We demonstrate that ligation of CD28 by either anti‐CD28 monoclonal antibodies or the natural ligand B7.1, results in the marked activation of PKB in both the leukemic T cell line Jurkat and freshly isolated human peripheral blood‐derived normal T lymphocytes. Our data suggest therefore, that PKB may be an important intracellular signal involved in CD28 signal transduction and demonstrate CD28 coupling to downstream elements of a signaling cascade known to promote cell survival.
Plasmodium falciparum sporozoite invasion is inhibited by naturally acquired or experimentally induced polyclonal antibodies to the STARP antigen
Authors: Fidock David A. , Pasquetto Valérie , Gras Hélène , Badell Edgar , Eling Wijnand , Ballou W. Ripley , Belghiti Jacques , Tartar André , Druilhe Pierre 
Published: March 2007

AbstractAntibody(Ab)‐mediated inhibition of sporozoite invasion of hepatocytes is a mechanism that has been clearly demonstrated to act upon Plasmodium falciparum pre‐erythrocytic stages in humans. Consequently we have analyzed the Ab response to a recently identified P. falciparum sporozoite surface protein, STARP, in malaria‐exposed individuals and tested the inhibitory effect of these Ab upon hepatocyte invasion in vitro. STARP‐specific IgG were detected in 90 and 61 % of sera from regions where individuals were exposed to 100 and 1–5 infectious bites per year, respectively. These IgG were predominantly of the cytophilic IgG1 or IgG3 type. STARP and the major sporozoite surface protein, CS, elicited equivalent IgG levels in adults. When affinity purified from either African immune sera or the serum of an individual experimentally protected by irradiated sporozoite immunization, STARP‐specific Ab prevented up to 90% of sporozoites from invading human hepatocytes. The dose‐dependent and reproducible inhibition was more pronounced than that observed with human CS‐specific Ab affinity purified under identical conditions. Substantial reduction of sporozoite invasion was also observed with Ab induced by artificial immunization with recombinant STARP protein and reactive with the native protein. Taken together with recent findings of human cytotoxic T lymphocytes specific for this antigen, these results promote the interest of studying the efficacy of STARP as a target for immune effector mechanisms operating upon preerythrocytic stages.
Zinc inhibits interleukin‐1‐dependent T cell stimulation
Authors: Wellinghausen Nele , Martin Michael , Rink Lothar 
Published: March 2007

AbstractZinc is a trace element which is essential for immune functions. It directly induces monokine secretion by monocytes; however, effects of zinc on T cells appear contradictory. Apart from enhanced lymphocyte proliferation in peripheral blood mononuclear cells (PBMC), inhibitory properties of high zinc dosages have also been described. In this study, PBMC failed to produce lymphokines like interferon (IFN)‐γ after stimulation with zinc in a serum‐ and LPS‐free cell culture system, whereas monokine secretion [interleukin (IL)‐1β] occurred. Zinc‐uptake studies with the zinc‐specific fluorescent probe zinquin revealed that zinc is taken up by PBMC within a few minutes, reaching nearly equal levels in PBMC, isolated monocytes, and T cells. However, if zinc was depleted 1 h after monocyte induction, zinc‐free pre‐cultured T cells were stimulated to secrete IFN‐γ by zinc‐induced monokines. Furthermore, the necessity for a cell‐cell interaction between monocytes and T cells for IFN‐γ induction was elucidated. Zinc ions inhibited the proliferation of the IL‐1‐dependent T cell line D 10N in a dose‐dependent manner, suggesting a direct inhibitory effect of zinc. By immunoprecipitation we revealed a specific inhibition of IL‐1 receptor‐associated protein kinase (IRAK) by zinc ions. Therefore, in contrast to an indirect stimulation of T cells due to zinc‐induced monokines, higher concentrations of zinc directly inhibit T cell functions by means of specific inhibition of IRAK and subsequent signaling events such as NFxB activation. The divergent effects of zinc on different cell populations, depending on the zinc concentration, could explain contradictory results of zinc stimulation. Furthermore, our data suggest new strategies of specific zinc‐mediated immune modulation.
A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling
Authors: Alexopoulou Lena , Pasparakis Manolis , Kollias George 
Published: March 2007

AbstractThe arthritogenic activities of tumor necrosis factor (TNF) and its p55TNF‐receptor (R) have been well documented in experimental animal models of arthritis, and in transgenic mice expressing wild‐type or mutant transmembrane human TNF proteins in their joints. In this study we show that chronic inflammatory arthritis also develops in transgenic mice made to overexpress a mutant transmembrane from of the murine TNF protein (muTNFΔ1–12) which is known to utilize efficiently both the p55 and the p75TNFR. Cross‐breeding of the transgene into a TNF knockout background did not alter development of disease. Analysis of TNF bioactivity in sera from lipopolysaccharide‐stimulated mice orex vivomacrophage cultures demonstrated that the muTNFΔ1–12protein accumulates on the cell surface and is not processed to bioactive soluble TNF, indicating that transmembrane TNF is by itself sufficient to mediate pathogenesis of arthritis. Furthermore, using TNFR knockout mice, it is shown that development of transmembrane TNF‐mediated arthritis requires the presence of the p55TNFR but is significantly delayed in the absence of the p75TNFR, suggesting a positive cooperation between the two TNFR in the arthritogenic process. These results indicate that blocking the activities of both soluble and transmembrane TNF may be required to effectively neutralize the pathogenic potential of this cytokine in arthritis.
Antigen‐specific CD8+ T cells inhibit IgE responses and interleukin‐4 production by CD4+ T cells
Authors: Holmes Beverly J. , Macary Paul A. , Noble Alistair , Kemeny D. Michael 
Published: March 2007

AbstractThere is a growing body of evidence which suggests that CD8+ T cells play an important part in regulating the IgE response to non‐replicating antigens. In this study we have systematically investigated their role in the regulation of IgE and of CD4+ T cell responses to ovalbumin (OVA) by CD8+ T cell depletion in vivo. Following intraperitoneal immunization with alum‐precipitated OVA, OVA‐specific T cell responses were detected in the spleen and depletion of CD8+ T cells in vitro significantly enhanced the proliferative response to OVA. Depletion of CD8+ T cells in vivo 7 days after immunization failed to enhance IgE production, while depletion of CD8+ T cells on days 12–18 greatly enhanced the IgE response, which rose to 26 μ/ml following a second injection of anti‐CD8 on day 35 and remained in excess of 1 μ/ml over 300 days afterwards. Reconstitution on day 21 of rats CD8‐depleted on day 12 with purified CD8+ T cells from animals immunized on day 12 completely inhib ited the IgE response. This effect was antigen specific; CD8+ T cells from OVA‐primed animals had little effect on the IgE response of bovine serum albumin immunized rats. In vivo, CD8+ T cell depletion decreased interferon (IFN)‐γ production but enhanced interleukin (IL)‐4 production by OVA‐stimulated splenic CD4+ T cells. Furthermore, CD8+ T cell depletion and addition of anti‐IFN‐γ antibody enhanced IgE production in vitro in an IL‐4‐supplemented mixed lymphocyte reaction. These data clearly show that antigen‐specific CD8+ T cells inhibit IgE in the immune response to non‐replicating antigens. The data indicate two possible mechanisms: first, CD8+ T cells have direct inhibitory effects on switching to IgE in B cells and second, they inhibit OVA‐specific IL‐4 production but enhance IFN‐γ production by CD4+ T cells.
Secreted proteophosphoglycan of Leishmania mexicana amastigotes activates complement by triggering the mannan binding lectin pathway
Authors: Peters Christopher , Kawakami Masaya , Kaul Marcus , Ilg Thomas , Overath Peter , Aebischer Toni 
Published: March 2007

AbstractCutaneous lesions induced by infection of mice with the protozoan parasite, Leishmania mexicana, contain abundant amounts of a high molecular mass proteophosphoglycan (PPG), which is secreted by the amastigote stage residing in phagolysosomes of macrophages and can then be released into the tissue upon rupture of the infected cells. Amastigote PPG forms sausage‐shaped but soluble particles and belongs to a novel class of serine‐rich proteins that are extensively O‐glycosylated by phosphooligosaccharides capped by mannooligosaccharides. The purified molecule is shown here to efficiently activate complement (C) and deplete hemolytic activity of normal serum and may prevent the opsonization of L. mexicana amastigotes. Complement activation is Ca2+ dependent but does not depend on antibodies or the complement component C1. PPG binds to serum mannan binding protein (MBP), thus activating the MBP‐associated serine protease, P100. Subsequently, the C cascade is triggered through C4 leading to covalent modification probably of carbohydrate hydroxyls of PPG by C3 fragments. Thus, PPG is able to activate C via the mannan binding lectin pathway which is unusual for secreted, soluble products of microbial origin. The proteophosphoglycan‐induced complement activation is postulated to contribute to the lesion development and pathology caused by the parasite.