bluuebunny/crossref_metadata_2025_split huggingface dataset:
Carcinogen‐modified dendritic cells induce immunosuppression by incomplete T‐cell activation resulting from impaired antigen uptake and reduced CD86 expression
Authors: Woods G. M. , Doherty K. V. , Malley R. C. , Rist M. J. , Muller H. K. 
Published: March 2003

SummaryExposure of the skin to environmental stimuli, such as chemical or physical carcinogens, modifies the local skin environment, including depletion of epidermal Langerhans’ cells (LC). Any subsequent exposure of the LC‐depleted skin to antigen results in the generation of antigen‐specific tolerance. In this study we evaluated the antigen‐bearing cells in the draining lymph nodes by capitalizing on the fluorescent nature of the contact sensitizer, fluorescein isothiocyanate (FITC). When FITC was applied to the skin of normal mice, two distinct populations of antigen‐bearing cells were identified in the draining lymph nodes. They were classified as either FITChi or FITClo on the basis of their fluorescence intensity and thus the amount of antigen they internalized. Only FITClo cells were detected in the lymph nodes draining FITC‐treated murine skin that had been depleted of epidermal LC by prior treatment with the complete carcinogen 9,10‐dimethyl 1,2‐benzanthracene (DMBA). Functional analysis of these cells revealed that the FITChi cells, but not the FITClo cells, induced antigen‐specific T‐cell proliferation. Further analysis of the FITClo cells from the DMBA‐treated mice demonstrated that these cells had reduced levels of CD80 expression, had substantially reduced levels of CD86 expression and performed poorly as co‐stimulator cells in an anti‐CD3‐mediated proliferative assay. Nonetheless these cells still induced early signs of T‐cell activation and interleukin‐12 production. Consequently the FITClo cells migrating from the LC‐depleted skin, through a combination of reduced antigen presentation and reduced co‐stimulatory activity, induced a state of unresponsiveness or anergy in the responder T cells in a similar manner to that observed when antigen presentation occurs in the absence of co‐stimulation. We propose that these unresponsive, or anergic cells, account for the antigen‐specific tolerance observed in these experiments.
DBA/2J (Mls‐1a) B‐cell differentiation in BALB.xid recipients
Authors: Tocce K. , Suppiah K. , Rago C. , Liberchuk R. , Duffy K. , Riggs J. 
Published: March 2003

SummaryStudies of superantigens (SAg) have focused primarily on their impact on CD4+ T cells, largely bypassing the impact of the sequelae of this interaction upon the antigen‐presenting cell (APC). Sequelae of SAg‐induced CD4+ T‐cell activation include the ‘bathing’ of the SAg‐presenting cell with cytokines that promote the differentiation of the APC. In this report, the SAg‐induced differentiation of Mls+ DBA/2J B cells was studied in vivo by their transplantation into B‐cell‐defective BALB.xid recipients. Rapid, high‐level serum immunoglobulin M (IgM) production was noted shortly after transfer, disappearing by 3 weeks. Donor B cells, as evidenced after their chemical and genetic impairment and by the use of an IgM allotype‐disparate donor–recipient combination, contributed to this transient IgM production. These results clarify a discrepancy in the literature regarding donor B‐cell contribution to IgM production and illustrate a model system to utilize SAg to study B‐lymphocyte diversity.
Recessive expression of the H2A‐controlled immune response phenotype depends critically on antigen dose
Authors: Barcenas‐morales G. , Merkenschlager M. , Wahid F. , Döffinger R. , Ivanyi J. 
Published: March 2003

SummaryMajor histocompatibility complex (MHC) alleles acting as immune response genes are coexpressed in heterozygous individuals and therefore control of immune responses is usually codominant. As an exception to this rule, however, several examples of recessive immune responses have been ascribed to regulatory, e.g. suppressive, interactions. We report here that the recessive phenotype of both antibody and T‐cell responses to the mycobacterial 16 000‐MW antigen depends critically on a low antigen dose for immunization. On the basis of similar responses in hemi‐ and heterozygous mice, we suggest that the mechanism of recessive MHC control does not involve regulation by the low‐responder allele. We also demonstrated mixed haplotype restriction of peptide recognition for a significant fraction of high‐antigen‐dose primed T cells. Their paucity under limiting antigen dose conditions may lead to the recessive expression of MHC control. In conclusion, our results suggest that recessive MHC control can be explained as a simple gene dosage effect under conditions where antigen is limiting, without a need for regulatory mechanisms.
Human B‐cell lines constitutively express and secrete interleukin‐16
Authors: Sharma V. , Sparks J. L. , Vail J. D. 
Published: March 2003

SummaryInterleukin‐16 (IL‐16), produced by activated CD8+ T lymphocytes, is inhibitory to human immunodeficiency virus‐1 (HIV‐1) replication. In an attempt to determine whether human B cells express and secrete IL‐16, a wide panel of B‐cell lines derived from patients with acquired immune deficiency syndrome (AIDS)‐associated B‐cell lymphomas (AABCL) (n = 5) and from non‐AABCLs (n = 8) were studied. Using reverse transcription–polymerase chain reaction (RT–PCR) analysis, we were able to observe ubiquitous expression of IL‐16 mRNA. Kinetic studies on constitutive mRNA turnover and secretion for IL‐16 suggests that the optimum expression is at 24 hr. Interestingly, we report, for the first time, IL‐16 secretion by human B‐cell lines.
T‐cell tolerance induction is normal in the (NZB × NZW)F1 murine model of systemic lupus erythematosus
Authors: Wither J. , Vukusic B. 
Published: March 2003

SummaryThe (New Zealand black (NZB) × New Zealand white (NZW))F1 (NZB/W) mouse strain spontaneously develops an autoimmune disease characterized by anti‐dsDNA antibody production and glomerulonephritis. Although evidence suggests that production of pathogenic autoantibodies is T‐cell dependent, the immunological defects that lead to activation of these autoreactive T cells are unknown. In particular, it has not been resolved whether autoreactive T cells become activated in these mice because of a generalized defect in T‐cell tolerance induction. Previous work has demonstrated that thymic and peripheral tolerance to strongly deleting antigens are intact in NZB/W mice. In this study we investigate whether these mice possess a more subtle T‐cell tolerance defect. To this end, we have produced NZB/W mice carrying a transgene encoding beef insulin (BI) which is expressed at levels close to the threshold for T‐cell tolerance induction. In BALB/c mice this transgene produces a profound but incomplete state of BI‐specific T‐cell tolerance, mediated predominantly by clonal anergy. Comparison of BI‐specific tolerance in NZB/W, major histocompatibility complex (MHC)‐matched (BALB/c × NZW)F1, and BALB/c BI‐transgenic mice clearly demonstrates that T‐cell tolerance induction is normal in NZB/W mice. The data suggest that the loss of T‐cell tolerance that ultimately supports nephritogenic autoantibody production in NZB/W mice does not result from a generalized defect in T‐cell tolerance, and by extension likely results from aberrant activation of specific autoreactive T cells.
Molecular remodelling of human CD46 for xenotransplantation: designing a potent complement regulator without measles virus receptor activity
Authors: Begum N. A. , Murakami Y. , Mikata S. , Matsumoto M. , Hatanaka M. , Nagasawa S. , Kinoshita T. , Seya T. 
Published: March 2003

SummaryIn pig‐to‐human discordant xenotransplantation, human complement (C) is a major barrier to long survival of xenografts. The current idea on how to cope with this barrier is that human complement regulatory proteins are forcibly expressed on xenografts to serve as safeguards against host C‐induced hyperacute rejection of xenografts. Co‐expression of decay‐accelerating factor (DAF) (CD55) and membrane cofactor protein (MCP) (CD46) would be the first choice for this trial, because most of the human cells are protected from C‐mediated damage by two different modes with these two kinds of C‐regulators. Many problems have arisen, however, for MCP expression on grafts. (i) MCP acts as a measles virus receptor, which may function to render donor pigs measles virus (MV) sensitive. (ii) MCP signals immune suppression which causes devastation of the recipient's immune responses. (iii) MCP exerts relatively low self‐protective activity against C compared with other cofactors; development of more efficient forms is desirable. (iv) Grafts with a high expression level of MCP are difficult to produce. In this study, we made a number of cDNA constructs of MCP, expressed them on swine endothelial cell lines, and tested cell‐protective potency and MV susceptibility. The short consensus repeat 1 (SCR1)‐deleted MCP with glycosyl phosphatidylinositol (GPI)‐anchored form (Δ1MCP‐PI) of MCP was found to be most suitable for the purpose of overcoming these problems. However, it was also found that MV induces two modes of cytopathic effect (CPE) on swine endothelial cells, either MCP‐dependent or ‐independent. Here, we discuss these two points which will be raised through study of MCP‐transgenic animals.
Capacity of mouse mast cells to prime T cells and to induce specific antibody responses in vivo
Authors: Villa I. , Skokos D. , Tkaczyk C. , Peronet R. , David B. , Huerre M. , Mécheri S. 
Published: March 2003

SummaryMouse, human and rat mast cells have been shown to express major histocompatibility complex II molecules and present antigens to specific T‐cell hybridomas in vitro. The purpose of our investigation was to determine whether mouse mast cells are able to initiate specific immune responses in vivo. Induction of anti‐dinitrophenyl (DNP) immunoglobulin G1 (IgG1) and IgG2a antibodies was performed by transferring ovalbumin (OVA)–DNP‐pulsed bone marrow‐derived mast cells (BMMC), B cells, or macrophages into naive mice which were boosted later with soluble antigen. Cultured spleen cells from immunized mice were tested for their cytokine content. Our data show that mast cells were by far better inducers of anti‐DNP IgG1 antibodies than were B cells and macrophages. In contrast, anti‐DNP IgG2a response induced by macrophages was much stronger than that obtained with mast cells whereas B cells were completely unable to elicit this response. In addition to a high index of cell proliferation, spleen cells from mast cell‐injected mice produced more interferon‐γ than those mice who received macrophages or B cells by two‐ to fivefold, and almost 10‐fold, respectively. Mast cell‐deficient Wf/Wf mice were compared with their normal +/+ littermates and with mast cell‐reconstituted Wf/Wf mice to develop delayed‐type hypersensitivity (DTH) reactions as well as humoral immune responses. Mast cell sufficient mice as well as mast cell‐reconstituted Wf/Wf mice developed significantly increased DTH reactions (P = 0·02, and 0·03, repectively) and higher anti‐OVA‐specific antibody responses as compared with Wf/Wf mice. Our data suggest that mast cells have the potential to up‐regulate both humoral and cellular immune responses in vivo.
Perpetuation of immunological memory: a relay hypothesis
Authors: Nayak R. , Mitra‐Kaushik S. , Shaila M. S. 
Published: March 2003

SummaryA mechanism is proposed which explains the perpetuation of B‐cell immunological memory indefinitely without requiring the presence of long‐living memory cells or persisting antigen. The salient feature of this model is that immunological memory can be perpetuated indefinitely through the mutual interaction of idiotypic and anti‐idiotypic B cells. These cells mutually stimulate and clonally expand with either specific or bystander T‐cell help. Because B cells can present antigen, they present ‘apparently foreign’ idiopeptides to T cells. The idiopeptides of de novo synthesized antibody is presented to CD8+ T cells that recognize the idiopeptide‐presenting cell as targets and regulate their population. The recycling of immunoglobulins from surface to endosomal compartment of B cells leads to the presentation of idiopeptides by major histocompatibility complex (MHC) class II to CD4+ T cells. Even if the majority of the clonally expanded cells die because of lack of stimulation, cytotoxic T lymphocyte (CTL) lysis or for other reasons, the surviving cells will be able to carry forward the memory. This mechanism also provides a means for affinity maturation through idiotypic selection of somatically mutated high affinity cells or those from the naïve pool. We have termed these two types of complementary B cells as Burnet B cells: those which recognize the antigen or antigen mimic, and Jerne B cells, which can recognize the idiotypes of antibody and carry antigen mimics. The proposed hypothesis can explain differential duration of memory for different antigens, the shelf space paradox, affinity maturation, repertoire shift, etc.
Endocytosis and recycling of the complex between CD23 and HLA‐DR in human B cells
Authors: Karagiannis Sophia N. , Warrack John K. , Jennings Kevin H. , Murdock Paul R. , Christie Gary , Moulder Kevin , Sutton Brian J. , Gould Hannah J. 
Published: March 2003

SummaryThe presentation of extremely low doses of antigen to T cells is enhanced by immunoglobulin E (IgE)‐dependent antigen focusing to CD23, the low‐affinity receptor for IgE, expressed on activated B cells. CD23 contains a C‐type lectin domain in its extracellular sequence and a targeting signal for coated pits, required for endocytosis, in its cytoplasmic sequence. CD23 is non‐covalently associated with the major histocompatibility complex class II antigen, human leucocyte antigen HLA‐DR, on the surface of human B cells, but the fate of this complex following endocytosis is unknown. To answer this question we have labelled these proteins on the surface of RPMI 8866 B cells and traced their route through the cytoplasm. Endocytosis mediated by anti‐CD23 antibodies (BU38 and MHM6) led to the loss of CD23 from the cells. Endocytosis mediated by an antibody to HLA‐DR (CR3/43) or an antigen–IgE complex (NP‐BSA–anti‐NP IgE), however, led to recycling of the HLA‐DR–CD23 complex to the cell surface on a time scale (3–6 hr) consistent with the recycling of HLA‐DR in antigen presentation. Along the latter pathway CD23 label was observed in cytoplasmic organelles that resembled the ‘compartments for peptide loading’ or ‘class II vesicles’ described by previous authors. Two features of the recycling process may contribute to the efficiency of antigen presentation. Peptide exchange may be facilitated by the proximity of HLA‐DR and antigen in peptide loading compartments of the endosomal network. The return of CD23 with HLA‐DR to the cell surface may then help to stabilize specific B‐cell–T‐cell interactions, contributing to T‐cell activation.
Influence of ageing on Langerhans cell migration in mice: identification of a putative deficiency of epidermal interleukin‐1β
Authors: Cumberbatch Marie , Dearman Rebecca J. , Kimber Ian 
Published: March 2003

SummaryPrevious studies in mice have reported a decrease in epidermal Langerhans cell (LC) density in aged skin, however, the impact of this reduction on LC function and cutaneous immune responses is unclear. In the present series of experiments, the frequency of major histocompatibility complex class II+ LC in the epidermis of older (6‐month‐old) mice was found to be reduced significantly compared with that observed for young (6–8‐week‐old) mice. LC mobilization and the subsequent accumulation of dendritic cells (DC) in regional lymph nodes in response to topical challenge with a chemical allergen were found to be less vigorous in older mice. Flow cytometric analyses of DC derived from the draining lymph nodes of fluorescein isothiocyanate (FITC)‐sensitized mice revealed that the frequency of FITC+‐DC arriving in draining lymph nodes was also reduced in older mice but that the fluorescence intensity was comparable. Control and allergen‐treated‐older mice also displayed decreased total lymph node cellularity. Contact hypersensitivity responses were found not to be compromised in older mice. However, the cytokine regulation of LC migration in the two age groups of mice did differ. LC migration provoked by intradermal injection of tumour necrosis factor‐α (TNF‐α) was reduced in older animals, whereas, the percentage of LC that migrated in response to exogenous interleukin‐1β (IL‐1β) was comparable for both young and aged mice. Since both allergen‐ and TNF‐α‐induced LC responses are known to require receipt by LC of a signal from IL‐1β for effective migration, the suggestion is that impaired LC migration in older mice may be due to a reduced availability of epidermal IL‐1β.
Phosphodiester CpG oligonucleotides as adjuvants: polyguanosine runs enhance cellular uptake and improve immunostimulative activity of phosphodiester CpG oligonucleotides in vitro and in vivo
Authors: Dalpke Alexander H. , Zimmermann Stefan , Albrecht Inka , Heeg Klaus 
Published: March 2003

SummaryBacterial DNA and oligonucleotides (ODN) containing CpG‐motifs strongly activate cells of the immune system. Accordingly CpG‐DNA is a powerful adjuvant in vaccination protocols for B‐cell as well as for cytotoxic T‐cell responses. A decisive propensity of CpG‐DNA is its capacity to induce preferentially T helper type 1 (Th1)‐dominated immune responses. To exert its function CpG‐DNA has to be taken up by responsive cells, e.g. antigen‐presenting cells (APC). The rate of uptake is influenced by the DNA's backbone modification and critically determines activity of CpG‐DNA. CpG ODN with a phosphothioate backbone (PTO) are currently used for most in vivo and in vitro studies, since PTO modification protects ODN from the attack of nucleases. However, after administration of PTO‐modified CpG‐ODN long‐lasting effects including lymphadenopathy as well as sustained local interferon‐γ (IFN‐γ) and interleukin‐12 (IL‐12) production have been reported. To circumvent these restrictions we investigated the effects of DNA sequence as well as DNA backbone modification on cellular uptake and resulting immunostimulation. We show here that uptake of phosphodiester (PO)‐CpG‐ODN can be strongly enhanced by poly guanosine runs added at the 3′ end of the ODN. In addition these ODN showed an improved immunostimulatory activity in vivo and in vitro. This included protection of mice against lethal Th2‐dependent leishmaniasis as well as priming of antigen specific Th1 responses. More importantly, guanosine‐rich PO‐CpG‐ODN neither induced lymphadenopathy nor prolonged cytokine production after local administration. Since these improved PO ODN are efficient in vitro and in vivo and lack long lasting undesired effects they could be used preferably as adjuvants in vaccination protocols.
Accumulation of a potent γδ T‐cell stimulator after deletion of the lytB gene in Escherichia coli
Authors: Eberl Matthias , Altincicek Boran , Kollas Ann‐Kristin , Sanderbrand Silke , Bahr Ute , Reichenberg Armin , Beck Ewald , Foster Donald , Wiesner Jochen , Hintz Martin , Jomaa Hassan 
Published: March 2003

SummaryActivation of human Vγ9/Vδ2 T cells by many pathogens depends on the presence of small phosphorylated non‐peptide compounds derived from the 2‐C‐methyl‐d‐erythritol 4‐phosphate (MEP) pathway of isoprenoid biosynthesis. We here demonstrate that in Escherichia coli mutants deficient in lytB, an essential gene of the MEP pathway, a potent Vγ9/Vδ2 T‐cell activator accumulates by a factor of approximately 150 compared to wild‐type E. coli. The compound responsible for the strong immunogenicity of this E. coli mutant was subsequently characterized and identified as a small pyrophosphorylated metabolite, with a molecular mass of 262 Da, derived from the MEP pathway. Stimulation of human peripheral blood mononuclear cells (PBMC) with extracts prepared from the lytB‐deficient E. coli mutant led to upregulation of T‐cell activation markers on the surface of Vγ9/Vδ2 T cells as well as proliferation and expansion of Vγ9/Vδ2 T cells. This response was dependent on costimulatory growth factors, such as interleukin (IL)‐2, IL‐15 and IL‐21. Significant levels of interferon‐γ (IFN‐γ) and tumour necrosis factor‐α (TNF‐α) were secreted in the presence of IL‐2 and IL‐15, but not in the presence of IL‐21, demonstrating that proliferating phosphoantigen‐reactive Vγ9/Vδ2 T cells do not necessarily produce proinflammatory cytokines.
Do functional subsets of leukocytes arise by divergent or linear differentiation?
Authors: Noble Alistair , Kemeny David M. 
Published: March 2003

SummaryThe T helper type 1 (Th1)/Th2 paradigm has been extended to a wide variety of leukocyte lineages since its inception, including innate immune cells such as dendritic cells and natural killer (NK) cells. Recently, studies of human NK cells have led to the proposition of a new model of linear differentiation in which cell phenotype is controlled by regulation of proliferation versus differentiation, rather than by divergent differentiation programmes. It was suggested that this model might also apply to T cells. Here we discuss the relevance of each model to different leukocyte lineages and argue that the linear differentiation model does not apply to αβ T cells.
Interleukin‐3, but not granulocyte–macrophage colony‐stimulating factor and interleukin‐5, inhibits apoptosis of human basophils through phosphatidylinositol 3‐kinase: requirement of NF‐κB‐dependent and ‐independent pathways
Authors: Zheng Xueyan , Karsan Aly , Duronio Vincent , Chu Fanny , Walker David C. , Bai Tony R. , Schellenberg R. Robert 
Published: March 2003

SummaryBasophils are key effector cells of allergic reactions. Although proinflammatory cytokines, such as interleukin (IL)‐3, granulocyte–macrophage colony‐stimulating factor (GM–CSF) and IL‐5, inhibit eosinophil apoptosis in vitro, little is known about basophil apoptosis, and the signalling mechanisms required for basophil survival remain undefined. To address this issue, we used a novel negative‐selection system to isolate human basophils to a purity of > 95%, and evaluated apoptosis by morphology using light and transmission electron microscopy, and by annexin‐V binding and propidium iodide incorporation using flow cytometry. In this study, we demonstrated that the spontaneous rate of apoptotic basophils was higher than that of eosinophils as, at 24 hr, 57·6 ± 4·7% of basophils underwent apoptosis compared with 39·5 ± 3·8% of eosinophils. In addition, basophil cell death was significantly inhibited when cultured with IL‐3 for 48 hr (84·6 ± 4·9% vehicle‐treated cells versus 40·9 ± 3·9% IL‐3‐treated cells). IL‐3 also up‐regulated basophil CD69 surface expression. The effects of IL‐3 on apoptosis and CD69 surface expression of human basophils were completely blocked by LY294002 (LY), a potent inhibitor of phosphatidylinositol 3‐kinase (PI3‐K), but only partially inhibited by lactacystin, a proteasome inhibitor that prevents degradation of IκB and NF‐κB translocation. These observations reveal the novel finding that IL‐3 prevents basophil apoptosis through the activation of PI3‐K, which is only partially NF‐κB dependent. As basophils are active participants in allergic reactions and IL‐3 is one of the abundant proinflammatory cytokines in secretions from allergic tissue, we suggest that IL‐3‐mediated inhibition of basophil apoptosis may exacerbate the inflammation associated with allergic disorders.