bluuebunny/crossref_metadata_2025_split huggingface dataset:
T lymphocyte development in the absence of Fcϵ receptor Iγ subunit: analysis of thymic‐dependent and independent αβ and γδ pathways
Authors: Heiken Hans , Schulz Ralf‐Joachim , Ravetch Jeffrey V. , Reinherz Ellis L. , Koyasu Shigeo 
Published: March 2007

AbstractDuring fetal development, early thymocyte progenitors transiently express low affinity Fc receptors for IgG (FcγR) of both FcγRII and III isoforms. Only the FcγRIII isoform requires association of an FcγRIII (CD16) α subunit with an FcϵRIγ homodimer for surface expression. To address the role of FcγR in ontogeny, we studied thymic development in FcϵRIγ−/− mice. We find that day 14.5 CD4−CD8− double‐negative (DN) fetal thymocytes of FcϵRIγ−/− mice express mRNA of both FcγRIIb1 and FcγRIII. Surface expression of FcγRII/III is readily detected on these cells. It appears that FcγRIIb1, whose surface expression is FcϵRIγ independent, replaces FcγRIII during thymic development in these animals. Moreover, subsequent development into CD4+CD8+ double‐positive and CD4+CD8− and CD4−CD8+ single‐positive subsets appears normal even in the absence of FcϵRIγ. However, alterations were noted in adult animals among the DN αβ TCR+ thymocytes and peripheral splenic DN T cells as well as CD8αα+ intestinal intraepithelial lymphocytes (iIEL). In contrast to conventional T lymphocytes, which do not express either FcγRIII or FcϵRIγ, DN αβ TCR+ thymocytes and extrathymically derived αβ TCR+ and γδ TCR+ CD8αα+β− iIEL express TCR which incorporate FcϵRIγ as one of their subunits. Consistent with this, the TCR levels of these cells are lower than the TCR levels on cells from wild‐type C57BL/6 mice. Despite the reduction in the level of surface TCR, the development of these cells was unaltered by the absence of FcϵRIγ. Thus, we observed alterations in adult DN αβ TCR+ thymocytes, splenic DN αβ TCR+ and DN γδ TCR+ large granular lymphocytes (LGL), and αβ TCR+ and γδ TCR+ CD8αα+β− iIEL, but no detectable changes in their major fetal thymic developmental pathways. Cultivation of peripheral DN αβ TCR+ and DN γδ TCR+ cells from FcϵRIγ−/− mice with interleukin‐2 generates LGL which mediate natural killer activity. Unlike LGL from wild‐type C57BL/6 mice, LGL from FcϵRIγ−/− mice lack FcγRIII expression and could not mediate antibody‐dependent cellular cytotoxicity through FcγRIII.
Threonine 80 on HLA‐B27 confers protection against lysis by a group of natural killer clones
Authors: Luque Isabel , Solana Rafael , Galiani M. Dolores , González Rafael , García Fernando , López de Castro José A. , Peña José 
Published: March 2007

AbstractRecognition of major histocompatibility complex (MHC) class I molecules on target cells by natural killer (NK) cells inhibits NK cell‐mediated lysis. Although it is known that this inhibitory effect is regulated by MHC polymorphism, the precise structural determinants remain undefined. Based on the capacity of different HLA‐C and HLA‐B motifs specifically to inhibit cytotoxicity of some NK clones, three different NK cell specificities (NK1, NK2 and NK3) have been described. In this study, the recognition of HLA‐B27 by NK clones has been analyzed using C1R cells transfected with different HLA‐B27 subtypes as target cells. Cytotoxicity was inhibited by the HLA‐B*2705, ‐B*2701 ‐B*2703, ‐B*2704 and ‐B*2706 alleles, but not by ‐B*2702. This subtype is distinguished from the other B27 subtypes by the presence of isoleucine instead of threonine at position 80. Direct involvement of this residue was assessed by showing that site‐directed mutagenesis of Thr80 to Ile80 in HLA‐B*2705 reverted the NK protective effect of HLA‐B*2705. Based on these data, we suggest that Thr80 could act as a single residue conferring target cell protection from lysis by a group of NK clones, tentatively designated NK4.
Selective stimulation of T helper 2 cytokine responses by the anti‐psoriasis agent monomethylfumarate
Authors: de Jong Rolien , Bezemer Anja C. , Zomerdijk Timo P. L. , van de Pouw‐Kraan Tineke , Ottenhoff Tom H. M. , Nibbering Peter H. 
Published: March 2007

AbstractType 2 cytokines are thought to have a protective role in psoriasis vulgaris by dampening the activity of T helper 1 (Th1) lymphocytes. The aim of the present study was to determine the effect of monomethylfumarate (MMF), the most active metabolite of the new anti‐psoriatic drug Fumaderm®, on the production of cytokines and the development of Th subsets. MMF was found to enhance interleukin (IL)‐4 and IL‐5 production by CD2/CD8 monoclonal antibody‐stimulated peripheral blood mononuclear cells (PBMC) in a dose‐dependent manner. Maximal effects of MMF were found at a concentration of 200 μM and resulted in tenfold enhanced levels of IL‐4 and IL‐5 production. MMF did not affect the levels of IL‐2 production, interferon (IFN)‐γ production or proliferative T cell responses in these cultures. Similar effects of MMF were observed in cultures of purified peripheral blood T cells indicating that this compound can act directly on T cells. MMF did not influence cytokine production by purified CD4+CD45RA+ (unprimed) T cells, but greatly enhanced IL‐4 and IL‐5 production without affecting IFN‐γ production by purified CD4+CD45R0+ (primed) T cells. Furthermore, MMF also augmented IL‐4 and IL‐5 production in established Th1/Th0 clones that were stimulated with CD2/CD28 monoclonal antibody. Finally, when PBMC were challenged with Mycobacterium tuberculosis that typically induces Th1 recall responses with strong IFN‐γ secretion, MMF again appeared to induce high levels of IL‐4 and IL‐5 secretion while IFN‐γ production was unaffected. These results may be relevant for the development of therapeutic regimens designed to correct inappropriate Th1 subset development in immunopathologic conditions.
TNF2, a polymorphism of the tumour necrosis‐α gene promoter, is a component of the celiac disease major histocompatibility complex haplotype
Authors: Mc Manus Ross , Wilson Anthony G. , Mansfield John , Weir Donald G. , Duff Gordon W. , Kelleher Dermot 
Published: March 2007

AbstractCeliac disease (CD) is an immune disease triggered by the cereal antigen gliadin, resulting in villous atrophy in the small intestine. Susceptibility to the development of CD is strongly influenced by genes in the major histocompatibility complex, in particular alleles of the DQ genes in the class II region. However recent evidence has suggested that the major histocompatibility complex (MHC) class III region may be linked to celiac disease independently of the class II region. Among the genes located in this area is TNF‐α, which encodes the cytokine tumor necrosis factor‐α which has a broad range of pro‐inflammatory, immunomodulatory and catabolic activities. Therefore, aberrant expression of TNF‐α could be important in the pathogenesis of MHC‐associated immune disorders. A TNF‐α variant with a polymorphism in its promoter region has been described and designated TNF2. TNF2 has been associated with a variety of MHC‐linked diseases, including systemic lupus erythematosus, dermatitis herpetiformis and insulin‐dependent diabetes mellitus (IDDM), as well as parasitic infections. TNF2 has previously been shown to be associated with the MHC haplotype HLAA1‐B8‐DR3‐DQ2, which confers susceptibility to CD. We have analyzed the distribution of TNF2 alleles in a group of celiac patients (n = 52) compared to controls (n = 52) in an effort to evaluate its role, if any, in susceptibility to the condition. TNF2 has a frequency of 0.5000 (SE ± 0.0490) in CD, compared to 0.1635 (± 0.0362) in a control sample (p < 10−6). Of 52 patients, 44 carried one or more TNF2 alleles. Analysis indicates that the distribution of TNF2 is best explained by assuming 100% allelic association between it and HLA‐DQB1*0201 (frequency = 0.7791 ± 0.0447). However, the number of TNF2 heterozygotes significantly exceeds expectations and measurements of linkage disequilibrium confirm that allelic associations spanning the DQ and TNF regions are strongly maintained in CD. Taken together, these results indicate that TNF2 may have a role in the pathogenesis of CD; however, since it is not an independent association, the possibility that TNF2 constitutes a passive component of the CD haplotype cannot be excluded.
Opposite effects of interleukin‐13 and interleukin‐12 on the release of inflammatory cytokines, cytokine inhibitors and prostaglandin E from synovial fibroblasts and blood mononuclear cells
Authors: Seitz Michael , Loetscher Pius , Dewald Beatrice , Towbin Harry , Baggiolini Marco 
Published: March 2007

AbstractWe examined the effects of interleukin‐12 (IL‐12) and interleukin‐13 (IL‐13) on cytokine, cytokine inhibitor and prostaglandin E (PGE) release from synovial fibroblasts and blood mononuclear cells (MNC). In resting synovial fibroblasts, we found that IL‐13 is an inhibitor of IL‐8 and PGE release. A significant decrease of PGE synthesis caused by IL‐13 was also observed in tumor necrosis factor (TNF)‐α‐stimulated synovial fibroblasts, whereas IL‐12 had no regulatory effects on these cells. In resting and cytokine‐stimulated MNC, IL‐13 markedly inhibited IL‐1β, IL‐8 and monocyte chemoattractant protein‐1 (MCP‐1) release and potently stimulated interleukin‐1 receptor antagonist (IL‐1ra) synthesis. In contrast, IL‐12 stimulated the production of IL‐1β and MCP‐1 in TNF‐α‐stimulated MNC and inhibited IL‐1ra synthesis in cytokine‐stimulated cells. These findings identify novel biological actions of IL‐12 and IL‐13 on connective tissue and on blood mononuclear cells which indicate their regulatory functions as enhancer and suppressor of inflammatory processes, respectively.
Neurons induced to express major histocompatibility complex class I antigen are killed via the perforin and not the Fas (APO‐1/CD95) pathway
Authors: Rensing‐Ehl Anne , Malipiero Ursula , Irmler Martin , Tschopp Jürg , Constam Daniel , Fontana Adriano 
Published: March 2007

AbstractCytotoxic T lymphocytes (CTL) kill target cells by perforin‐mediated pore formation, induction of apoptosis by the Fas ligand, or both. It has been demonstrated that depolarized neurons can be induced to express major histocompatibility complex (MHC) class I antigens by interferon‐γ. Evidence for antigen‐dependent CTL‐mediated killing was obtained by transfecting neurons with MHC class I cDNA. The present study was designed to investigate the mechanisms of killing of cerebellar granule neurons depolarized by high K+ concentrations and thereby inducible for MHC class I antigen expression. We found that neurons express only low levels of Fas (APO‐1/CD95) and are resistant to Fas ligand‐mediated killing even when pretreated with cytokines. However, granules extracted from CTL as well as purified perform induce almost complete lysis of neurons. These data suggest that CTL‐mediated elimination of neurons involves the perform, but not the Fas pathway of target cell killing.
The outer surface lipoprotein OspA of Borrelia burgdorferi provides co‐stimulatory signals to normal human peripheral CD4+ and CD8+ T lymphocytes
Authors: Knigge Heidrun , Simon Markus M. , Meuer Stefan C. , Kramer Michael D. , Wallich Reinhard 
Published: March 2007

AbstractStudies in man and mice have indicated that T cells induced during Borrelia burgdorferi infection are involved in the pathogenesis of the disease. We analyzed the ability of B. burgdorferi to provide co‐stimulatory signals to highly enriched normal human CD2+ T lymphocytes in the presence of suboptimal concentrations of immobilized anti‐CD3 antibodies. Here we show that the lipid‐containing recombinant outer surface lipoprotein A (rlip‐OspA) of B. burgdorferi but not its delipidated derivative rNS1‐OspA augmented CD3‐induced T cell proliferation in a dose‐dependent manner and at levels similar to that obtained with anti‐CD28 antibodies. Lipopolysaccharide had no effect in this system at any concentration tested, suggesting that the active principle of co‐stimulation is associated with the lipid moiety of rlip‐OspA and distinct from conventional lipid A. Furthermore, incubation of CD2+ T cells or selected CD4+ as well as CD8+ subpopulations with rlip‐OspA, but not with rNS1‐OspA led to the production of interferon (IFN)‐γ, interleukin (IL)‐6 and tumor necrosis factor (TNF)‐α, but not IL‐4. In contrast, co‐stimulation of the respective T cell populations with anti‐CD28 antibodies resulted in the generation of IFN‐γ, IL‐4 and TNF‐α, but not IL‐6. This indicated that the signal transduction pathway induced by rlip‐OspA is distinct from that elicited via the CD28 receptor. Co‐stimulation of T cells with rlip‐OspA also resulted in the development of cytolytic effector cells. In light of the fact that inflamed tissues of B. burgdorferi‐infected hosts contain blood leukocytes together with spirochetes, their degradation products, or both, these results suggest that infiltrating CD4+ and CD8+ T cells of any specificities, including spirochetes, autoantigens, or both, participate in the pathogenesis of Lyme disease.
Antigen‐specific targeting of CD28‐mediated T cell co‐stimulation using chimeric single‐chain antibody variable fragment‐CD28 receptors
Authors: Alvarez‐Vallina Luis , Hawkins Robert E. 
Published: March 2007

AbstractT cells require two distinct signals for optimal activation. One is an antigen‐specific signal and is provided by engagement of the T cell receptor (TCR). The second is an antigen‐independent signal mediated by engagement of the T cell surface molecule CD28 with members of the B7 family. To endow CD28 molecules with antibody‐type recognition, we have constructed chimeric single‐chain antibody variable fragment (scFv)‐CD28 molecules; following transfection of the genes encoding such constructs into the Jurkat human T cell line we show that they are stably expressed as functional cell surface receptors. These chimeric molecules have no apparent negative effects on the expression and signaling ability of the wild‐type CD28 and TCR/CD3 molecules. When combined with signaling via the TCR/CD3 complex, these antigen‐specific scFv‐CD28 chimeric molecules provide signals similar to those elicited by the cross‐linking of the unmodified CD28 molecules. Furthermore, the generation of double transfectants simultaneously expressing scFv‐CD28 and scFv‐CD3ζ chimeras demonstrates that antigen‐specific co‐stimulatory signals can also synergize with signals mediated through chimeric CD3ζ chains to secrete maximal levels of interleukin‐2. Overall, our results suggest that optimal, predefined antigen‐specific activation of T cells directed by the specificity of the scFv should be possible.
Tyrosine kinase and cAMP‐dependent protein kinase activities in CD40‐activated human B lymphocytes
Authors: Lapointe Réjean , Lemieux Réal , Olivier Martin , Darveau André 
Published: March 2007

AbstractIn vitro, human B lymphocytes undergo long‐term proliferation when activated through CD40, a protein expressed on their cell surface. The nature of CD40‐dependent signals in proliferating fresh human Epstein‐Barr virus‐negative B lymphocytes is currently unknown. In this study, a CD40‐dependent B cell culture system was used to examine the role of different signal transduction elements. Protein kinase C (PKC) depletion generated by a long‐term phorbol 12‐myristate 13‐acetate treatment had weak effects on proliferation. Rather, tyrosine phosphorylation was shown to be directly involved in mediating CD40‐dependent signals. The use of the protein tyrosine kinase (PTK)‐specific inhibitor herbimycin A dramatically decreased cellular proliferation without altering the activity of the human immunodeficiency virus‐1 long terminal repeat (HIV‐1 LTR), a promoter largely dependent on the binding of nuclear factor ϰB (NF‐ϰB). In contrast, the cAMP‐dependent protein kinase specific inhibitor H‐89 totally inhibited HIV‐1 LTR activity at a concentration as low as 100 nM without affecting cellular proliferation. Electrophoretic mobility shift assay (EMSA) and supershift assay using an NF‐ϰB binding sequence from the ϰ light chain as a probe, revealed that both p65 (RelA) and c‐Rel were present in CD40‐stimulated B cells. While PKC depletion did not alter the NF‐ϰB level, treatment of B lymphocytes with H‐89 or herbimycin A provoked a decrease in the NF‐ϰB level. These observations establish the importance of different signal transducing pathways leading to CD40 activation of B lymphocytes.
Chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice: enhancement by monoclonal antibodies against interferon‐γ
Authors: Heremans Hubertine , Dillen Chris , Groenen Marleen , Martens Eric , Billiau Alfons 
Published: March 2007

AbstractExperimental autoimmune encephalomyelitis (EAE) is a T cell‐mediated inflammatory and demyelinating disorder of the central nervous system. Depending on the experimental conditions, it takes an acute monophasic or a chronic relapsing‐remitting course. We have previously reported that the incidence and severity of acute EAE in mice are reduced by administration of interferon (IFN)‐γ and augmented by treatment with neutralizing antibodies against IFN‐γ. Here, we investigated the role of IFN‐γ in chronic relapsing models of EAE (CREAE) in SJL/J and Biozzi ABH mice. Spontaneous relapses in Biozzi mice as well as induced relapses in SJL/J mice were facilitated by administration of neutralizing monoclonal antibody (mAb) against IFN‐γ in the disease‐free interval. The enhancing effect of anti‐IFN‐γ mAb given before and during the primary attack did not carry over to the relapses. However, early administration of IFN‐γ in Biozzi mice, which developed spontaneous relapses in a high proportion, provided partial protection not only against the first attack, but also against subsequent relapses. Administration of exogenous IFN‐γ during the remission phase provided some protection against subsequent relapses. These results indicate that in both types of relapses, IFN‐γ is produced and does provide a certain degree of protection against disease progression.
Characterization of T cell receptor single‐chain Fv fragments secreted by myeloma cells
Authors: Grégoire Claude , Malissen Bernard , Mazza Gilbert 
Published: March 2007

AbstractMyeloma cells have been used to produce milligram quantities of soluble αβ T cell receptor (TCR) molecules as single‐chain polypeptides in which the TCR variable (V) domains are connected by a peptide linker (TCR scFv). Unlike most TCR scFv produced in bacteria, the purified TCR scFv were stable and showed no tendency to aggregate when kept at concentrations up to 10 mg/ml. Circular dichroism analyses of the TCR scFv indicated that they contained a high proportion of β‐pleated sheet structures. Since the Vα subunits present in the TCR scFv contained their own signal sequences, they provided the opportunity to determine by N‐terminal amino acid sequencing the position of the signal cleavage of three distinct mouse Vα. Two of the experimentally determined signal cleavage sites differed from those previously predicted on the basis of biochemical and statistical criteria. The expression approach outlined in this report has been applicable to three distinct αβ TCR and should contribute to the large scale production of soluble TCR amenable to structural studies.
Purified human peripheral blood basophils release interleukin‐13 and preformed interleukin‐4 following immunological activation
Authors: Gibbs Bernhard F. , Haas Helmut , Falcone Franco H. , Albrecht Claudia , Vollrath Ilka B. , Noll Tobias , Wolff Helmut H. , Amon Ulrich 
Published: March 2007

AbstractRecent studies have shown that human basophils, like mast cells, generate interleukin (IL)‐4 following immunological activation and may thus participate in late‐phase allergic and inflammatory processes. Here, we report the capacity of human basophils to release IL‐13 within 24 h following stimulation with anti‐IgE. Additionally, in 14 out of 31 experiments, we observed that basophils rapidly release preformed IL‐4 within 5–10 min, as well as newly generated IL‐4, which was released 4 h following stimulation of the cells with anti‐IgE. In contrast to the biphasic release of IL‐4 from the cells, no preformed IL‐13 was detected at earlier times (5–30 min). Preformed IL‐4 and IL‐4 and IL‐13 generated de novo were also released after stimulation of the cells with IL‐3; an enhanced production of these cytokines was observed using a combination of IL‐3 and anti‐IgE. We conclude from these data that, by releasing preformed IL‐4 and IL‐4 and IL‐13 generated de novo, human basophils may be centrally involved in the orchestration of allergic inflammation by providing a trigger to IL‐4‐mediated T helper 2 lymphocyte activation, B cell IgE switching, and increased vascular adhesion molecule expression.
Negative regulation of rat natural killer cell activity by major histocompatibility complex class I recognition
Authors: Kraus Elmar , Lambracht Doris , Wonigeit Kurt , Hünig Thomas 
Published: March 2007

AbstractThe cytolytic activity of human and mouse natural killer (NK) cells is negatively regulated by self major histocompatibility complex (MHC) class I molecules on potential target cells. In the rat, protection by RT1 class I gene products has so far not been formally shown although the complex effects of foreign and self RT1 genes on polyclonal NK cell activity suggest that MHC recognition can have both stimulatory and inhibitory effects. Here we report that the expression of self‐MHC class I molecules on target cells strongly inhibits lysis by a long term NK cell line derived from LEW (RT1l) rats and by LEW NK cells activated by short‐term culture in the presence of interleukin‐2. This was demonstrated with mouse‐rat hybridoma target cells expressing different rat MHC alleles and with mouse tumor target cells transfected with classical (RT1.Al) and nonclassical (RT1.Cl) rat MHC class I genes. With hybridoma target cells, the strongest reduction in lysis as compared to the parental mouse myeloma line was observed when “self” (LEW) MHC was expressed, while hybridomas expressing other MHC alleles showed less and variable reduction. Transfection of RT1.Al protected both L‐929 fibroblasts and P815 mastocytoma cells from lysis by the NK cell line, while RT1.Cl only protected P815 cells, indicating that additional target cell properties regulate rat NK cell activity.
Dendritic cells process exogenous viral proteins and virus‐like particles for class I presentation to CD8+ cytotoxic T lymphocytes
Authors: Bachmann Martin F. , Lutz Manfre D. B. , Layton Guy T. , Harris Stephen J. , Fehr Thomas , Rescigno Maria , Ricciardi‐Castagnoli Paola 
Published: March 2007

AbstractPrevious reports have indicated that both dendritic cells and macrophages have the ability to induce cytotoxic T lymphocyte (CTL) and T helper (Th) cell responses in vivo. Dendritic cells process exogenous antigens conventionally for presentation on major histocompatibility complex (MHC) class II molecules. However, unconventional processing of exogenous antigens in vitro for presentation on MHC class I molecules is still an open question. In this study, we report that a cloned dendritic cell line (D2SC/1) is able to present cell debris‐associated exogenous viral proteins to MHC class I‐restricted CTL in vitro The dendritic cell line was very efficient in processing recombinant lymphocytic choriomeningitis virus nucleoprotein (LCMV NP) and presenting the class I‐restricted epitope to CTL primed in vivo. Peritoneal macrophages could also process the recombinant LCMV NP for subsequent MHC class I presentation, but were less efficient compared to the dendritic cells. Furthermore, recombinant yeast‐derived virus‐like particles carrying the HIV‐1 V3 loop (V3‐VLP), which are protenaceous and do not contain any lipid, were also found to be efficiently processed by the dendritic cell line for presentation of the class I‐restricted epitope. These results clearly indicate that viral proteins, in particulate form or associated with cell debris, are processed by dendritic cells for CTL induction.