bluuebunny/crossref_metadata_2025_split huggingface dataset:
A transgenic T cell receptor restores thymocyte differentiation in interleukin‐7 receptor α chain‐deficient mice
Authors: Crompton Tessa , Outram Susan V. , Buckland Jennifer , Owen Michael J. 
Published: March 2007

AbstractInterleukin‐7 (IL‐7) receptor α chain‐deficient (IL‐7Rα‐/‐) mice have severely depleted lymphocyte populations and thymocyte development is arrested at the double‐negative (DN) stage. We show that thymocyte development in these mice can be reconstituted by the introduction of a transgenic T cell receptor (TCR), implying that one function of the IL‐7Rα chain is to initiate TCR gene rearrangement. Expression of the recombinase‐activating genes RAG1 and RAG2 was greatly reduced in the IL‐7Rα‐/‐ thymuses, and in DN thymocytes from the TCR transgenic IL‐7Rα‐/‐ mice, but was restored in double‐positive thymocytes from the TCR transgenic IL‐7Rα‐/‐ mice. These data suggest that the IL‐7Rα chain controls RAG expression and initiation of TCRβ chain VDJ rearrangement in DN cells. In contrast, once cells have progressed beyond the DN stage of development the IL‐7Rα chain becomes no longer essential for RAG expression.
X‐SCID B cell responses to interleukin‐4 and interleukin‐13 are mediated by a receptor complex that includes the interleukin‐4 receptor α chain (p140) but not the γ chain
Authors: Matthews David J. , Hibbert Linda , Friedrich Karlheinz , Minty Adrian , Callard Robin E. 
Published: March 2007

AbstractThis study investigates the effect of interleukin (IL)‐4 mutant proteins and a monoclonal antibody to the IL‐4 receptor α chain on IL‐4 and IL‐13 response by B cells from X‐linked severe combined immunodeficiency (X‐SCID) patients in which the common γ chain (γc chain) gene mutations have been fully characterized and no γc chain expression was detected. In this γc chain gene knockout model, it was confirmed that the γc chain is essential for B cell responses to IL‐2 but not for IL‐4 or IL‐13. Dose‐response curves for X‐SCID and normal B cell responses to IL‐4 were indistinguishable, showing that the loss of the γc chain did not diminish the sensitivity of B cells to IL‐4. The mutant protein IL‐4Y124Dand an antibody to the IL‐4R α chain both inhibited responses of X‐SCID B cells to IL‐4 and IL‐13, showing that X‐SCID B cell responses to these cytokines are mediated by a receptor complex that includes the IL‐4R α chain but not the γc chain. Another mutant protein, IL‐4R88D, which has greatly reduced affinity for IL‐4Rα, was found to inhibit responses by normal B cells to IL‐4 but not to IL‐13. IL‐4R88Ddid not, however, inhibit X‐SCID B cell responses to IL‐4. This result is consistent with IL‐4R88Dinhibition of responses mediated by receptor complexes that include the γc chain. We propose that X‐SCID B cells responses to IL‐4 are mediated by an IL‐13 receptor complex comprised of the IL‐4R α chain associated with the recently cloned IL‐13R binding protein. This model has major implications for understanding normal B cell responses to IL‐4.
Direct and sequential switching from μ to ε in patients with Schistosoma mansoni infection and atopic dermatitis
Authors: Baskin Berivan , Islam Khalid B. , Evengård Birgitta , Emtestam Lennart , Smith C. I. Edvard 
Published: March 2007

AbstractImmunoglobulin isotype switching to IgE in patients infected with Schistosoma mansoni and patients with atopic dermatitis was studied. Patients with parasitic infections or allergic diseases have a higher production of IgE. We found a fourfold increased production of Iε RNA in both patient groups as compared to control donors. The increased expression of germ‐line transcripts correlates with higher serum IgE levels. Nested primer polymerase chain reaction was used to generate Sμ/Sε fragments from DNA of patient peripheral blood mononuclear cells. Twenty‐nine out of fourty sequenced switch fragments had undergone direct joining from Sμ to ε whereas seven fragments showed mono sequential switching from Sμ via either Sμ, Sγ2, Sγ4 or Sε to Sε and four fragments demonstrated double sequential switch: Sμ/Sμ/Sγ1/Sε, Sμ/Sγ2/Sε/Sε or Sμ/Sγ1/Sγ2/Sε. The sequential switching had occurred either via deletions or inversions. Mapping of the breakpoints showed hot spots for recombination within Sμ, Sγ1 and Sε. To our knowledge, this is the first in vivo study in humans demonstrating that switching to IgE can occur from sequential rearrangements via γ1, γ2 or γ4.
Regulation of interleukin‐12 receptor β1 chain expression and interleukin‐12 binding by human peripheral blood mononuclear cells
Authors: Wu Chang‐You , Warrier Rajeev R. , Wang Xin , Presky David H. , Gately Maurice K. 
Published: March 2007

AbstractThe interleukin‐12 receptor (IL‐12R)β1 chain is an essential component of the functional IL‐12R on both human T and natural killer cells. In this report it is shown that activation of human peripheral blood mononuclear cells (PBMC) with anti‐CD3 monoclonal antibody (mAb) or phytohemagglutinin resulted in the up‐regulation of IL‐12Rβ1 expression and IL‐12 binding. Kinetic studies revealed that maximum expression of IL‐12Rβ1 and IL‐12 binding occurred on days 3–4. Anti‐CD3‐induced expression of IL‐12Rβ1 chain and IL‐12 binding by PBMC was augmented by anti‐CD28 mAb, indicating that the potentiating effect of anti‐CD28 on T cell responses to IL‐12 could be mediated, at least in part, by the enhancement of IL‐12R expression. Among 16 cytokines tested, IL‐2, IL‐7 and IL‐15 markedly induced IL‐12Rβ1 expression and IL‐12 binding on resting PBMC, whereas IL‐1α and tumor necrosis factor‐α had a minimal enhancing effect. In contrast, IL‐3, IL‐4, IL‐5, IL‐6, IL‐8, IL‐10, IL‐12, interferon (IFN)‐α, IFN‐γ, granulocyte/macrophage colony‐stimulating factor and transforming growth factor (TGF)‐β2 had no detectable enhancing effect. Anti‐CD3‐induced expression of IL‐12Rβ1 and of low‐affinity IL‐12 binding sites was partially inhibited by TGF‐β2, IL‐10 and IL‐4; however, TGF‐β2 and IL‐10 completely abolished anti‐CD3‐induced expression of high‐affinity IL‐12 binding sites. Consistent with the reduction of high affinity IL‐12 binding sites, PBMC activated with anti‐CD3 mAb in the presence of TGF‐β2 or IL‐10 failed to produce IFN‐γ or to proliferate in response to IL‐12. These results suggest that Th2 cell‐derived cytokines can inhibit IL‐12‐induced biological functions by inhibiting IL‐12R expression and that expression of a second subunit of the IL‐12R (IL‐12Rβ2), required for the formation of high‐affinity IL‐12 binding sites, may be more highly regulated by TGF‐β2 and IL‐10 than is expression of IL‐12Rβ1.
Blockade of CD28/B7 co‐stimulation by mCTLA4‐Hγ1 inhibits antigen‐induced lung eosinophilia but not Th2 cell development or recruitment in the lung
Authors: Harris Nicola , Campbell Chloë , Le Gros Graham , Ronchese Franca 
Published: March 2007

AbstractWe have studied the role of the CD28/B7 co‐stimulatory pathway in the development of a Th2‐type lung immune response. Mice injected two or three times intraperitoneally with ovalbumin in alum adjuvant and then re‐exposed to the same antigen by intranasal (i.n.) inoculation show infiltration of the lung tissue and appearance in the broncho‐alveolar lavage (BAL) fluid of significant numbers of eosinophils and lymphocytes, in a pattern which is reminiscent of asthmatic inflammation. The accumulation of eosinophils in the airways is completely dependent on interleukin (IL)‐5 secretion by CD4+ T cells. We have used mice transgenic for a soluble form of murine CTLA‐4 (mCTLA4‐Hγ1) which binds to B7 molecules on antigen‐presenting cells, thereby preventing their interaction with T cell‐expressed CD28. mCTLA4‐Hγ1‐transgenic mice immunized intraperitoneally and challenged i.n. with ovalbumin failed to generate any eosinophil infiltration, suggesting that little or no IL‐5 was secreted in the lungs of these mice. In contrast with the complete lack of eosinophils, the numbers and phenotypes of infiltrating lymphocytes were comparable in the lungs of mCTLA4‐Hγ1‐transgenic and normal mice. Also, lung lymphocytes from immunized mCTLA4‐Hγ1‐transgenic and normal mice could be shown to secrete comparable amounts of IL‐4 and IL‐5 when stimulated in culture in the absence of mCTLA4‐Hγ1. We conclude that mCTLA4‐Hγ1 can efficiently block the production of IL‐5 during in vivo responses and inhibit eosinophil recruitment, but that it does not block the development of CD4+ T cells into Th2 cells with the potential to secrete IL‐5.
Human naive B cells cultured with EL‐4 T cells mimic a germinal center‐related B cell stage before generating plasma cells. Concordant changes in Bcl‐2 protein and messenger RNA levels
Authors: Grimaǐtre Michel , Werner‐Favre Christiane , Kindler Vincent , Zubler Rudolf H. 
Published: March 2007

AbstractThe T cell‐dependent B cell response in vivo occurs in organized microenvironments. Alternative routes exist in that early plasma cells are generated in the T zone white others emerge later from the germinal center (GC) reaction. We investigated whether B cell stages resembling those defined in vivolex vivo might be induced in an in vitro system in which naive human B cells are activated by EL‐4 T cells and cytokines. Adult peripheral blood‐ or cord blood‐derived B cells were found to mimic an early activated stage (CD38low, IgD+, increased CD5+) followed by a centroblastic GC‐related stage (CD38int, CD77+, CD95(Fas)+, Bcl‐2 proteinlow) before differentiating into morphologically typical, CD38high, Fas‐ plasma cells of an immature type (Bcl‐2low, VLA‐5‐). The GC‐related cells and the plasma cells exhibited spontaneous apoptosis in medium, the former also undergoing anti‐Fas antibody‐induced apoptosis in medium as well as during CD40L exposure in the EL‐4 cultures. These Bcl‐2low cells maintained a high viability in contact with EL‐4 cells. Thus, some, major B cell stages with typical functional features as described for cells in vivolex vivo are sequentially generated in this in vitro system and the kinetics of the changes can be analyzed in a synchronized cell population. With regard to previous apparently conflicting observations on the Bcl‐2 mRNA level in GC B cells, we performed competitive reverse‐transcription polymerase chain reaction. Concordant changes in Bcl‐2 mRNA and protein levels were found, i.e. during Bcl‐2 down‐regulation in the GC‐related B cells in ongoing EL‐4 cultures or in medium, and during a more modest up‐regulation upon contact with fresh EL‐4 cells. Regulation of Bcl‐2 protein, therefore, predominantly occurred at the mRNA steady‐state level.
Prevention of autoimmune diabetes mellitus in NOD mice by transgenic expression of soluble tumor necrosis factor receptor p55
Authors: Hunger Robert E. , Carnaud Claude , Garcia Irène , Vassalli Pierre , Mueller Christoph 
Published: March 2007

AbstractThe non‐obese diabetic (NOD) mouse represents a relevant animal model of autoimmunity for insulin‐dependent diabetes mellitus. The pathogenic role of tumor necrosis factor (TNF) in insulitis and β cell destruction observed in these mice remains controversial, since injections of TNF or of anti‐TNF antibodies have been reported to exert protection or acceleration of diabetes, depending on the timing of administration. In this study, we demonstrate that, in contrast to the non‐transgenic littermates, NOD mice with permanent neutralization of TNF by high blood levels of soluble TNF receptor p55‐human FcIgG3‐fusion molecules resulting from the expression of a transgene are protected from spontaneous diabetes. They are also protected from accelerated forms of disease caused by transfer of NOD spleen cells or cyclophosphamide injections. This protection is associated with a marked decrease in the severity and incidence of insulitis and in the expression of the adhesion molecules MAdCAM‐1 and ICAM‐1 on the venules of pancreatic islets. These data suggest a central role for TNF‐α in the mediation of insulitis and of the subsequent destruction of insulin‐secreting β‐cells observed in NOD mice. They may be relevant to cell‐mediated autoimmune diseases in general, in which treatment with soluble TNF receptors might be beneficial.
Direct interaction of Syk and Lyn protein tyrosine kinases in rat basophilic leukemia cells activated via type I Fcε receptors
Authors: Amoui Mehran , Dráberová Lubica , Tolar Pavel , Dráber Petr 
Published: March 2007

AbstractActivation of rat mast cells through the receptor with high affinity for IgE (FcεRI) requires a complex set of interactions involving transmembrane subunits of the FcεRI and two classes of nonreceptor protein tyrosine kinase (PTK), the Src family PTK p53/p56lyn (Lyn) and the Syk/ZAP‐family PTK p72syk (Syk). Early activation events involve increased activity of Lyn and Syk kinases and their translocation into membrane domains containing aggregated FcεRI, but the molecular mechanisms responsible for these changes have remained largely unclear. To determine the role of FcεRI subunits in this process, we have analyzed Syk‐ and Lyn‐associated proteins in activated rat basophilic leukemia (RBL) cells and their variants deficient in the expression of FcεRI β or γ subunits. Sepharose 4B gel chromatography of postnuclear supernatants from Nonidet‐P40‐solubilized antigen (Ag)‐ or pervanadate‐activated RBL cells revealed extensive changes in the size of complexes formed by Lyn and Syk kinases and other cellular components. A fusion protein containing Src homology 2 (SH2) and SH3 domains of Lyn bound Syk from lysates of nonactivated RBL cells; an increased binding was observed when lysates from Ag‐ or pervanadate‐activated cells were used. A similar amount of Syk was bound when lysates from pervanadate‐activated variant cells deficient in the expression of FcεRI β or γ subunits were used, suggesting that FcεRI does not function as the only intermediate in the formation of the Syk‐Lyn complexes. Further experiments have indicated that Syk‐Lyn interactions occur in Ag‐activated RBL cells under in vivo conditions and that these interactions could involve direct binding of the Lyn SH2 domain with phosphorylated tyrosine of Syk. The physical association of Lyn and Syk during mast‐like cell activation supports the recently proposed functional cooperation of these two tyrosine kinases in FcεRI signaling.
Lack of F1 anti‐parental resistance in H‐2b/d F1 hybrids devoid of β2‐microglobulin
Authors: Höglund Petter , Olsson‐Alheim Mats Y. , Johansson Maria , Kärre Klas , Sentman Charles L. 
Published: March 2007

AbstractF1 hybrid mice often reject parental hematopoietic grafts, a phenomenon known as hybrid resistance. Hybrid resistance is mediated by natural killer (NK) cells and although the molecular interactions responsible for this phenomenon are largely unknown, one hypothesis suggests that parental cells are rejected because they fail to express a complete set of host major histocompatibility complex (MHC) class I molecules. Inherent in this theory is that NK cells in the F1 hybrid are instructed by self MHC class I molecules to form an NK cell repertoire capable of reacting against cells lacking these self MHC class I molecules. Here, we show that C57BL/6 x DBA/2 mice (H‐2b/d) devoid of β2‐microglobulin (β2m) are incapable of rejecting β2m−/− parental C57BL/6 cells (H‐2b) both in vivo and in vitro. From this, we conclude that the development of an NK cell repertoire, at least in F1 mice of the H‐2b/d haplotype, requires expression of MHC class I molecules complexed with β2m.
Susceptibility to ankylosing spondylitis correlates with the C‐terminal residue of peptides presented by various HLA‐B27 subtypes
Authors: Fiorillo Maria Teresa , Meadows Leslie , D'Amato Mauro , Shabanowitz Jeffrey , Hunt Donald F. , Appella Ettore , Sorrentino Rosa 
Published: March 2007

AbstractSusceptibility to spondyloarthropaties is strongly associated with some HLA‐B27 alleles. Evidence suggests a direct pathogenic role for the B27 molecules which possibly present an arthritogenic peptide to the T cells. If this hypothesis is true, B27 subtypes that differ structurally but are disease‐associated ought to be capable of presenting such peptide(s), while non‐disease‐associated ones would not. We have recently described a B27 subtype, B*2709, and shown its absence in ankylosing spondylitis (AS) patients. Here, we show the elution and sequence of peptides from HLA‐B*2709 molecules. Similar to other B27 subtypes, these peptides are mainly nonamers with an Arg at position P2. Comparison of the C‐terminal anchors of peptides eluted from B*2702 and B*2705 with those eluted from B*2709 reveals that, while B*2702 and B*2705 have a broader specificity, B*2709 molecules appear to only accept C‐terminal hydrophobic residues. A common feature shared by the two caucasoid AS‐associated subtypes (B*2702 and B*2705) but different from B*2709, is the presence of a Tyr as peptide C‐terminal anchor. The substitution of Val for Tyr at the C terminus in one of the eluted peptides greatly reduces the binding to B*2709 molecules. This finding suggests Tyr as a discriminative amino acid allowed at the C terminus of peptides bound to the AS‐associated B27 subtypes, but not to those which are not associated with AS.
CD45‐associated protein is a lymphocyte‐specific membrane protein expressed in two distinct forms
Authors: Kitamura Koichi , Matsuda Akio , Motoya Satoshi , Takeda Akiko 
Published: March 2007

AbstractCD45‐AP is a recently identified CD45‐associated protein. The two proteins interact specifically through their respective transmembrane segments. Northern hybridization analysis of CD45+ T lymphocytes and their CD45− variants demonstrated that the production of CD45‐AP and CD45 mRNA is regulated independently. On the other hand, Western blotting analysis indicated that the CD45‐AP protein has a shorter half‐life in the absence of CD45 in three out of four variants. Similar analysis of various types of leukocytes demonstrated that CD45‐AP is expressed in T, B, and pre‐B cells, but not in plasma cells or cells of the monocyte/macrophage lineage. Two forms of CD45‐AP mRNA exist in all types of CD45‐AP‐expressing lymphocytes analyzed. One form corresponds to the previously reported CD45‐AP cDNA and the other form encodes an additional 12 amino acids at the N terminus. The two CD45‐AP proteins are identical in their capacity for specific binding to CD45, but employ different mechanisms for endoplasmic reticulum membrane translocation.
gp160 of HIV or anti‐CD4 monoclonal antibody ligation of CD4 induces inhibition of JNK and ERK‐2 activities in human peripheral CD4+ T lymphocytes
Authors: Jabado Nada , Pallier Annaïck , Jauliac Sébastien , Fischer Alain , Hivroz Claire 
Published: March 2007

AbstractUnder physiological conditions, activation of CD4+ T cells by major histocom‐patibility complex (MHC) antigen complexes requires engagement of both the T cell receptor and the CD4 molecule. However, CD4 ligands binding to the CD4 molecule has also been shown to inhibit T cell proliferation and interleukin (IL)‐2 production in human CD4+ T cells, in an MHC‐independent way. We have previously shown that this inhibition was associated with a diminished binding activity of the IL‐2 transcription factors NF‐AT, NF‐χB, and AP‐1. AP‐1 plays a key role in the regulation of IL‐2 transcription, and ERK and JNK activities are necessary for regulating AP‐1 at both the transcriptional and the post‐transcriptional levels. We therefore studied, in human peripheral CD4+ T cells, the regulation of the activities of extracellular signal‐regulated protein kinases (ERK) and c‐Jun N‐terminal kinases (JNK) by two CD4 ligands, gpi60 the envelope glycoprotein of human immunodeficiency virus (HIV) and an anti‐CD4 monoclonal antibody (mAb). Pre‐incubation of CD4+ T lymphocytes in the presence of anti‐CD4 mAb or gp160 inhibits the activation of JNK in response to phorbol 12‐myristate 13‐acetate and ionomycin. In the same conditions, phos‐phorylation and activation of ERK‐2 were also inhibited. Inhibition of both JNK and ERK‐2 activities are specific for binding of CD4 ligands to the CD4 molecule. They were not observed in CD8+ T lymphocytes. These results suggest that a specific inhibition of JNK and ERK‐2 activities contributes to defective IL‐2 production in T lymphocytes pre‐incubated with CD4 ligands.
On the mechanisms of immunodominance in cytotoxic T lymphocyte responses to minor histocompatibility antigens
Authors: Pion Stéphane , Fontaine Pierre , Desaulniers Michel , Jutras Julie , Filep Janos G. , Perreault Claude 
Published: March 2007

AbstractAlthough there are numerous minor histocompatibility antigens (MiHA), T cell responses leading to graft‐versus‐host (GVH) and graft‐versus‐tumor effects involve only a small number of immunodominant MiHA. The goal of the present study was to analyze at the cellular and molecular levels the mechanisms responsible for MiHA immunodominance. Cytotoxic T lymphocytes (CTL) generated in eight combinations of H2b strains of mice were tested against syngeneic targets sensitized with HPLC‐fractionated peptides eluted from immunizing cells. The number of dominant MiHA was found to range from as little as two up to ten depending on the strain combination used. The nature of dominant MiHA was influenced by both the antigen profile of the antigen‐presenting cells (APC) and the repertoire of responding CTL. When C57BL/6 dominant MiHA (B6dom) and H‐Y were presented on separate APC, they showed similar immunogenicity. In contrast, when they were presented on the same APC, B6dom MiHA totally dominated H‐Y. B6dom MiHA did not suppress anti‐H‐Y responses by acting as T cell receptor antagonists for anti‐H‐Y CTL, nor were anti‐B6dom CTL precursors more abundant than anti‐H‐Y CTL precursors. Dominance resulted from competition for the APC surface between anti‐B6dom and anti‐H‐Y CTL; the crucial difference between the dominant and the dominated MiHA appears to depend on the differential avidity of their respective CTL for APC. The only B6dom epitope thus far identified is the nonapeptide AAPDNRETF presented by H2‐Db. We found that compared with other known Db‐binding peptides, AAPDNRETF is expressed at very high levels on the cell surface, binds to the Db molecule with very high affinity, and dissociates very slowly from its presenting class I molecule. These data indicate that one cannot predict which MiHA will be dominant or dominated based simply on their respective immunogenicity when presented on separate APC. Indeed, the avidity of T cell/APC interactions appears to determine which antigen(s) will trigger T cell responses when numerous epitopes are presented by the same APC.
High and low doses of haptens dictate whether dermal or epidermal antigen‐presenting cells promote contact hypersensitivity
Authors: Bacci Stefano , Alard Pascale , Dai Ruoping , Nakamura Toshiaki , Streilein J. Wayne 
Published: March 2007

AbstractIn the induction of contact hypersensitivity (CH) to an epicutaneously applied hapten, we have previously proposed that low doses of hapten sensitize primarily through epidermal Langerhans' cells (LC), whereas high doses rely largely on dermal antigen‐presenting cells (APC). To examine this issue further, we applied either high or low doses of dinitrofluorobenzene (DNFB) epicutaneously to mice. We observed reduced LC density at the site after 12 h (nadir), which returned to normal levels at 24 h only after a low dose of hapten. When a low dose of an unrelated hapten, oxazolone, was painted on skin that had been painted 12 h previously with high dose of DNFB, oxazolone‐specific CH was impaired. When grafts of whole skin, dermis alone, and epidermis alone prepared from skin painted 2 h previously with low or high doses of DNFB were placed onto naive, syngeneic mice, CH was induced by whole skin after both types of doses, by epidermis only after a low dose, and by dermis only after high dose. When epidermal cell suspensions were derivatized in vitro with low or high doses of DNFB, only cells exposed to a low dose induced proliferation of hapten‐specific T cells. Thus, only a low dose of hapten reveals the APC functions of LC without the participation of dermal APC.