bluuebunny/crossref_metadata_2025_split huggingface dataset:
The internalization of the IgG2a antigen receptor does not require the association with Ig‐α and Ig‐β but the activation of protein tyrosine kinases does
Authors: Weiser Peter , Riesterer Christa , Reth Michael 
Published: March 2007

AbstractThe B cell antigen receptor of class IgM is a multimeric protein complex containing the membrane‐bound immunoglobulin molecule and a heterodimer of the two B cell‐specific transmembrane proteins Ig‐α and Ig‐β. The B cell antigen receptor fulfills a dual role on the surface of B cells. First, it is a signal transduction complex which can activate protein tyrosine kinases and induce the release of Ca2+ ions from intracellular stores. Second, its internalization mediates the specific uptake of bound antigens, which are processed intracellularly and presented as major histocompatibility complex‐bound peptides on the cell surface. In case of the IgM antigen receptor, the association with the heterodimer is necessary for expression of large amounts of IgM on the surface. We show here that the IgG2a antigen receptor can be expressed on the surface of myeloma cells in two structurally different forms: either with or without the Ig‐α/Ig‐β heterodimer. A functional comparison of the two forms of antigen receptors demonstrates that the Ig‐α and Ig‐β molecules are required for the activation of protein tyrosine kinases after cross‐linking of the B cell antigen receptor. In contrast, both forms of IgG2a are equally well internalized. This suggests that Ig‐α and Ig‐β are essential for signal transduction through the IgG2a antigen receptor, whereas internalization can occur independently of the heterodimer.
Kinetics of intestinal intraepithelial lymphocytes during acute graft‐versus‐host disease in mice
Authors: Tsuzuki Toyonori , Yoshikai Yasunobu , Ito Masafumi , Mori Naoyoshi , Ohbayashi Masaharu , Asai Junpei 
Published: March 2007

AbstractWe examined the kinetics of intestinal intraepithelial lymphocytes (IEL) and the incidence of apoptosis at villus or crypt sites during the development of non‐irradiated acute graft‐versus‐host disease (GVHD). The first IEL to increase were host‐origin on day 3 and the donor‐derived IEL appeared first on day 12 after GVHD induction. Unique CD3+CD4+CD8α/α+ IEL were significantly increased on day 6 and an appreciable number of IEL bearing T cell receptor Vβ capable of recognizing self‐superantigen were detected on day 9. The sudden appearance of apoptosis and reduction of mitotic activity occurred on day 12, accompanied by a dramatic decrease of CD3+CD4−CD8α/α+ IEL of host origin. CD8α/α+ IEL of host origin, which expand and then decrease by apoptosis at the early stage of acute GVHD, may be associated with pathogenesis of the enteropathy occurring during acute GVHD.
Heat‐stable antigen/CD24 on mouse T lymphocytes: evidence for a costimulatory function
Authors: Hubbe Marcus , Altevogt Peter 
Published: March 2007

AbstractHeat‐stable antigen (HSA)/mouse CD24 (formerly termed Nectadrin) is a membrane glycoprotein with an unusual structure consisting of a small protein core and extensive glycosylation. It is expressed by hematopoietic cells but not by mature T lymphocytes. HSA on accessory cells is an important costimulatory molecule required for the clonal expansion of T lymphocytes. HSA is also involved in cell‐cell adhesion events and the isolated antigen has been shown to possess self‐binding properties. In the present study we have re‐investigated the role of HSA in T cell proliferation. We find that following stimulation of T lymphocytes with concanavalin A or of CD4+ T lymphocytes with a combination of anti‐CD3/CD28 monoclonal antibodies (mAb) the HSA antigen is transiently expressed. The expression correlated with the appearance of CD25 and a CD2 activation epitope at the cell surface. Induction of HSA was also seen in vivo on Vβ8+ T lymphocytes in BALB/c mice that were injected with Staphylococcal enterotoxin B. Biosynthetic labeling and analysis of mRNA by reverse transcriptase‐polymerase chain reaction showed that HSA was synthesized by activated T lymphocytes. A combination of anti‐CD3 and mAb 79 to HSA was incapable of inducing proliferation of purified CD4+ T lymphocytes. However, the antibody strongly enhanced the response obtained with a combination of anti‐CD3/CD28 mAb. The augmenting effect of the HSA‐specific mAb was dose dependent. Since HSA is bound to the membrane via a glycosyl‐phosphatidylinositol (GPI) anchor and GPI‐anchored molecules have been implicated in lymphocyte activation, it is conceivable that HSA is not only a costimulatory molecule on accessory cells but is also a signaling molecule in T lymphocytes. The possibility of a homotypic HSA/HSA interaction between T lymphocytes and accessory cells is discussed.
“Natural” presentation of human papillomavirus type‐16 E7 protein to immunocompetent mice results in antigen‐specific sensitization or sustained unresponsiveness
Authors: Chambers Mark A. , Wei Zhang , Coleman Nicholas , Nash Anthony A. , Stanley Margaret A. 
Published: March 2007

AbstractWe have used a mouse model that utilizes the exclusively epithelial nature of human papillomavirus (HPV) infections to investigate the in vivo immune response to the E7 protein of human papillomavirus type‐16. A keratinocyte cell line expressing E7 protein has been established and grafted onto syngeneic mice using a transplantation technique that permits the reformation of a differentiated epithelium on a granulation tissue bed. In this way viral antigens may be presented to the immune system in a way comparable to natural infection. A delayed‐type hypersensitivity (DTH) response was studied post grafting by intradermal challenge with recombinant E7 protein. A significant response to E7 has been demonstrated in this way; however, priming with a low amount of HPV‐16 E7 antigen induces immunological unresponsiveness, as measured by a loss of DTH reactivity to the protein, and persistence of keratinocytes expressing E7. Lymphocytes from mice exhibiting DTH reactivity have been shown to proliferate when stimulated with purified recombinant E7 protein in vitro, while immunoperoxidase staining from the sites of immunologically‐induced inflammation has defined the cell infiltrate to be phenotypically characteristic of DTH. The observations reported here have important implications for vaccine strategy.
Leishmania major‐specific CD8+ T cells are inducers and targets of nitric oxide produced by parasitized macrophages
Authors: Stefani Mariane M. A. , Müller Ingrid , Louis Jacques A. 
Published: March 2007

AbstractLines of Leishmania major‐specific CD8+ T cells were derived from the lymph nodes and spleens of CBA mice, immune following resolution of a primary infection, 7 days after secondary challenge with viable L. major. Specific stimulation of these CD8+ T cells by bone marrow‐derived macrophages infected with L. major led to the release of interferon‐γ by CD8+ T cells and nitric oxide by macrophages. Interestingly, the nitric oxide released by bone marrow‐derived macrophages down‐regulated the production of interferon‐γ by specifically activated CD8+ T cells. The proliferation and long‐term maintenance of these parasite‐specific CD8+ T cells was impaired by the nitric oxide produced by stimulating infected macrophages as a result of cytokines released by activated CD8+ T cells. Taken together, the results indicate that L. major‐specific CD8+ T cells are sensitive to the toxic effect of the nitric oxide that they induce.
Differential expression of APO‐1 on human thymocytes: Implications for negative selection?
Authors: Debatin Klaus‐Michael , Süss Dorothee , Krammer Peter H. 
Published: March 2007

AbstractNegative selection during T cell ontogeny involves selective induction of apoptosis in thymocytes. In peripheral lymphoid cells, apoptosis may be mediated via the APO‐1 pathway. Here we report that APO‐1 is constitutively expressed on the vast majority of human thymocytes but down‐regulated at a mature stage of thymocyte development (TCRhi). This stage of development is characterized by CD28hi, CD44hi, CD69hi and up‐regulation of Bcl‐2 protein. We define a new thymocyte subpopulation that expresses high levels of APO‐1 and intermediate levels of T cell receptor α/β (TCRim/APO‐1hi). The TCRim/APO‐1hi population contains a large fraction of dead cells, suggesting that the APO‐1 pathway may be involved in negative selection of at least a fraction of thymocytes after intrathymic activation.
Two tyrosinase nonapeptides recognized on HLA‐A2 melanomas by autologous cytolytic T lymphocytes
Authors: Wölfel Thomas , Van Pel Aline , Brichard Vincent , Schneider Jörg , Seliger Barbara , Zum Büschenfelde Karl‐Hermann Meyer , Boon Thierry 
Published: March 2007

AbstractA number of cytolytic T lymphocyte (CTL) clones derived from several melanoma patients have been found to recognize a majority of melanomas from HLA‐A2 patients. We have reported previously that two such CTL clones recognize a product of the tyrosinase gene that is presented by HLA‐A2. Here we show that one of these CTL clones recognizes a peptide encoded by the first nine amino acids of the putative signal sequence of tyrosinase. The other CTL clone recognizes a different tyrosinase peptide corresponding to amino acids 368–376. Both peptides contain consensus motifs of HLA‐A2 binding peptides.
Identification of wild‐type and mutant p53 peptides binding to HLA‐A2 assessed by a peptide loading‐deficient cell line assay and a novel major histocompatibility complex class I peptide binding assay
Authors: Stuber György , Leder Gerhard H. , Storkus Walter J. , Lotze Michael T. , Modrow Susanne , Székely László , Wolf Hans , Klein Eva , Kärre Klas , Klein George 
Published: March 2007

AbstractMutations of the p53 gene are the most frequently observed genetic changes in human cancers; often leading to an overexpression of the wild‐type (wt) p53 protein. Demonstrable T cell reactivity against tumor cells overexpressing wt or mutant p53‐derived peptides could support the application of such epitopes in cancer immunotherapies. As the binding of peptide to MHC class I molecules is a prerequisite for antigen‐specific T cell recognition, we evaluated the ability of wt and mutant p53 peptides to bind to HLA‐A2.1 using two independent flow cytometry‐based assay systems, the T2 major histocompatibility complex (MHC) class I peptide stabilization assay (stabilization assay) and the peptide‐induced MHC class I reconstitution assay (reconstitution assay). The twenty selected wt sequences each conformed to the previously reported HLA‐A2.1 peptide binding motif. Seven of the wt p53 and 2/13 mutant p53 peptides derived from the previously chosen wt peptides bound to HLA‐A2.1 in both the stabilization and the reconstitution assays. An additional six wt and six mutant p53 peptides, presumably exhibiting lower affinity for HLA‐A2.1, were identified only in the reconstitution assay. Those p53 peptides binding HLA‐A2.1 may provide useful immunogens for the generation of HLA‐A2.1‐restricted cytolytic T lymphocytes in vitro and in vivo.
Modulation of the transcripts for tumor necrosis factor‐α and its receptors in vivo
Authors: De Kossodo Sylvie , Critico Brigitte , Grau Georges E. 
Published: March 2007

AbstractWe investigated the effects of a single bacterial lipopolysaccharide (LPS) injection in vivo on the gene expression of tumor necrosis factor‐α (TNF) and its receptors: TNF receptor type I (TNF‐R 55 kDa or TNF‐R1) and TNF receptor type II (TNF‐R 75 kDa or TNF‐R2) in various tissues and white blood cells. While TNF mRNA rapidly accumulated in most tissues, TNF‐R1 and TNF‐R2 mRNA levels were found to be differentially regulated in lung, spleen, lymph nodes and white blood cells. In most cases, TNF‐R mRNA levels did not parallel TNF mRNA levels. These observations indicate that TNF‐R of both types are capable of modulating the host response to LPS, not only by shedding of their extracellular domains, but also by strict regulation of their gene expression.
A simple assay for detection of peptides promoting the assembly of HLA class I molecules
Authors: Connan Francine , Hlavac Frédéric , Hoebeke Johan , Guillet Jean‐GÉRard , Choppin Jeannine 
Published: March 2007

AbstractSynthetic peptides derived from influenza virus and human immunodeficiency virus were tested for their ability to promote the assembly of HLA‐A2 and HLA‐B51 molecules in T2 cell lysates. Specific assembly was detected by an enzyme‐linked immunosorbent assay. The most significant HLA‐A2 assembly was obtained in the presence of peptides known to be targets for HLA‐A2‐restricted cytotoxic T lymphocytes (influenza matrix M.58–66 and HIV Pol 476–484). Three of a batch of Nef peptides corresponding to epitopic regions for cytotoxic T lymphocytes, caused significant assembly of HLA‐A2 (Nef 83–91, 137–145 and 144–153), but only at high concentrations (100 μM). As these peptides bound relatively weakly, it is unlikely that they are good candidates for HLA‐A2‐restricted CTL epitopes. Peptides matrix M.60–68, Nef 186–194, and Plasmodium falciparum sh. 77–85 produced the most significant assembly of HLA‐B51. These peptides have a dominant hydrophobic anchor residue (V, L. I) at position 9 that could occupy pocket “F”. Our results also suggest that another hydrophobic residue (V, L) at position 3 or 4 may anchor to hydrophobic pocket “d” of HLA‐B51. Proline at position 2 greatly increases HLA‐B51 anchoring.
B cells regulate expression of CD40 ligand on activated T cells by lowering the mRNA level and through the release of soluble CD40
Authors: van Kooten Cees , Gaillard Claude , Galizzi Jean‐Pierre , Hermann Patrice , Fossiez François , Banchereau Jacques , Blanchard Dominique 
Published: March 2007

AbstractThe expression of CD40 ligand (CD40L) on activated T cells (CD4+ T cell clone MT9) is diminished when the T cells are cultured in the presence of B cells. This effect, observed both with normal tonsil B cells and with the B cell line JY, was detected after 6 h and sustained at least until 18 h of co‐culture. Analysis of mRNA showed that CD40L mRNA levels were not modified after 6 h, but were significantly down‐regulated after 18 h of co‐culture with B cells. Although CD40L expression could not be detected by a CD40‐Fc chimera, the molecule was still expressed at the membrane as shown with a polyclonal antiserum against CD40L (anti‐TRAP). In addition, T cells activated in the presence of B cells were stained by a polyclonal antiserum against CD40, without the appearance of CD40 mRNA. These results indicated that a soluble form of CD40 (sCD40) bound to the expressed CD40L on T cells. The existence of sCD40 was confirmed by detection of sCD40 in B cell supernatants using a specific enzyme‐linked immunosorbent assay. Collectively, these data show that B cells can regulate the expression of CD40L on activated T cells at least by two different mechanisms.
Expression and function of the costimulatory molecule B7 on murine Langerhans cells: Evidence for an alternative CTLA‐4 ligand
Authors: Razi‐Wolf Ziba , Falo Louis D. , Reiser Hans 
Published: March 2007

AbstractWe have previously shown, through transfection experiments, that the murine B7 (mB7) molecule, a ligand for the CD28 and CTLA‐4 receptors, is a sufficient costimulatory signal for the antigen‐specific and major histocompatibility complex (MHC)‐restricted activation of murine CD4+ T lymphocytes. In addition to mB7, another ligand with affinity for CTLA‐4 has been described on spleen cells. Here we report our studies on the expression and function of these molecules on murine Langerhans cells (LC). Both anti‐mB7 monoclonal antibody (mAb) 16‐10A1 and human CTLA4Ig (hCTLA4Ig), a chimeric fusion protein consisting of the extracellular domain of human CLTA‐4 and the constant domain of human IgG1, detected antigens(s) on cultured but not freshly isolated LC. Preincubation of cultured LC with anti‐mB7 mAb did not significantly affect binding of hCTLA4Ig to these cells. This result demonstrate the existence of at least one other ligand for the CLTA‐4 receptor on cultured LC. Functional studies revealed that the costimulatory activity of LC was inhibited better by hCTLA4Ig than by the anti‐mB7 mAb. This differential effect was seen in the case of both alloreactive and antigen‐specific, syngeneic T cell responses. These findings suggest that the non‐mB7‐ligand for CTLA‐4 is functional and participates in the induction of immune responses by LC. Importantly, even synergistic combinations of anti‐mB7 mAb and hCTLA4Ig did not inhibit completely the activity of LC. These findings therefore raise the possibility that LC express other costimulatory ligands besides mB7 and related family members.
CD5 is associated with the human B cell antigen receptor complex
Authors: Lankester Arjan C. , van Schijndel Gijs M. W. , Cordell Jacqueline L. , van Noesel Carel J. M. , van Lier René A. W. 
Published: March 2007

AbstractOn human B cells the antigen receptor complex is composed of the membrane form of the immunoglobulin molecule and the non‐covalently associated Igα/β heterodimer. A small subpopulation of normal B cells and chronic lymphocytic leukemia B cells express (analogous to T cells) the transmembrane molecule CD5, a counterstructure of B cell‐specific CD72. Numbers of CD5+ B cells are increased in several physiological and pathological conditions. Moreover, CD5+ B cells are being held responsible for the production of autoreactive antibodies and seem to have signaling characteristics distinct from conventional B cells. On T cells, CD5 associates with the T cell receptor CD3 complex and ligation of CD5 leads to the generation of co‐stimulatory signals, that act on T cell activation. We here demonstrate that CD5 is associated with the B cell receptor (BCR) complex and serves as substrate for BCR‐induced tyrosine kinase activity. Hence, CD5+ B cells have a unique potential to modulate BCR signals.
A second promoter and enhancer element within the immunoglobulin heavy chain locus
Authors: Kottmann Andreas H. , Zevnik Branko , Welte Markus , Nielsen Peter J. , Köhler Georges 
Published: March 2007

AbstractThe joining of immunoglobulin gene segments during B cell development consists of a tightly regulated series of rearrangement steps. A variety of experiments have suggested that transcription is involved in activating the locus as substrate for the V(D)J recombinase. Here, we have characterized a region located immediately upstream of the most J‐proximal D element (DQ52), which contains both promoter and enhancer activities preferentially active in precursors of B cells. Interestingly, this DQ52 regulatory element is inevitably deleted in fully rearranged H chain genes. We propose that it is involved in the early activation and rearrangement events at the IgH locus.
Activation of CD4+ T cells by delivery of the B7 costimulatory signal on bystander antigen‐presenting cells (trans‐costimulation)
Authors: Ding Linna , Shevach Ethan M. 
Published: March 2007

AbstractIncreasing evidence in both murine and human systems suggests that the interaction of the T cell surface antigens CD28/CTLA4 with their ligand B7 on the antigen‐presenting cells (APC) is the critical costimulatory pathway involved in the induction of maximal T cell activation and the prevention of induction of anergy. It has also been demonstrated that efficient induction of clonal expansion of normal CD4+ T cells requires the delivery of the T cell receptor (TCR) ligand and costimulation by the same APC. We demonstrate here that normal murine CD4+ T cells can be efficiently activated by soluble anti‐CD3 cross‐linked by fixed macrophages and by a costimulatory signal delivered by a bystander APC, B7‐transfected L cells. The major factor which determined the ability of an APC to provide costimulation in “trans” was the level of cell surface B7 expression. The requirement for B7 costimulation appears to be at initial stage of TCR engagement since optimal T cell activation was only observed when TCR triggering and B7 costimulatory activity were delivered at same time by different APC. Induction of maximal proliferation of both naive CD45RBhi and memory CD45RBlo CD4+ T cells was B7 dependent and both populations of cells responded equally well to the B7 costimulation delivered in “trans”. Furthermore, trans‐costimulation provided by B7 transfected L cells efficiently prevented the induction of anergy in normal murine CD4+ T cells induced by anti‐CD3 cross‐linked by fixed‐resting macrophages. Addition of exogenous interleukin‐2 (IL‐2) and IL‐7 to the primary culture in the absence of B7‐transfected L cells or addition of IL‐2 to the culture containing the B7 transfectant and CTLA4Ig completely prevented the induction of hyporesponsiveness. These findings raise the possibility that in certain pathological states, CD4+ T cells in vivo may be activated by costimulation delivered by bystander APC.
B precursor acute lymphoblastic leukemia third complementarity‐determining regions predominantly represent an unbiased recombination repertoire: Leukemic transformation frequently occurs in fetal life
Authors: Steenbergen Eric J. , Verhagen Onno J. H. M. , van Leeuwen Eleonore F. , Behrendt Henk , Merle Pauline A. , Wester Mieke R. , Von Dem Borne Albert E. G. Kr. , van der Schoot C. Ellen 
Published: March 2007

AbstractTo determine whether the ALL (acute lymphoblastic leukemia) CDR3 (third complementarity‐determining region) repertoire represents the recombination repertoire, or shows evidence of selectional processes inherent to normal B cell differentiation or malignant transformation, we analyzed 68 ALL CDR3 regions and included 127 previously published sequences in the analyses. We found no evidence of selection prior to malignant transformation as recombination was random with 1/3 “in frame” and 2/3 “out of frame” joinings and usage of all three D reading frames was observed. D and JH gene segments were predominantly umutated which allowed a detailed analysis of gene usage and rearrangement characteristics. JH4 and JH6 usage (both 32.2%) was significantly different (p = 0.005) from that observed in peripheral B lymphocytes. D gene family usage roughly represented D gene family size with the exception of the DXP and DA/K family which were over‐ and underrepresented (p = 0.05), respectively. D‐D fusions were found in 26.2% of CDR3 regions. If less stringent criteria were applied DIR homology was found in 40/65 sequences, suggesting the frequent involvement of DIR gene segments in human CDR3 formation. The rearranged D genes were evenly distributed over the D locus, suggesting that D recombination is a predominantly random process, independent of physical location at the locus. Also, there was no correlation between JH gene usge and physical location of the rearranged D gene segment, which excludes a major contribution of the DJH replacement recombination mechanism. In 36.1% of CDR3 regions N‐nucleotides at the DJH junction were absent. This frequency is higher than observed for peripheral B lymphocytes. It is suggested that for a number of ALL the initial transformational event took place in early fetal life. We conclude that ALL CDR3 sequences show no evidence of selection prior to malignant transformation, nor of extensive changes subsequent to malignant transformation.