bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting major histocompatibility complex class II molecules to the cell surface by invariant chain allows antigen presentation upon recycling
Authors: Nijenhuis Marga , Calafat Jero , Kuijpers Karel C. , Janssen Hans , De Haas Marcel , Nordeng Tommy W. , Bakke Oddmund , Neefjes Jacques J. 
Published: March 2007

AbstractWe studied the functional consequences of targeting class II molecules to either the cell surface or to endocytic structures by expressing HLA‐DR1 in human kidney cells in the presence or absence of different forms of the invariant chain (Ii). Transfectants expressing class II molecules in the absence of Ii present influenza virus efficiently and co‐expression of full length Ii does not further increase antigen presentation. Chimeric Ii containing the cytoplasmic domain of the transferrin receptor (Tfr‐Ii) delivers class II molecules associated with Tfr‐Ii to endosomal compartments, but this does not result in efficient antigen presentation. When class II molecules are targeted to the cell surface by Ii lacking either 15 (Δ15Ii) or 23 (Δ23Ii) amino acids from the cytoplasmic domain, a fraction of free class II molecules is also observed. Whereas Δ15Ii did not affect antigen presentation by class II molecules, Δ23Ii inhibited, but did not abrogate, the response. We show that class II molecules expressed in the presence of Δ23Ii can be internalized, followed by degradation of Δ23Ii and return of free class II αβ heterodimers to the cell surface. A fraction of the resulting free class II molecules is sodium dodecyl sulfate stable, indicating that internalization and reappearance of class II molecules at the cell surface can be an alternative route for antigen presentation. In all transfectants, class II molecules were found in endocytic compartments that labeled for CD63 and resembled the multilaminar MIIC compartments found in B cell lines. Ii is not required for endosomal targeting of class II molecules. The number of class II molecules observed in the multilaminar compartments correlates with the efficiency of antigen presentation.
Self class I molecules protect normal cells from lysis mediated by autologous natural killer cells
Authors: Ciccone Ermanno , Pende Daniela , Vitale Massimo , Nanni Luca , Di Donato Carolina , Bottino Cristina , Morelli Luigia , Viale Oriane , Amoroso Antonio , Moretta Alessandro , Moretta Lorenzo 
Published: March 2007

AbstractThe surface expression of given HLA class I alleles protects target cells from lysis mediated by natural killer (NK) clones specific for these (or related) alleles. We could define two groups of NK clones specifically recognizing either Cw4 and related C alleles (“group 1”) or Cw3 and related C alleles (“group 2”), respectively. Monoclonal antibodies (mAb) to class I molecules should interfere with the interaction between NK receptors and class I molecules, thus resulting in lysis of protected target cells. However, none of the numerous available mAb to class I molecules had this effect. Therefore, we attempted to select new mAb on the basis of their ability to induce lysis of Cw4‐ or Cw3‐protected lymphoblastoid cell lines by “group 1” or “group 2” NK clones, respectively. From mice immunized with phytohemagglutinin (PHA)‐activated lymphocytes expressing either Cw3 or Cw4 alleles, two mAb were selected, the 6A4 (IgG1) and the A6‐136 (IgM), on the basis of their ability to induce lysis of protected target cell. Both mAb immunoprecipitated molecules which, in sodium dodecyl sulfate‐polyacrylamide gel electrophoresis, gave two bands of 45 and 12 kDa, typical of the class I heavy chain and β2 microglobulin, respectively. It has been proposed (but not proven), that self major histocompatibility complex class I molecules protect normal cells from autologous NK cell lysis. Thus, we used the 6A4 and A6‐136 mAb to assess this possibility directly. Cw4‐specific (“group 1”) and Cw3‐specific (“group 2”) NK clones were isolated from donors expressing the corresponding (or related) protective C alleles. None of these clones lysed autologous PHA‐induced blasts, used as target cells. However, addition of the F(ab′)2 of 6A4 mAb or the A6‐136 mAb resulted in lysis of autologous target cells by “group 1” or “group 2” NK clones, respectively. These data provide direct evidence that the expression of class I molecules protects normal cells from lysis by autologous NK cells.
Are primed CD4+ T lymphocytes different from unprimed cells?
Authors: Constant Stephanie , Zain Mona , West Jeff , Pasqualini Theresa , Ranney Patricia , Bottomly Kim 
Published: March 2007

AbstractPrimed and unprimed lymphocytes are usually classified as separate subsets of cells, based on phenotypic and functional distinctions. In the case of CD4+ T lymphocytes, primed cells are thought to proliferate more vigorously, quickly and easily, and to release a different profile of cytokines, than their naive equivalent. However, most of these data were obtained from studies in which populations of lymphocytes were compared before and after antigenic stimulation, and therefore did not distinguish between the effects resulting from the clonal expansion of specific precursor cells within such populations and those due to cell differentiation per se. We have investigated the contribution of precursor cell frequency to some of the functional changes observed in populations of CD4+ T cells following antigenic stimulation, using approaches in which antigen‐specific precursor frequencies are high in both primary and secondary stimulations: mixed leukocyte reaction responses and cells from αβ T cell receptor transgenic mice. Our data suggest that when equivalent numbers of antigen‐specific naive and previously primed CD4+ responder T cells are compared, there is no difference in their potency to proliferate but only the previously activated subset can generate cytokines such as interferon‐γ.
Clonal expansion of T lymphocytes causes arthritis and mortality in mice infected with toxic shock syndrome toxin‐1‐producing staphylococci
Authors: Abdelnour Arturo , Bremell Tomas , Holmdahl Rikard , Tarkowski Andrzej 
Published: March 2007

AbstractErosive arthritis is a common and feared complication of staphylococcal infection. The reason(s) for the progressive course of the arthritis is unknown. It has been recently established that enterotoxins produced by Staphylococcus aureus display superantigen properties leading to stimulation of T cells carrying distinct T cell receptor Vβ elements. This finding provides a potential connection between staphylococcal exoproteins and endogenous immune mechanisms participating in the infectious process. We have recently described successful induction of infectious arthritis in mice after intravenous inoculation of a toxic shock syndrome toxin‐1 (TSST‐1)‐producing S. aureus LS‐1 strain. Using this model we have now found a clonal expansion of T cells expressing Vβ11+ T cell receptor in the synovial tissue of arthritic mice. The role of TSST‐1 as a superantigen inducing oligoclonal expansion was confirmed in an in vitro culture system. The expansion of Vβ11+ T cells proved to be of arthritogenic significance since mice genomically deleted of the Vβ11+ T cells did not develop arthritis and since pretreatment of healthy mice with anti‐CD4 or anti‐Vβ11 monoclonal antibodies inhibited arthritis. In addition, CD4+ and Vβ11+ T cells showed themselves to be of pathogenic significance in staphylococcal‐induced mortality, since mice depleted of such populations showed increased survival. We propose that in hematogenously spread S. aureus‐induced arthritis the TSST‐1‐dependent clonal expansion of CD4+ Vβ11+ T cells is a driving pathogenic force.
Structure of the T cell receptor in a TiαVβ2,αVβ8‐positive T cell line
Authors: Hou Xiaohong , Dietrich Jes , Kuhlmann Jan , Wegener Anne‐Marie K. , Geisler Carsten 
Published: March 2007

AbstractThe T cell receptor (TcR) is composed of at least six different polypeptide chains consisting of the clonotypic Ti heterodimer (Tiαβ or Tiγδ) and the noncovalently associated CD3 chains (CD3γδϵζ). The exact number of subunits constituting the TcR is still not known; however, it has been suggested that each TcR contains two Ti dimers. To gain insight into the structure of the TcR we constructed a TiαVβ2,αVβ8‐positive T cell line which expressed the endogenous human TiVβ8 and the transfected mouse TiVβ2 both in association with the endogenous Tiα and CD3 chains at the cell surface. Preclearing experiments with radioiodinated cell lysate prepared with digitonin lysis buffer demonstrated that depleting the lysate of TiαVβ8 by immunoprecipitation with anti‐Vβ8 monoclonal antibody (mAb) did not reduce the amount of TiαVβ2 in the lysate, and likewise, depleting the lysate of TiαVβ2 with anti‐Vβ2 mAb did not reduce the amount of TiαVβ8. Comodulation experiments showed that Vβ8 and Vβ2 did not comodulate with each other. Furthermore, functional tests demonstrated that TcR containing Vβ8 and TcR containing Vβ2 mediated transmembrane activation signals independently of each other. These data demonstrate that mouse Vβ2 and human Vβ8 were not expressed in the same TcR in agreement with a TcR model where each TcR contains only one Ti dimer.
Transforming growth factor‐β2 induces apoptosis of murine T cell clones without down‐regulating bcl‐2 mRNA expression
Authors: Weller Michael , Constam Daniel B. , Malipiero Ursula , Fontana Adriano 
Published: March 2007

AbstractTransforming growth factor‐β (TGFβ) is a potent immunosuppressive cytokine which inhibits the antigen (Ag)‐dependent expansion of T cells both in vitro and in vivo by mechanisms not well defined yet. Here we report that exposure of interleukin (IL)‐2‐dependent T cell lines to TGFβ2 results in apoptosis defined by morphology, nucleosomal size DNA fragmentation and in situ DNA end labeling. TGFβ2‐induced T cell apoptosis showed the following characteristics: (1) in contrast to the rapid evolution of apoptosis following IL‐2 deprivation, apoptosis of T cells triggered by TGFβ2 was delayed; (2) cycloheximide prevented TGFβ2‐induced apoptosis of CTLL‐2 but not of OVA‐7 T helper cells; (3) in contrast to apoptosis following IL‐2 deprivation, TGFβ2‐mediated T cell apoptosis was not associated with decreased expression of the proto‐oncogenes, bcl‐2 or c‐myc; (4) TGFβ2‐induced apoptosis was not restricted to IL‐2‐dependent T cell lines since the IL‐4‐dependent T cell line, CT.4S, as well as EL4 lymphoma cells, which grow independently of exogenous IL‐2, were also susceptible to TGFβ2‐mediated apoptosis. Taken together, these data may present a novel mechanism of TGFβ2‐mediated suppression of T cell expansion in response to Ag and IL‐2, the activation of the endogenous death program of apoptosis, which appears to operate independently of direct interactions of TGFβ2 with the IL‐2/IL‐2 receptor system.
The anti‐La response of a single MRL/Mp‐lpr/lpr mouse: Specificity for DNA and VH gene usage
Authors: Bloom Debra D. , Clair E. William St. , Pisetsky David S. , Clarke Stephen H. 
Published: March 2007

AbstractAutoantibodies to ribonucleoproteins (RNP) occur prominently in human systemic lupus erythematosus and murine lupus models. In previous studies we demonstrated a relationship in MRL/Mp‐lpr/lpr (MRL/lpr) mice between antibodies to Sm, an RNP autoantigen, and antibodies to DNA. Thus, many anti‐Sm monoclonals bound DNA and expressed the same V region genes as anti‐DNA. In addition, many had multiple VHCDR3 Arg residues suggestive of selection by DNA, and some had somatic mutations suggesting selection for mutant B cells by DNA. To determine whether autoantibodies to other RNP antigens are also associated with the anti‐DNA response, we have analyzed the response to the La RNP. Six anti‐La B cell hybridomas were generated from a single MRL/lpr mouse. Southern blot analysis of Ig V gene rearrangements and V gene sequences indicated two clonally related pairs, suggesting an oligoclonal response. Antibodies from all six hybridomas bound single‐stranded DNA, while antibodies from five hybridomas bound double‐stranded DNA. Two hybridomas expressed a VH7183 gene which is used by members of two previously reported anti‐DNA clones and two anti‐Sm/DNA clones of MRL/lpr origin. These data demonstrate an association between the anti‐La and anti‐DNA responses in MRL/lpr mice, suggesting that cross‐reactive anti‐RNP and anti‐DNA responses are a general feature of autoimmunity in this lupus model.
Decreased anti‐donor major histocompatibility complex class I and increased class II alloantibody response in allograft tolerance in adult rats
Authors: Cuturi Maria‐Cristina , Josien Régis , Cantarovich Diego , Bugeon Laurence , Anegon Ignacio , Menoret Séverine , Smit Helga , Douillard Patrice , Soulillou Jean‐Paul 
Published: March 2007

AbstractPermanent tolerance to allografts can be induced in adult rats by donor‐specific transfusions (DST) prior to transplantation. We have previously reported, in a model of heart allograft, the presence of a heavy leukocyte infiltrate, in the allograft which displayed a strong allospecific cytotoxicity when tested in vitro against donor cells, and a strong accumulation of mRNA for granzyme A and perforin in vivo. In contrast, there was a major decrease in the accumulation of mRNA for interleukin‐2 and interferon‐γ. These results suggested that the DST‐induced tolerance was associated with a decrease in type‐1 T helper (Th1) cell function. The major role of preformed antibodies in xeno and allorejection is clearly established. Nevertheless, the consequences of alloantibody production in acute rejection and tolerance induction remains to be elucidated. We here analyze the alloantibody response in rejecting and DST‐treated recipients. We show that, after transplantation, tolerant recipients, in contrast to rejecting ones, mount a low IgM alloresponse that switches to low IgG production. Detailed analysis of IgG alloantibodies in DST‐treated recipients revealed that their production decrease was not equally distributed. Whereas rejecting animals mounted a strong anti‐class I and II IgG alloantibody response, DST‐treated recipients produced anti‐class II and low titers of anti‐class I IgG alloantibodies. Furthermore, among IgG subclasses, tolerant recipients predominantly produced IgG2a, a profile which, in the rat, is compatible with a Th2‐controlled response. Finally, the passive transfer of immune serum from rejecting animals to DST‐treated recipients could abrogate the tolerance. We suggest that the absence of anti‐class I alloantibodies combined with preserved and/or increased anti‐class II production plays a major role in graft tolerance in this model. These results reinforced the role of alloantibodies in rejection and in induction of tolerance.
Properties of mouse CD40: Cellular distribution of CD40 and B cell activation by monoclonal anti‐mouse CD40 antibodies
Authors: Hasboldu Jhagvaral , Johnson‐Légeru Caroline , Atkinsu Chris J. , Clark Edward A. , Klaus Gerry G. B. 
Published: March 2007

AbstractWe describe here the derivation of a rat monoclonal antibody (mAb) against mouse CD40 (designated 3/23), which stains 45–50% of spleen cells of adult mice, approximately 90% of which are B cells. Interestingly, some 5–10% of both CD4+ and CD8+ T cells in the spleens of (some, but not all) adult, unimmunized mice are also CD40+, whereas CD40+ cells were not detectable in the thymus, even following collagenase digestion. Some 35–40% of lymphoid cells in the bone marrow of adult mice are CD40+ and virtually all of these are B220+, and hence of the B cell lineage: triple‐color flow cytometry showed that CD40 is expressed at low levels on some 30% of pre‐B cells, at intermediate levels on 80% of immature B cells and on essentially all mature B cells in the bone marrow. These results, therefore, suggest that in the mouse CD40 is expressed relatively late during the process of B cell differentiation. The mAb induced marked up‐regulation of major histocompatibility complex class II molecules, CD23 and B7.2 antigens on mature B cells. It also stimulated modest levels of DNA synthesis in mature B cells by itself: this was markedly enhanced by suboptimal concentrations of mitogenic (but not non‐mitogenic) anti‐μ and anti‐δ mAb, and moderately enhanced by co‐stimulation with interleukin‐4. Hyper‐cross‐linking of CD40 (using biotinylated mAb and avidin) also enhanced the proliferative response to anti‐CD40.
Insulin‐specific T cells are a predominant component of islet infiltrates in pre‐diabetic NOD mice
Authors: Wegmann Dale R. , Norbury‐Glaseru Mary , Danielf Dylan 
Published: March 2007

AbstractNumerous investigations have demonstrated that T cells are involved in destruction of β cells in the NOD mouse, a widely studied model of type I diabetes. In this report we describe a series of islet‐specific T cell lines established from islet‐infiltrating lymphocytes obtained from individual pre‐diabetic NOD mice as well as a large panel of clones derived from these lines. Proliferation assays indicated that these nominally islet‐specific lines responded vigorously to porcine insulin. Furthermore, of 40 islet‐specific clones derived from lines established from 12‐week‐old mice, 22 (55%) responded to insulin. A similar analysis of islet‐specific clones established from 7‐week‐old mice indicated that 2 of 14 (14%) were insulin specific. These findings demonstrate that insulin‐specific T cells can comprise a major portion of the spontaneously arising T cell response to islets in NOD mice.
Phosphate is essential for stimulation of Vγ9Vδ2 T lymphocytes by mycobacterial low molecular weight ligand
Authors: Schoel Bernd , Sprengeru Silvia , Kaufmannf Stefan H. E. 
Published: March 2007

AbstractT lymphocytes are divided into two subsets which express different T cell receptor heterodimers. In the peripheral blood of healthy individuals, the majority of T cells express the α/β T cell receptor (> 90%) while a minority have the γ/δ T cell receptor (< 10%). The γ/δ T cells of adults use preferentially the Vγ9Vδ2 chain combination. Although the stimulation requirements for γ/δ T lymphocytes are still undetermined, it has been reported that γ/δ T cells are not only stimulated, like α/β T cells, by conventional protein antigens and superantigens, but also by unusual ligands. Mycobacteria selectively stimulate Vγ9Vδ2 T cells, and a nonproteinacious low molecular weight fraction of 1–3 kDa has been identified as the tentative active component. Here, we confirm the nonproteinacious nature of this ligand, and show that it is comprised of unusual carbohydrate and phosphate. Importantly, cleavage of the terminal phosphate by alkaline phosphatase completely abrogates the stimulatory activity of the low molecular weight ligand for Vγ9Vδ2 T cells. Even mycobacterial whole lysate loses its stimulatory activity, for this T cell subset, after dephosphorylation with alkaline phosphatase. These findings identify phosphocarbohydrates as a novel molecular entity with selective stimlatory activity for a defined T cell subset.
Interleukin‐7 induces the association of phosphatidylinositol 3‐kinase with the α chain of the interleukin‐7 receptor
Authors: Venkitaraman Ashok R. , Cowling Rachel J. 
Published: March 2007

AbstractThe recently characterized receptor for interleukin (IL)‐7 (IL‐7R) includes a unique α chain as well as a common γ chain shared with the receptors for IL‐2 and IL‐4. Engagement of the IL‐7R activates the intracellular enzyme phosphatidylinositol (PtdIns) 3‐kinase but the mechanism of PtdIns 3‐kinase activation and the molecular basis of its interaction with IL‐7R are not known. Here we show that IL‐7 causes the 85‐kDa regulatory subunit of PtdIns 3‐kinase (p85), and PtdIns 3‐kinase activity, to associate with the IL‐7R. This interaction can be ascribed to ligand‐induced phosphorylation of a single Tyr residue in the receptor's unique α chain. Herbimycin A, a specific protein tyrosine kinase inhibitor, suppresses not only tyrosine phosphorylation of the IL‐7R but also its association with p85. A phosphopeptide corresponding to the sequence surrounding Tyr449 in the cytoplasmic tail of the IL‐7R α chain, but not its non‐phosphorylated analogue or phosphopeptides coincident with the sequences surrounding other α chain Tyr residues, efficiently competes out p85 binding. Replacement of Tyr449 with Phe results in a loss of p85 binding. Finally, soluble forms of the src homology 2 domains of p85, which bind directly to phosphotyrosyl peptides, specifically inhibit the association of p85 with the IL‐7R. Thus, PtdIns 3‐kinase recruitment occurs through a single, phosphotyrosine dependent recognition motif surrounding Tyr449 in the IL‐7R α chain. This motif corresponds to a canonical sequence for p85 binding, Tyr(P)‐X‐X‐Met. Since the closely related IL‐2R and IL‐4R also activate PtdIns 3‐kinase but are devoid of such canonical motifs, our results suggest that the mechanism by which IL‐7R recruits and activates PtdIns 3‐kinase differs fundamentally from that used by the other receptors. PtdIns 3‐kinase may, therefore, play a unique and important role in the biological response to IL‐7.
Moslecular and biological characterization of human 4‐1BB and its ligands
Authors: Alderson Mark R. , Smith Craig A. , Tough Teresa W. , Davis‐Smith Terri , Armitage Richard J. , Falk Ben , Roux Eileen , Baker Elizabeth , Sutherland Grant R. , Din Wenie S. , Goodwin Raymond G. 
Published: March 2007

Abstract4‐1BB was originally described as a cDNA expressed by activated murine T cells and subsequently demonstrated to encode a member of the tumor necrosis factor receptor family of integral membrane proteins. Recently, we identified and cloned a murine ligand for 4‐1BB (mu4‐1BB‐L) and demonstrated it to be a member of an emerging family of ligands with structural homology to tumor necrosis factor. To characterize further the role of 4‐1BB in the immune response we undertook to clone the human homologue of 4‐1BB‐L. However, attempts to isolate a cDNA encoding the human 4‐1BB‐L by cross‐hybridization with the murine cDNA were unsuccessful. Therefore we first utilized cross‐species hybridization to isolate a cDNA encoding human 4‐1BB (hu4‐1BB). A fusion protein consisting of the extracellular portion of hu4‐1BB coupled to the Fc region of human immunoglobulin G1 (hu4‐1BB.Fc) was then used to identify and clone a gene for human 4‐1BB‐L from an activated CD4+ T cell clone using a direct expression cloning strategy. Human 4‐1BB‐L shows 36% amino acid identity with its murine counterpart and maps to chromosome 19p13.3. Scatchard analysis demonstrated high‐affinity binding of hu4‐1BB.Fc to either native or recombinant human 4‐1BB‐L. Both monoclonal antibody to hu4‐1BB and cells transfected with hu4‐1BB‐L induced a strong proliferative response in mitogen co‐stimulated primary T cells. In contrast, ligation of 4‐1BB on T cell clones enhanced activation‐induced cell death when triggered by engagement of the TCR/xsCD3 complex.