bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of proliferation and differentiation during early T cell development by anti‐transferrin receptor antibody
Authors: Brekelmans Pieter , Van Soest Peter , Leenen Pieter J. M. , van Ewijk Willem 
Published: March 2007

AbstractProliferating cells require iron and, therefore, express the transferrin receptor (CD71) that mediates cellular iron uptake. Cycling thymocytes, which have the CD4−8−3−, CD4−8+3−, or CD4+8+3− phenotypes, also express CD71. The importance of CD71‐mediated iron uptake for proliferation and maturation of thymocytes was studied using fetal thymus organ cultures at day 14 of gestation and treating them for 7 days with a CD71 monoclonal antibody (mAb). The intracellular iron deficiency caused by this treatment, inhibits both proliferation and maturation of the thymocytes. Cell recovery was reduced by 60%, but cells still expanded tenfold during the culture. Remarkably, the final maturation of αβ T cells was completely blocked as no thymocytes with low or high CD3/αβTcR expression developed. Moreover, only few cells reached the CD4+8+3− stage of T cell development. CD4−8−3− thymocytes, however, as well as its CD44−25+ subset developed in normal numbers, suggesting that CD44−25+ CD4−8−3− cells, or their immediate progeny, were most vulnerable to CD71 mAb treatment. The development of γδ T cells, which also express CD71, was not affected in these cultures. This suggests that γδ T cells are either less iron‐dependent or possess alternative iron‐uptake mechanisms. Thus, our observations indicate that CD71 treatment, causing decreased intracellular iron levels, severely inhibits the major proliferation phase from the CD44−25+ CD4−8−3− to the CD4+8+3− cells, and completely abrogates the final maturation of CD4+8+3− cells into αβTcR‐expressing cells. In contrast, proliferation and differentiation of the earliest thymic precursors into CD44−25+ CD4−8−3− cells is not affected by CD71 treatment.
GM1, a ganglioside that specifically enhances immunoglobulin production and proliferation in human plasma cells
Authors: Kimata Hajime 
Published: March 2007

AbstractThe effects of gangliosides on human plasma cell responses were studied. Among the various gangliosides tested, only GM1 enhanced immunoglobulin (Ig) production and proliferation in the human plasma cell lines, IM‐9 and AF‐10, while other gangliosides (GM2, GM3, GD1a, GD1b, GD3, GT1b, and GQ1b) had no effect. Among the various cytokines tested, including interleukin (IL)‐1β, IL‐2, IL‐3, IL‐4, IL‐5, IL‐6, IL‐9, IL‐10, IL‐12, IL‐13, interferon (IFN)‐α and IFN‐γ, only IL‐6 enhanced Ig production and proliferation in IM‐9 and AF‐10 cells. However, the enhancement of plasma cell responses by GM1 was specific and was not mediated by IL‐6, since GM1 activity was blocked by anti‐GM1 monoclonal antibody (mAb), but not by control IgM, anti‐IL‐6 Ab or the anti‐IL‐6 receptor mAb, PM1. Conversely, the enhancement by IL‐6 was blocked by anti‐IL‐6 Ab and PM1, but not by anti‐GM1 mAb. GM1, but not other gangliosides, also enhanced Ig production and proliferation in freshly separated plasma cells from patients with plasma cell leukemia and in plasma cells generated in vitro. These actions of GM1 were specifically blocked by anti‐GM1 mAb, but not by anti‐IL‐6 Ab or PM1. These results indicate that GM1 may be an important regulator of plasma cell responses.
Ionizing radiation induces apoptotic cell death in human TcR‐γ/δ+ T and natural killer cells without detectable p53 protein
Authors: Seki Hidetoshi , Kanegane Hirokazu , Iwai Kazuyuki , Konno Akihiro , Ohta Kunio , Yachie Akihiro , Taniguchi Noboru , Miyawaki Toshio 
Published: March 2007

AbstractThe p53 tumor suppressor gene has been shown to be involved in programmed cell death, apoptosis, in murine immature thymocytes after treatment with ionizing radiation. Ionizing radiation also induces apoptosis in peripheral mature lymphocytes. In this work, we investigated the p53 participation in radiation‐induced apoptosis in human peripheral blood lymphocytes (PBL) subpopulations. Exposure to γ‐irradiation resulted in an appreciable induction of apoptotic cell death in TcR‐α/β+ (CD4+ and CD8+) T cells, TcR‐γ/δ+ T cells, B cells and natural killer (NK) cells, as assessed by DNA fragmentation as well as the morphological characteristics. Importantly, it was found that there was a marked difference among PBL subpopulations as regards the induction of p53 protein by γ‐irradiation. Similar to previous observations for murine thymocytes, p53 induction in TcR‐α/β+ T cells and B cells after γ‐irradiation was evident by Western blot analysis. Radiation‐induced apoptosis in TcR‐α/β+ T cells and B cells was efficiently inhibited by cycloheximide, indicating the requirement of de novo protein synthesis, including p53 protein, for radiation‐induced apoptosis in both subpopulations. In marked contrast, no identifiable levels of p53 protein were induced in either TcR‐γ/δ+ T or NK cells after γ‐irradiation. In addition, it was demonstrated that radiation‐induced cell death in TcR‐γ/δ+ T and NK cells could be prevented by interleukin‐2, but not by cycloheximide. These results imply that radiation‐induced lymphocytic apoptosis can be mediated by p53‐dependent or ‐independent mechanisms.
Deletion of CD4+ T cells and thymocytes by apoptosis in mouse mammary tumor virus (C4)‐infected Vβ2 transgenic mice
Authors: Wang Hong , Gill Randall F. , Lichlyter Darcy , Iglesias Antonio , Bluethmann Horst , Wei Wei‐Zen 
Published: March 2007

AbstractMouse mammary tumor virus MMTV(C4) encodes a Vβ2‐specific superantigen. In Vβ2 transgenic (TG2) mice more than 98 % of peripheral T cells express Vβ2. Infection of Tg2 mice with MMTV(C4) at birth through their mothers' milk or at 6–8 weeks of age by intravenous injection resulted in massive deletion of peripheral CD4+ T cells and suppressed thymopoiesis. The number of peripheral CD8+ T cells was not affected in neonatally infected mice. In older mice injected with MMTV(C4), splenic CD8+ T cells were significantly elevated. Suppressed thymopoiesis was observed in both neonatally infected and older mice injected with MMTV(C4). Thymocytes which expressed high level CD3 or Vβ2 were deleted. To determine if T cells or thymocytes were deleted through apoptosis, DNA fragmentation was examined by flow cytometry and diphenylamine (DPA) binding assay. Approximately 31 % of CD4+ T cells from MMTV(C4)‐infected Tg2 mice as compared to 6% from normal Tg2 mice contained fragmented nuclear DNA by flow‐cytometric analysis. The DPA binding assay showed significantly increased total soluble DNA in lymph node cells and thymocytes from MMTV(C4)‐infected mice. The kinetics of T cell and thymocyte apoptosis correspond to their deletion, supporting apoptosis as the mechanism of T cell and thymocyte deletion. CD4+ T cell and thymocyte deletion by MMTV(C4) in Tg2 mice provides a sensitive system for the analysis of retrovirus superantigen‐induced apoptosis.
Stimulated natural killer cells secrete factors with chemotactic activity, including NAP‐1/IL‐8, which supports VLA‐4‐ and VLA‐5‐mediated migration of T lymphocytes
Authors: Somersalo Kristina , Carpén Olli , Saksela Eero 
Published: March 2007

AbstractIn vivo, natural killer (NK) cells dominate among the early invading cells in allografts and virus‐infected tissues, and they are followed later by an influx of T cells. The same sequence of events was seen in our modified Boyden chamber assay. The migration of both CD3+/CD4+ and CD3+/CD8+ cells through fibronectin‐coated filters increased after co‐culture with NK cells. The migratory response to a soluble factor from NK cells supernatants was predominantly chemotactic rather than chemokinetic. Endogenous NK cells, purified in the presence of human serum albumin, did not induce T cell chemotaxis, but NK cells which were purified in the presence of 10% fetal calf serum (FCS), or which were activated in the absence of FCS with 10−4 M histamine, with 300 IU/ml interleukin (IL)‐2, or with a combination of 10 IU/ml IL‐2 and 10 μg/ml CD16 monoclonal antibody increased T cell migration by 30–70%. Both the random and chemotactic migration were dependent on fibronectin receptors VLA‐4 and VLA‐5 on T cells. About 60% of the chemotactic was neutralized by NAP‐1/IL‐8 polyclonal antibody. Northern blot analysis revealed IL‐8 mRNA expression in highly purified, stimulated NK cells; dimeric IL‐8 protein secreted by NK cells was detected by immunoblotting, and, in immunofluorescence staining IL‐8 was visualized in NK cells. These observations suggest that NK cells, early invaders in the foci of injury, participate in the initiation of a specific immune response by facilitating T cell recruitment.
T helper cell unresponsiveness: Rapid induction in antigen‐transgenic and reversion in non‐transgenic mice
Authors: Bachmann Martin F. , Rohrer Urs Hoffmann , Steinhoff Ulrich , Bürki Kurt , Skuntz Susan , Arnheiter Heinz , Hengartner Hans , Zinkernagel Rolf M. 
Published: March 2007

AbstractT cell tolerance is usually established by clonal deletion of self‐specific T cells in the thymus, or some times, in the periphery. Alternatively, tolerance may also be achieved by induction of clonal T cell unresponsiveness by a poorly understood mechanism called “anergy”. We found that transgenic mice expressing a soluble form of vesicular stomatitis virus (VSV) glycoprotein (G) predominantly in liver and kidney exhibited normal B cell responses. VSV‐G‐specific T help‐independent neutralizing IgM responses were within normal ranges, but no T help‐dependent neutralizing IgG antibodies were generated upon immunization with recombinant VSV‐G protein and recombinant vaccinia virus expressing VSV‐G. This demonstrated absence of B cell tolerance but presence of T helper cell unresponsiveness. After adoptive transfer of transgenic spleen cells into thymectomized immuno‐incompetent hosts, the unresponsive T helper cells regained function and switched the neutralizing IgM response to IgG, comparably to control T helper cells, within 7 days. Conversely, when naive non‐transgenic spleen cells were transferred into transgenic mice, VSV‐G‐specific T helper cells became unresponsive within 3–4 days. These results suggest that VSV‐G‐specific T helper cells are rendered unresponsive within a few days in the VSV‐G transgenic host also outside of the thymus and that this unresponsiveness was reversed by transfer into antigen‐free recipients.
Shared amino acid sequences in the NDβN and Nα regions of the T cell receptors of tumor‐infiltrating lymphocytes within malignant glioma
Authors: Ebato Michimasa , Nitta Taizo , Yagita Hideo , Sato Kiyoshi , Okumura Ko 
Published: March 2007

AbstractThe purpose of this study was to assess the V‐(D)‐J junctional region of the T cell receptor (TCR), the CDR3 region, which is responsible for glioma‐specific antigen contact in αβ TCR‐mediated recognition. We sequenced the TCR α and β chians of Vα7, and Vβ13.1 cDNA derived from tumor‐infiltrating lymphocytes (TIL) of 12 glioma patients and also the corresponding clones from the patients' peripheral blood lymphocytes (PBL). A shared Vβ13.1 DJ sequence of the CDR3 region, NDβN, was demonstrated in 49 of 66 Vβ13.1+ clones (74.2 %) from the glioma TIL, whereas only 4 of 33 clones (12.1 %) were observed in the Vβ13.1+ clones from the PBL (p < 0.001). A common VDJ sequence, FCASS (Vβ13.1)‐YRLPWGTSDS (NDβN)‐GELFF(Jβ2.2), was observed not only in the gliomas from each patient, but also among all the patients with a preference for Vβ13.1. In contrast, the amino acid sequences of the Vβ13.1+ PBL clones were diverse and random. Next, we sequenced subclones from other Vβ subfamilies randomly selected to compare their VDJ region rearrangements (Vβ3 and Vβ5.1). In contrast to Vβ13.1, the amino acid sequences of these junctional regions were completely different in these subclones. The V‐J junctional region of the α chain is dominated by a few clones in some patients, and no shared amino acid sequences were detected in the TCR Vα junctional region. However, in the Nα region of the Vα7‐bearing TIL clones, arginine was used in 27 of 44 clones (61.4%) compared to only 3 of 12 clones from the PBL (p < 0.05). These results are consistent with the hypothesis that a clonal expansion/accumulation of glioma lineage‐specific T cells occurred in vivo at the tumor site and that these T cells may be recognizing glioma‐specific antigens.
Co‐stimulation by anti‐immunoglobulin is required for B cell activation by CD40Llow T cells
Authors: Poudrier Johanne , Owens Trevor 
Published: March 2007

AbstractDuring cognate B : T interactions, B cells encounter antigen (Ag) through surface immuno‐globulin (sIg) and present antigenic peptides to T helper (Th) cells. However, most in vitro systems used to study contact events involved in the delivery of T help for B cells circumvent the requirement for T cell Ag specificity by using anti‐CD3/T cell receptor (TcR) monoclonal antibodies (mAb) to activate T cells. To study the role of sIg engagement in the responsiveness of B cells to T help, we pre‐treated small resting B cells with soluble anti‐χ mAb prior to contact with an activated Th1 clone. By reducing the concentration of anti‐TcR mAb we obtained low levels of CD40 ligand (CD40Llow) on Th cells, comparable to those expressed by lymph node T cells activated in vitro (ex vivo T cells). In contrast to untreated B cells, which did not respond to CD40Llow Th, anti‐Ig‐treated B cells responded strongly. Low buoyant density B cells also responded to CD40Llow Th cells. There was no B cell response to resting Th cells. mAb against CD54/intercellular adhesion molecule‐1 or major histocompatibility complex (MHC) class II completely inhibited B cell responses to CD40Llow Th1 cells, equivalent to the effects of blocking CD40 interactions. This contrasts with mAb blocking responses to CD40LhighTh, where CD40 effects predominate. Our data show that sIg engagement is necessary for the induction of B cell response to CD40Llow Th cells. Anti‐CD3‐activated ex vivo T cells that were also CD40Llow did not provide help to small resting B cells, but did induce responses from sIg‐stimulated B cells. Thus, our data support a requirement for sIg signaling in physiological B cell activation, and further confirm previous work showing CD40 ligation to be necessary but not sufficient for delivery of T help to B cells.
Activation‐induced proteolysis of the cytoplasmic domain of ζ in T cell receptors and Fc receptors
Authors: Taupin Jean‐Luc , Anderson Paul 
Published: March 2007

AbstractThe CD3‐T cell receptor (TCR) complex on T cells and the Fcγ receptor type III (FcγRIII)‐ζ‐γ complex on natural killer cells are functionally analogous activation receptors that associate with a family of disulfide‐linked dimers composed of the related subunits ζ and γ. Immunochemical analysis of receptor complexes separated on two‐dimensional diagonal gels allowed the identification of a previously uncharacterized ζ‐p14 heterodimer. ζ‐p14 is a component of both CD3‐TCR and FcγRIII‐ζ‐γ. Peptide mapping analysis shows that p14 is structurally related to ζ, suggesting that it is either: (i) derived from ζ proteolytically or (ii) the product of an alternatively spliced mRNA. The observation that COS cells transformed with a cDNA encoding ζ express ζ‐p14 supports the former possibility. The expression of CD3‐TCR complexes including ζ‐p14 increases following activation with phorbol 12‐myristate 13‐acetate or concanavalin A, suggesting that proteolysis of ζ may contribute to receptor modulation or desensitization.
Maternal immunization modulates the primary immune response to 2‐phenyl‐oxazolone in BALB/c mice
Authors: Lemke Hilmar , Lange Hans , Berek Claudia 
Published: March 2007

AbstractThe development of the antibody repertoire in newborn mice is greatly influenced by idiotypic network interactions. It has been demonstrated that anti‐idiotypic antibodies either directly injected or transferred from the mother may alter the repertoire for life. For an elucidation of the underlying mechanisms we have analyzed the primary immune response to 2‐phenyl‐5‐oxazolone (phOx) coupled to chicken serum albumin (CSA) in BALB/c mice after complete disappearance of maternal antibodies which originated from different stages of affinity maturation. Depending on the serum titers of the mothers after primary (1° mo), secondary (2° mo) or tertiary (3° mo) immunization, maternal anti‐phOx IgG persisted in F1 mice for up to 9 months. In addition, F1 mice born to 2° mo developed – even without immunization – an anti‐phOx IgM titer which reached levels similar to an antigen‐induced primary response. An enhancement of the early primary anti‐phOx as well as anti‐CSA response was seen in F1 mice born from 1° mo, whereas the response was delayed when born to 2° mo and 3° mo. The antibody titers in the latter group of mice remained at a lower level for 3 months. In contrast, mice of the F2 generation which received a smaller amount of the same collection of maternal antibodies as F1 mice from 3° mo exhibited a quite different primary response: (i) They showed an earlier onset in their anti‐CSA response. (ii) Whereas normally a plateau in antibody titer was reached by the 4th weak after immunization, in 55 % of the F2 mice a prolonged increase of the anti‐phOx and anti‐CSA antibody titers was observed. At 12 weeks after antigenic challenge, titers reached plateau levels of 6 × 105 which were never before seen in a primary phOx or CSA response. Thus, depending on its own immunological experience, the maternal immune system induces a state of memory in the offspring which results in a faster and/or enhanced immune response in the F1 and F3 generations.
CD8+ T cell‐mediated protection against an intracellular bacterium by perforin‐dependent cytotoxicity
Authors: Kägi David , Ledermann Birgit , Bürki Kurt , Hengartner Hans , Zinkernagel Rolf M. 
Published: March 2007

AbstractGrowth of Listeria monocytogenes is mainly controlled by macrophages, which are activated by specific T cells. A potential role of CD8+ T cells by direct lysis of infected cells was investigated in perforin‐deficient mice generated by homologous recombination. The absence of perforin‐mediated cytotoxicity resulted in delayed clearance of Listeria from the spleen but not the liver after primary infection, overall susceptibility to Listeria however was not increased. Protection against a secondary infection was drastically impaired in perforin‐deficient mice. Adoptive transfer of immune spleen cells to recipients revealed that anti‐Listeria protection by CD8+ T cells from perforin‐deficient versus normal mice was about 10‐fold reduced in livers and about 100‐fold reduced in the spleen of recipients. CD4+ T cells from immune control and perforin‐deficient mice conferred comparable protection. These results indicate that the protective effect of CD8+ T cells against an intracellular bacterium mainly evident in secondary infection is mediated by a perforin‐dependent pathway, presumably cytotoxicity, and less by other direct or indirect effector mechanisms.
Interleukin‐2 induces tyrosine phosphorylation and nuclear translocation of stat3 in human T lymphocytes
Authors: Nielsen Mette , Svejgaard Arne , Skov Søren , Ødum Niels 
Published: March 2007

AbstractAn early biochemical event associated with T cell activation through the interleukin‐2 receptor (IL‐2R) is tyrosine phosphorylation of several intracellular substrates. The exact mechanism by which IL‐2 regulates transcription of different genes is presently unknown. Here, we report that stimulation through the IL‐2R induced tyrosine phosphorylation and subsequent nuclear translocation of stat3, a newly identified member of the signal transducers and activators of transcription (STAT) family of proteins. In contrast, stat1 proteins were not tyrosine phosphorylated after IL‐2 ligation, whereas tyrosine‐phosphorylated stat1 proteins (91 and 84 kDa proteins) were translocated to the nucleus following interferon‐γ treatment of HeLa cells.Apart from stat3, another cytoplasmic protein was tyrosine phosphorylated and subsequently translocated to the nucleus in response to IL‐2. This protein had an apparent molecular mass of 84 kDa and was not recognized by stat3 or stat1 mAb or antisera. Since IL‐2 induced nuclear translocation of the 84 kDa protein and stat3 followed identical kinetics, p84 is a candidate for a new, yet undefined, member of the STAT family. Taken together, we report that IL‐2 induces tyrosine phosphorylation and subsequent nuclear translocation of stat3 and an as yet undefined 84‐kDa protein in antigen‐specific human T cell lines.
T lymphocyte‐mediated antiviral immune responses in mice are diminished by treatment with monoclonal antibody directed against the interleukin‐2 receptor
Authors: Utermöhlen Olaf , Tárnok Attila , Bönig Lutz , Lehmann‐Grube Fritz 
Published: March 2007

AbstractBlocking the interleukin‐2 receptor's α‐chain in lymphocytic choriomeningitis virus‐infected mice by treatment with monoclonal antibodies diminished the increase of numbers of CD8+ T lymphocytes in spleens and prevented CD8+ T lymphocyte‐mediated virus clearance from organs as well as generation of virus‐specific cytotoxic T lymphocytes. Also, the CD8+ T cell‐mediated early phase of the delayed‐type hypersensitivity footpad swelling reaction was decreased. The same treatment had no effect on the number of CD4+ spleen T lymphocytes, which, however, did not enlarge during infection, but these cells' heightened DNA synthesis and cytokine production were reduced by antibody treatment; yet the generation of antiviral antibodies remained unaffected, and the CD4+ T lymphocyte‐mediated second part of the footpad reaction was somewhat augmented. We conclude that blocking of the interleukin‐2 receptor by antibody in lymphocytic choriomeningitis virus‐infected mice diminishes both CD8+ and CD4+ T cell‐mediated antiviral immune responses, the former more than the latter.
Expression of Bruton's tyrosine kinase protein within the B cell lineage
Authors: Genevier Helen C. , Hinshelwood Steve , Gaspar Hubert B. , Rigley Kevin P. , Brown Derek , Saeland Sem , Rousset Francoise , Levinsky Roland J. , Callard Robin E. , Kinnon Christine , Lovering Ruth C. 
Published: March 2007

AbstractDefects in the gene encoding Bruton's tyrosine kinase (Btk), normally expressed in B cells, cause X‐linked agammaglobulinemia (XLA). The phenotype of XLA is characterized by a lack of circulating B cells and immunoglobulin. It has been suggested that B cell maturation from the pre‐B cell stage to more mature stages is dependent on the appropriate expression of this gene. The Btk mRNA is expressed in B cells and myeloid cells, but protein expression in relation to B cell maturation has not been determined. Moreover, expression of the Btk protein has so far only been investigated in human Epstein‐Barr virus‐transformed B cell lines, and in murine splenocytes and B cell lines. We have developed an antiserum which recognizes the human Btk protein and shown that normal human tonsillar B cells, peripheral blood monocytes and myeloid cells express the protein, whereas tonsil‐derived T cells do not. We also show that the protein is present in early and mature human B cell lines, but is absent in terminally differentiated plasma cell lines. Furthermore, expression is reduced or absent in three B lineage cell lines derived from two patients with defined genetic mutations in Btk and suffering from XLA.