bluuebunny/crossref_metadata_2025_split huggingface dataset:
The cytoplasmic tail of the T cell receptor ζ chain is dispensable for antigen‐mediated T cell activation
Authors: Hermans Mirjam H. A. , Malissen Bernard 
Published: March 2007

AbstractThe T cell antigen receptor consists of an antigen‐binding αβ heterodimer and a group of invariant polypeptides denoted CD3‐γ, CD3‐δ, CD3‐εand CD3‐ζ. Whether antigen responsiveness is dependent on the expression of functional CD3‐ζ subunit remains controversial. Forinstance, transfection of a ζ− / n− variant of the 2B4.11. T cell hybridoma with mutated ζ cDNA that encoded a ζ protein truncated at residue 108, restored the surface expression of T cell antigen receptor complexes with, however, impaired antigen responsiveness [Frank, S. J., Niklinska, B. B., Orloff, D. G., Mercep, M., Ashwell, J. D. and Klausner, R. D., Science 1990. 249: 174.]. In marked contrast, BW5147 transfectants that expressed T cell antigen receptors devoid of functional ζ subunits were still able to trigger the production of interleukin‐2 in response to antigen [Wegener, A.‐M. K., Letourneur, E, Hoeveler, A., Brocker, T., Luton, F. and Malissen, B., Cell 1992. 68: 83.].To assess if the above discrepancies may have resulted from the use of different recipient T cells, we transfected a ζ/n‐deficient variant of 2B4.11 (MA5.8) with the very same truncated ζ cDNA we previously used in BW5147. Consistent with our initial observations in BW5147, the cytoplasmic tail of the ζ polypeptide was found dispensable for antigenic responsiveness. Furthermore, a difference between the two recipient T cells was detected when cells were challenged via the Thy‐1 and Ly‐6 molecules. Once expressed in MA5.8, but not in BW5147, T cell antigen receptor complexes devoid of functional ζ subunits were able to sustain activation initiated via Thy‐1 and Ly‐6 molecules.
Plasmodium berghei‐specific T cells respond to non‐processed sporozoites presented by B cells
Authors: Link Heidi T. , White Katherine , Krzych Urszula 
Published: March 2007

AbstractThe mechanism of malaria protective immunity induced by immunization with radiation‐attenuated Plasmodium sporozoites (SPZ) is only partially understood. For example, B and T cell responses specific for the circumsporozoite (CS) protein, a 46 kDa SPZ surface protein, have been characterized; however, events leading to SPZ‐specific T cell activation, i.e., processing and presentation of SPZ by antigen‐presenting cells have not been investigated. In the present study we describe the in vitro analysis of requirements for accessory cell function in the presentation of SPZ to SPZ‐immune T cells. The results establish that SPZ‐induced proliferative T cells are reactive to non‐processed SPZ presented by activated B cells and, thus, imply that the non‐processed form of the SPZ‐associated CS protein restricts the induction of the potential CS protein T cell repertoire.
Collaboration of helper and cytotoxic T lymphocytes
Authors: Stuhler Gemot , Walden Peter 
Published: March 2007

AbstractCytotoxic T lymphocytes are major effector cells in responses to viral infections and in allograft rejection and are implicated in many other immunological reactions. Efficient induction of cytotoxic activity in these cells in many but not all cases depends upon helper Tand antigen‐presenting cells so that at least three different cell types have to work together. Here we present an in vitro model for the helper T cell‐dependent induction of cytotoxic T lymphocytes which allows the investigation of the collaboration of helper and cytotoxic T cells. First results demonstrate that linkage of helper and killer epitopes on the surface of one antigen‐presenting cell is a prerequisite for productive interaction between the two T cells that results in induction of cytolytic activity. T helper 1 and T helper 2 cells are equally efficient. The crucial roles of interleukin‐2 and interferon‐y in this process were confirmed. Activated CD4 cells can influence cytotoxic T lymphocytes in such a way that they produce interferon‐y independent from recognition of cognate peptide. The possibility of direct T‐T contacts mediated by adhesion molecules that promote collaboration of the two cells is discussed.
B cells are anergic in transgenic mice that express IgM anti‐DNA antibodies
Authors: Tsao Betty P. , Chow Anne , Cheroutre Hilde , Song Yeong W. , McGrath Mary E. , Kronenberg Mitchell 
Published: March 2007

AbstractB lymphocytes in individuals with systemic lupus erythematosus (SLE) secrete pathogenic auto antibodies to DNA which cause clinical nephritis. (NZB x NZW) Fl (BW) female mice also secrete pathogenic anti‐DNA auto antibodies, and therefore are considered to be an animal model of SLE. The rearranged immunoglobulin (Ig) genes that encode an anti‐DNA antibody from a diseased BW mouse have been cloned, and transgenic (Tg) mice have been created by microinjection of these constructs into fertilized eggs from normal mice. As we reported previously, when the construct contains the Cγ2a heavy chain constant (CH) region, the mice spontaneously secrete anti‐DNA IgG and they develop mild nephritis. This demonstrated that the Ig encoded by the transgene is pathogenic. In contrast, here we report that when the construct contains the same anti‐DNA Ig variable (V) regions used previously, along with the Cμ region, the auto reactive B cells are rendered tolerant. Most B cells in the Tg mice express the μ transgene product on their surface, and rearrangement of endogenous light chain genes is partially suppressed. Furthermore, most hybridomas made from Tg B cells secrete IgM anti‐DNA. Despite this, the Tg mice have reduced levels of total serum Ig and they do not secrete anti‐DNA IgM either spontaneously or following immunization with DNA. We conclude that most B cells in the Tg mice have been rendered anergic. Anergy is however reversiblein vitro;lipopolysaccharide stimulation of Tg B cells leads to the production of a significant amount of IgM anti‐DNA antibody. The studies demonstrate that in this line of Tg mice on a normal mouse genetic background potentially pathogenic B cells that express a high‐affinity Ig specific for a natural autoantigen are subject to tolerance by induction of anergy.
Leukotriene B4 induces interleukin 5 generation from human T lymphocytes
Authors: Yamaoka Kunio A. , Kolb Jean‐Pierre 
Published: March 2007

AbstractLeukotriene B4 (LTB4) has been shown to affect several interleukin (IL)‐linked functions of human lymphocytes. In this study, we investigated whether LTB4 regulates IL‐5 generation from human T cells and subsequently modulates eosinophil functions. Preincubation of T cells with very low concentrations (10−12 to 10−8 M) of LTB4 induced concentration‐dependent IL‐5 production, the event occurring after the first 24 h of cultivation. However, direct action of LTB4 to IL‐5 generation is strictly dependent on a preincubation with appropriate concentration of LTB4. In contrast, the stereoisomer of LTB4,5S,12S‐dihydroxy‐6,8,10,14‐eicosatetraenoic acid showed no enhancement of IL‐5 production. IL‐5 released from LTB4‐primed T cells elicited sustained viability of mature eosinophils and reduced the content of eosinophil cationic protein in their crystalloid matrix by degranulation. These data suggest that LTB4 induces bioactive IL‐5 production from T cells and that the released IL‐5 modulates eosinophil functions which might play a crucial role in eosinophil‐linked allergic inflammatory process.
Elevation of cytosolic calcium is sufficient to induce growth inhibition in a B cell lymphoma
Authors: Muthukkumar Subramanian , Udhayakumar Venkatachalam , Bondada Subbarao 
Published: March 2007

AbstractRecently, we have described that anti‐IgM antibodies profoundly inhibited the growth of BKS‐2, an immature B cell lymphoma. In this report, we demonstrated that ionomycin alone at very low concentrations (20 nM) inhibited the growth of BKS‐2 cells completely. The levels of intracellular Ca2+ induced by the inhibitory concentrations of ionomycin were comparable to those in anti‐IgM‐treated cells. The growth inhibition caused by ionomycin was reversed by phorbol 12‐myristate 13‐acetate and lipopolysaccharide. In addition, the immunosuppressants, cyclosporin A and FK506 conferred significant protection from the negative signal induced by ionomycin. However, either cyclosporin A, FK506 or lipopolysaccharide was not found to have direct effect on ionomycin‐induced Ca2+ mobilization in BKS‐2 cells. Also, ionomycin augmented the anti‐IgM‐induced growth arrest in these cells. Furthermore, BKS‐2 cells that were exposed to anti‐IgM or ionomycin underwent apoptosis as characterized by DNA fragmentation. Thus, the characteristics of growth inhibition induced by ionomycin and anti‐IgM appeared to be similar in that phorbol 12‐myristate 13‐acetate, lipopolysaccharide, cyclosporin A and FK506 caused significant reversal from such negative signals and both ionomycin and anti‐IgM induced apoptosis in these cells. Altogether, these results showed that the elevation of intracellular Ca2+ alone was sufficient to inhibit the growth of some B lymphoma cells.
Nonspecific augmentation of lymph node T cells and I‐E‐independent selective deletion of VβbTl4+ T cells by Mtv‐2 in the DDD mouse
Authors: Nakano Hideki , Yoshimoto Takayuki , Kakiuchi Terutaka , Matsuzawa Akio 
Published: March 2007

AbstractDDD/1 (DDD) mice were characterized by marked paucity of T cells in lymph nodes (LN). In DDD‐Mtv‐2/Mtv‐2 (DDD‐Mtv‐2) congenics, T cells were 4‐ to 18‐fold increased depending on ages but B cells doubled at the most. Thymus weight also increased. In DDDfDDD‐Mtv‐2, DDD neonatally infected with Mtv‐2‐derived exogenous MMTV (MMTV‐2), neither LN cells nor thymus weight increased. The Vβ 5+ and Vβ 8+ Tcell contents in LN were practically the same among three strains. The Mtv‐2‐induced expansion of LN Tcells was polyclonal and appeared indigenous to DDD mice. Both Mtv‐2 and MMTV‐2 induced progressive age‐dependent deletion of Vβ 14+CD4+ LN cells. Mtv‐2 but not MMTV‐2 caused deletion of Vβ 14+CD8+ LN cells and mature Vβ 14+CD4+ thymocytes. Thus, Mtv‐2‐ and MMTV‐2‐induced Vβ 14+ T cell deletion may reflect intrathymic and peripheral elimination, respectively. The absence of I‐E gene expression in DDD indicates that Vβ 14+ T cell deletion advances independently of I‐E molecules in this experimental system.
Evidence for programmed cell death of self‐reactive γδ T cell receptor‐positive thymocytes
Authors: Dent Alexander L. , Matis Louis A. , Bluestone Jeffrey A. , Hedrick Stephen M. 
Published: March 2007

AbstractThe negative selection of T cells expressing the γδ T cell antigen receptor (γδ T cells) was studied using transgenic mice expressing a γδ receptor with specificity for an H‐2T‐linked class I major histocompatibility complex molecule from H‐2b mice. The potentially self‐reactive γδ thymocytes in H‐2b/d transgenic mice are larger and have lower levels of γδ T cell receptor expression than γδ thymocytes from H‐2d mice. H‐2b/d γδ thymocytes do not respond to H‐2b antigen‐presenting cells, and thus are inactive compared to H‐2d γδ thymocytes. However, the H‐2b/d γδ thymocyte population, but not the H‐2d γδ thymocyte population, undergoes a high rate of programmed cell death when placed in overnight culture. These observations constitute the first direct evidence that self‐reactive γδ thymocytes undergo programmed cell death. This in vitro programmed cell death of self‐reactive γδ thymocytes may reflect the clonal deletion process that results in a depletion of γδ T cells in the peripheral lymphoid organs of adult H‐2b/d mice. We also present evidence that self‐reactive γδ T cells, similarly to αβ T cells, undergo a lesser degree of clonal deletion in neonatal mice compared to adult mice.
In vivo administration of major histocompatibility complex class I‐specific peptides from influenza virus induces specific cytotoxic T cell hyporesponsiveness
Authors: Müllbacher Arno , Hla Ron Tha 
Published: March 2007

AbstractWe have been investigating the immunogenicity of two class I major histocompatibility complex‐specific peptides with a sequence derived from influenza virus nucleoprotein specific for Kd and one for Db. Peptide‐modified splenocytes are unable to immunize for a primary cytotoxic T (Tc) cell response in vivo, or secondary response in vitro. Peptide‐modified stimulator cells can boost virus‐primed splenocytes for a strong secondary response in vitro. Animals primed with syngeneic peptide‐modified splenocytes upon challenge with virus in vivo do not generate strong secondary Tc cell responses on day 3 after challenge in contrast to virus primed animals. Day 6 responses of virus‐challenged, peptide‐primed animals are reduced as compared to unprimed mice. This hyporesponsiveness is independent of CD8+ T cells in the priming population and can be elicited with tumor cell lines. The data are discussed in the framework of the two‐signal model of immune induction.
The G protein‐coupled receptor BLR1 is involved in murine B cell differentiation and is also expressed in neuronal tissues
Authors: Kaiser Edelgard , Förster Reinhold , Wolf Ingrid , Ebensperger Cecilia , Michael Kuehl W. , Lipp Martin 
Published: March 2007

AbstractThe BLR1 gene, isolated initially from Burkitt lymphoma cells (Eur. J. Immunol. 1992. 22:2795), encodes a G protein‐coupled receptor with significant relationship to receptors for chemokines (IL‐8, MIP‐1α) and neuropeptides. The murine homologue of human BLR1 was cloned and used to investigate its expression in vivo. Brl1‐specific transcripts are observed in secondary lymphatic organs and to a lesser extent in brain of adult mice but not in other tissues. RNA in situ hybridization localizes blr1 transcription to primary follicles and to the mantle zone of secondary follicles. SCID mice in which mature B cell development is severely impaired exhibit a strongly reduced level of blr1‐specific RNA in the spleen. The analysis of murine lymphoid tumor cell lines representing distinct stages of the B cell lineage reveals elevated expression of blr1 in B cell lymphomas but not in pre‐B lymphomas or plasmacytomas. Induction of differentiation of resting B cells by cytokines or mitogens down‐regulates expression of blr1. RNA in situ hybridization using brain sections of adult mice detects blr1 transcription in the granule and Purkinje cell layer of the cerebellum. Interestingly, the blr1 gene is also expressed during late embryogenesis in fetal liver and brain. In view of the remarkable expression pattern in the B cell lineage we suggest that murine BLR1 may represent a cytokine/neuropeptide receptor exerting regulatory functions on recirculating mature B lymphocytes.
Characterization of host CD4+ T lymphocytes in mice neonatally tolerized to alloantigens
Authors: Kramar Giulia , Aguado Teresa , Louis Jacques , Del Giudice Giuseppe , Lambert Paul‐Henri 
Published: March 2007

AbstractBALB/c mice injected at birth with semi‐allogeneic F1 spleen cells become tolerant to alloantigens as shown by their CTL unresponsiveness to the corresponding alloantigen and the persistence of donor F1 cells into the BALB/c host. Moreover, these mice develop a transient systemic lupus erythematosis‐like autoimmune syndrome characterized by splenomegaly, glomerulonephritis, thrombocytopenia and abnormal serological findings, such as several autoantibodies and IgG1 hypergammaglobulinemia. Recent studies done in our laboratory have shown that donor F1 B cells persisting in the host are responsible for the production of autoantibodies and must be activated in vivo by the host CD4+ T lymphocytes in a MHC class II‐restricted fashion. In the present work, we have focused our attention on the ability of splenic CD4+ T cells recovered at different periods from BALB/c mice injected at birth with (CBA/Ca × BALB. Ighb) Fl spleen cells to interact with and activate F1 semi‐allogeneic spleen cells in vitro. We show that (i) only CD4+ T cells from 2‐ and 3‐week‐old tolerant BALB/c mice preferentially produce IL‐4 and IL‐5 in response to a F1 semi‐allogeneic in vitro stimulation, (ii) CD4+ T cells purified from 3‐week‐old tolerant BALB/c mice are able to induce in vitro IgG and IgM production by F1 B cells. Taken together, these results strongly suggest that host CD4+ T cells, belonging to the TH2 subset progressively lose their reactivity towards the F1 semi‐allogeneic persistent B cells, reaching a state of unresponsiveness that correlates with the disappearance of serum autoantibodies and autoimmune pathology.
Protein tyrosine phosphorylation is mandatory for CD40‐mediated rescue of germinal center B cells from apoptosis
Authors: Knox Kirstine A. , Gordon John 
Published: March 2007

AbstractSpontaneous apoptosis in germinal center (GC) B cells can be arrested either by engaging cell surface immunoglobulin (Ig) with immobilized ligand or, more effectively, by treatment with soluble monoclonal antibody (mAb) directed against CD40. The present study examines the intracellular signal transduction pathways through which rescue from spontaneous apoptosis is engendered in GC B cells following ligation of surface CD40. Cross‐linking the surface CD40 of GC B cells with mAb consistently resulted in enhanced tyrosine phosphorylation on a number of distinct substrates: this process could be blocked, in a dose‐dependent fashion, by pre‐treating GC B cells with the selective protein tyrosine kinase(s) (PTK) inhibitor, herbimycin A. Moreover, the pattern of phosphorylation on tyrosine observed following treatment with anti‐CD40 was remarkably similar to that triggered by polyvalent anti‐Ig. By contrast, anti‐CD40 failed to stimulate the increase in inositol 1,4,5‐trisphosphate and cytosolic free calcium observed in both GC B cells and resting B lymphocytes following ligation of surface Ig. The involvement of the signaling pathways generated in the rescue of GC B cells from apoptosis was studied by using selective inhibitors of PTK and of extracellular and intracellular Ca2+. Pre‐incubation with the PTK inhibitor herbimycin A (5 μM) abrogated anti‐CD40‐mediated rescue of GC B cells from apoptosis, while genistein (40 μM) and the tyrphostins AG490 (10 μ M) and AG814 (25 μ M) significantly inhibited this process. Consistent with these results, herbimycin A (5 μM) abolished the expression of the 26 kDa bcl‐2 protooncogene product, which confers resistance to apoptosis, normally observed following culture with anti‐CD40. The Ca2+ chelators BAPTA and EGTA did not significantly affect CD40‐promoted rescue. Taken together, these results indicate that CD40 of GC B cells is coupled to functional PTK but not to the phosphatidylinositol signaling pathway and that tyrosine phosphorylation is mandatory for CD40‐mediated rescue of GC B cells from apoptosis.
Mitogenicity of anti‐Thy‐1 monoclonal antibodies attributable to an Fc‐dependent mechanism
Authors: Kummer Udo , Haunschild Jutta , Reisbach Gilbert , Delecluse Henri‐Jacques , Thierfelder Stefan 
Published: March 2007

AbstractWe analyzed the mechanism by which certain anti‐Thy‐1 monoclonal antibodies (mAb) activate T cells directly without additional stimuli. Using a panel of rat anti‐Thy‐1 antibodies which included more than 30 IgG2c mAb, we found that only the IgG2c isotype was able to induce a strong proliferative response in both resting T cells and a T cell lymphoma, suggesting that this form of T cell activation is isotype restricted and might be a consequence of a unique physico‐chemical property of the IgG2c heavy chain. Results from surface distribution studies of Thy‐1 molecules, following specific interactions with anti‐Thy‐1 antibodies of different isotypes, again showed that only IgG2c mAb formed Thy‐1 aggregates of high valence on the surface of a T cell lymphoma, and such clustering always evoked a biological response. This led us to propose that IgG2c mAb have the inherent tendency to self‐associate, probably through homophilic Fc‐Fc contacts, and that this feature renders anti‐Thy‐1 mAb mitogenic. To prove this, we set up cross‐inhibition studies with randomly selected mitogenic (IgG2c) and non‐mitogenic (IgG2b) anti‐Thy‐1 mAb. The results clearly demonstrated that IgG2c antibodies enhance their own binding, analogous to the new form of antibody binding that was recently demonstrated between murine IgG3 mAb and a multivalent antigen. Confirmation of this was also provided by IgG2c‐derived F(ab')2 fragments, which were unable to cause proliferation. Furthermore, masking the Fc part of cell‐bound IgG2c mAb with a monomeric and thus non‐aggregating IgG‐binding protein A‐derived fragment cancelled their mitogenic ability. Finally, induction of T cell proliferation appeared to be independent of cross‐linking via FcγR. The results support a model in which noncovalent intermolecular homophilic contacts of the Fc regions of the IgG2c isotype bring about effective aggregation of Thy‐1 molecules, thereby stimulating the mitotic apparatus of the cell.
Th1 clones that suppress IgG2ab specifically recognize an allopeptide determinant comprising residues 435–451 of γ2ab
Authors: Bartnes Kristian , Rekdal Øystein , Briand Jean‐Paul , Hannestad Kristian 
Published: March 2007

AbstractWe have previously reported that γ2ab/I‐Ad‐specific Th1 clones from BALB/c mice (γ2aa, H‐2d) mediated a long‐lasting, selective suppression of serum IgG2ab levels when transferred to newborn (BALB/c X B10.D2)F1 (γ2a/b, H‐2d) mice (Bartnes, K. and Hannestad, K. Eur. J. Immunol. 1991. 21: 2365). We here analyze the peptide specificity of hybridomas derived from two suppressive T cell clones. The shortest synthetic peptide with optimal antigenicity comprises γ2ab residues 435–451 (Kabat numbering). The determinant core encompasses the γ2ab 440–446 (KLRVQKS) sequence which contains an I‐Ad allele‐specific motif. Challenge with single amino acid‐substituted γ2ab 435–447 analogs revealed that residues K440, R442 and K445 which are shared by the autologous and allogeneic γ2a, as well as residues Q444 and S446 which represent allogeneic differences, are critical for recognition. We obtained evidence that K440, R442 and Q444 are epitope residues, while K445 and S446 contribute to anchoring of the peptide to I‐Ad. Amino acids located outside of the core also influence antigenicity, the most striking effect being a 340–870‐fold augmentation of potency when γ2ab 437–451 is extended by F436. IgG2ab required processing in order to stimulate the hybridomas. The data support the contention that the Th1 clones specific for Fc of γ2ab mediated IgG2ab suppression by cognate interaction with sIgG2ab+ B cells that presented a Cγ2ab peptide(s) derived from their endogenous Ig on major histocompatibility complex class II. The T cells cross‐reacted weakly with peptide 435–451 of the autologous γ2aa allotype. This opens the possibility that self‐peptides from Ig C regions can target B cells for regulatory interactions with autologous Th cells.
Complementarity‐determining region 2 is implicated in the binding of staphylococcal protein A to human immunoglobulin VHIII variable regions
Authors: Randen Ingrid , Potter Kathleen N. , Li Yucheng , Thompson Keith M. , Pascual Virginia , Fθrre Østein , Natvig Jacob B. , Donald Capra J. 
Published: March 2007

AbstractStaphylococcal protein A (SPA) has two distinct binding sites on human immunoglobulins. In addition to binding to the Fc region of most IgG molecules, an “alternative” binding site has been localized to the Fab region of human immunoglobulins encoded by heavy chain variable gene segments belonging to the VHIH family. Comparison of amino acid sequences of closely related SPA‐binding and ‐non‐binding proteins suggested that VHIII‐specific residues in the second complementarity‐determining region (CDR2) were likely responsible for SPA binding activity. Site‐directed mutagenesis of a single amino acid residue in CDR2 converted an IgM rheumatoid factor which did not bind SPA to an SPA binder. These findings, therefore, locate a critical site involved in SPA binding to the CDR2 of human immunoglobulins encoded by VHIII family gene segments.