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1. |
Multiple sites of post‐activation CD8+T cell disposal |
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European Journal of Immunology,
Volume 27,
Issue 3,
1997,
Page 577-583
Andreas Wack,
Paola Corbella,
Nicola Harker,
I. Nicholas Crispe,
Dimitris Kioussis,
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摘要:
AbstractAntigen‐triggered activation of T cells leads to a sequence of differentiation steps including up‐regulation of activation markers, blast formation, proliferation, delivery of effector functions, and ultimately apoptosis. It is still controversial in which anatomical site activation‐induced apoptosis and elimination of T cells occur. To address this question, we used mice transgenic for a T cell receptor (F5) specific for an influenza virus nucleoprotein peptide (NP68) presented on the major histocompatibility complex H‐2 Dbmolecule. Accumulation and apoptosis of T cells was studied using terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end‐labelingin situcombined with immunohistology after intraperitoneal injection of the cognate peptide into F5 mice which are wild type or deficient for Rag‐1. After 4 days of peptide treatment, large perivascular infiltrations of CD8+cells were observed in liver, lung, and kidney of F5 mice. CD8+cell numbers were also increased in skin and small intestine, but not in brain or heart muscle of peptide‐treated animals. The infiltrating CD8+cells show an increased percentage of apoptosis in liver, lung and, most strikingly, the kidney. These data suggest that in the F5 system, T cell disposal after activation occurs in a number of organs. Essentially identical findings were obtained in Rag‐1+/+and Rag‐1‐/‐F5 mice, suggesting that the deletion mechanism did not i
ISSN:0014-2980
DOI:10.1002/eji.1830270302
出版商:WILEY‐VCH Verlag GmbH
年代:1997
数据来源: WILEY
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2. |
Cleavage of the low‐affinity receptor for human IgE (CD23) by a mite cysteine protease: Nature of the cleaved fragment in relation to the structure and function of CD23 |
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European Journal of Immunology,
Volume 27,
Issue 3,
1997,
Page 584-588
Oliver Schulz,
Brian J. Sutton,
Rebecca L. Beavil,
Jianguo Shi,
Herb F. Sewell,
Hannah J. Gould,
Peter Laing,
Farouk Shakib,
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摘要:
AbstractDer pI, a cysteine protease representing a major allergen of the house dust miteDermatophagoides pteronyssinus, has recently been shown to cleave CD23 from the surface of cultured human B cells (RPMI 8866 B cell line). We have now undertaken a detailed investigation of CD23 cleavage byDer pI. We demonstrate thatDer pI cleaves CD23 at two sites (Ser155‐Ser156 and Glu298‐Ser299) to produce a 17‐kDa fragment containing the lectin domain and only part of the C‐terminal tail. No such effect was demonstrable with mouse CD23, a finding which was anticipated based on its lack of the cleavage sites identified on human CD23. Based on the cleavage pattern and the model of CD23, we propose a sequence of events leading to the liberation of the 17‐kDa soluble CD23 fragment. The biological significance of such cleavage is underlined by the demonstration thatDer pI‐treated B lymphocytes lose their ability to bind IgE, and that the 17‐kDa fragment (amino acids 156–298) contains the minimum structural requirement (amino acids 156–288) for binding to
ISSN:0014-2980
DOI:10.1002/eji.1830270303
出版商:WILEY‐VCH Verlag GmbH
年代:1997
数据来源: WILEY
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3. |
Antigen‐presenting cells pulsed with unfractionated tumor‐derived peptides are potent tumor vaccines |
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European Journal of Immunology,
Volume 27,
Issue 3,
1997,
Page 589-597
Smita K. Nair,
David Boczkowski,
David Snyder,
Eli Gilboa,
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摘要:
AbstractVaccination with peptides isolated from tumor cells circumvents the need for identifying specific tumor rejection antigens and extends the use of active immunotherapy to the majority of cancers where specific tumor antigens have not yet been identified. In this study, we examined the efficacy of tumor vaccines composed of unfractionated tumor peptides presented by antigen‐presenting cells (APC) to induce cytotoxic T lymphocyte (CTL) responses and tumor immunity. RMA‐S cells pulsed with peptides isolated from ovalbumin (OVA)‐expressing tumor cells were highly effective at inducing primary, OVA‐specific CTL responsesin vitroand priming CTL responsesin vivo.In addition, tumor peptide‐pulsed RMA‐S cells induced protective immunity in mice when challenged with OVA‐expressing tumor cells. To enhance the clinical relevance of these studies, cells pulsed with tumor peptides were evaluated in the poorly immunogenic, B16/F10.9 melanoma post‐surgical metastasis model. Treatment of tumor‐bearing mice with peptide‐pulsed RMA‐S cells or with adherent splenocytes (enriched for professional APC) caused a significant reduction in lung metastases. The antimetastatic effect of peptide‐pulsed splenocytes could be further enhanced by pretreating the cells with antisense oligonucleotides directed against the TAP‐2 gene which was previously shown to increase the density of specific peptide/MHC class I complexes and thereby improve the APC function of the treated cells (Nair et el.,J. Immunol.1996.156: 1772). This study suggests that APC loaded with unfractionated peptides derived from poorly immunogenic, highly metastatic tumor cells may represent a pot
ISSN:0014-2980
DOI:10.1002/eji.1830270304
出版商:WILEY‐VCH Verlag GmbH
年代:1997
数据来源: WILEY
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4. |
B7‐1‐dependent co‐stimulation results in qualitatively and quantitatively different responses by CD4+and CD8+T cells |
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European Journal of Immunology,
Volume 27,
Issue 3,
1997,
Page 598-608
Matthew J. Deeths,
Matthew F. Mescher,
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摘要:
AbstractTo characterize better the co‐stimulatory activity of native B7‐1 in the absence of other receptor/ligand interactions that might contribute to the response, B7‐1 was purified by monoclonal antibody (mAb) affinity chromatography. Immobilization of purified B7‐1 with anti‐T cell receptor (TCR) mAb on cell‐sized latex microspheres provided an effective stimulus for activation of both CD4+and CD8+T cells as measured by proliferation, development of effector function, and changes in motility and adhesion. The CD4+T cell response was prolonged and resulted in efficient interleukin‐2 production and clonal expansion. In contrast, CD8+responses were transient. Proliferation and clonal expansion peaked on days 3 and 4, coincident with maximal expression of lytic effector function, and the cells then died. These results demonstrate that B7‐1 mediated co‐stimulation is sufficient for the induction of effector function in both helper and cytotoxic T cell precursors, but suggest that B7‐1 co‐stimulation is not sufficient to sustain helper‐independent CD8+CTL responses. When the dose responses of CD4+and CD8+T cells to B7‐1 were compared, CD8+T cells were found to require higher densities of B7‐1 to attain an equivalent level of activation, suggesting that the level of expression of B7‐1 by APC may influence the development of helper or CTL responses. Finally, in contrast to results obtained by others with B7‐1 transfectants, purified B7‐1 did not provide co‐stimulation when presented on a sur
ISSN:0014-2980
DOI:10.1002/eji.1830270305
出版商:WILEY‐VCH Verlag GmbH
年代:1997
数据来源: WILEY
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5. |
Assembly of an abundant endogenous major histocompatibility complex class II/peptide complex in class II compartments |
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European Journal of Immunology,
Volume 27,
Issue 3,
1997,
Page 609-617
Stanislaw Morkowski,
Graça Raposo,
Monique Kleijmeer,
Hans J. Geuze,
Alexander Y. Rudensky,
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摘要:
AbstractTo identify the intracellular site(s) of formation of an endogenous class II/peptide complex in a human B cell line, we employed kinetic pulse‐chase labeling experiments followed by subcellular fractionation by Percoll density gradient centrifugation and immunogold labeling on ultrathin cryosections. For direct demonstration of assembly of such complexes, we used the monoclonal antibody YAe, which detects an endogenous complex of the mouse class II molecule I‐Abwith a 17‐amino acid peptide derived from the α chain of HLA‐DR (DRα52–68). We show that in human B lymphocytes, these class II/peptide complexes assemble and transiently accumulate in major histocompatibility complex class II‐enriched compartments before reaching the
ISSN:0014-2980
DOI:10.1002/eji.1830270306
出版商:WILEY‐VCH Verlag GmbH
年代:1997
数据来源: WILEY
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6. |
Dimerization of Fab fragments enables ready screening of phage antibodies that affect hepatocyte growth factor/scatter factor activity on target cells |
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European Journal of Immunology,
Volume 27,
Issue 3,
1997,
Page 618-623
Manuela Zaccolo,
Andrew P. Griffiths,
Terence D. Prospero,
Greg Winter,
Ermanno Gherardi,
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摘要:
AbstractA number of applications of antibodies in diagnosis and therapy require multivalent reagents either because of the polymeric nature of the antigens or because biological activity depends on an effect on the formation of homodimeric species. Here, we report a procedure for mass screening of phage‐derived monomeric antibody fragments that depend on valency for activity. As a model system, a set of 13 phage‐derived human Fab fragments were first selected against mouse and human recombinant hepatocyte growth factor/scatter factor (HGF/SF), a high molecular weight polypeptide growth factor related to the blood protease plasminogen and involved in development and cancer. These Fab fragments were subsequently screened for an effect on HGF/SF activity either as monomeric fragments or after dimerization with a monoclonal antibody (9E10) directed against a peptide tag on the fragments. Fab were identified that either inhibited or enhanced HGF/SF activity on target cell lines, but dimerization was required for this effect. The approach proposed should facilitate mass screening of phage‐derived antibody fragments that depend on multiple valency for act
ISSN:0014-2980
DOI:10.1002/eji.1830270307
出版商:WILEY‐VCH Verlag GmbH
年代:1997
数据来源: WILEY
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7. |
Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor‐α, but not interleukin‐10: Possible relevance to pathophysiology of rheumatoid arthritis |
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European Journal of Immunology,
Volume 27,
Issue 3,
1997,
Page 624-632
Mireille Sebbag,
Sarah L. Parry,
Fionula M. Brennan,
Marc Feldmann,
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摘要:
AbstractPrevious studies in the laboratory have shown that the pro‐inflammatory cytokine tumor necrosis factor (TNF)‐α plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The mechanisms involved in regulating monocyte/macrophage cytokine production are not yet fully understood, but are thought to involve both soluble factors and cell/cell contact with other cell types. We and others have previously demonstrated that T cells activated through the T cell receptor/CD3 complex induce monocyte TNF‐α production by contact‐mediated signals. In this report, we investigated further whether T cells activated by cytokines in the absence of T cell receptor stimulation also regulate monocyte cytokine production. T cells were activated in an antigen‐independent manner using the cytokines interleukin (IL)‐15 or IL‐2 alone, or in combination with IL‐6 and TNF‐α. Subsequently, T cells were fixed and incubated with monocytes. Fixed, cytokine‐stimulated T cells induced monocytes to secrete TNF‐α in a dose‐dependent manner, but did not induce secretion of IL‐10, a potent endogenous down‐regulator of TNF‐α and other pro‐inflammatory cytokines. Stimulation of monocyte TNF‐α was markedly inhibited when T cells were physically separated from monocytes within the tissue culture well, confirming that T cell contact is necessary. T cell acquisition of monocyte‐activating capacity was shown to be dependent on the period of cytokine stimulation, with T cells activated for 8 days more effective than T cells activated for shorter periods. Addition of interferon‐γ or granulocyte/macrophage colony‐stimulating factor to the T cell/monocyte cultures enhanced T cell induction of monocyte TNF‐α by threefold and ninefold, respectively. The results from this model of cognate interaction suggest that cytokine‐stimulated T cells, interacting with macrophages in the rheumatoid synovial membrane, may contribute to the continuous excessive production of TNF‐α observed in the RA joint, and to the imbalance of pro
ISSN:0014-2980
DOI:10.1002/eji.1830270308
出版商:WILEY‐VCH Verlag GmbH
年代:1997
数据来源: WILEY
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8. |
Interleukin‐7 activates human naive CD4+cells and primes for interleukin‐4 production |
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European Journal of Immunology,
Volume 27,
Issue 3,
1997,
Page 633-640
Louise M. C. Webb,
Brian M. Foxwell,
Marc Feldmann,
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摘要:
AbstractInterleukin (IL)‐4 is considered to be essential for T helper (Th)2 cell development, yet in areas of primary T cell activation, CD4+cells are its only source. This implies that other signals must drive the initial expression of IL‐4 production. The role of CD28 co‐stimulation in Th2 subset development has been described. However, in mice deficient for CD28, Th2 responses are diminished, but not abrogated. Cytokines produced within the lymphoid tissue,e.g.IL‐7, may be important in the primary activation of naive CD4+cells. We have found that human naive CD4+cells purified from umbilical cord blood express the IL‐7 receptor and respond vigorously to IL‐7 during primary stimulation. Naive CD4+cells grown in IL‐4, in the presence or absence of IL‐2, fail to produce Th2 cytokines upon restimulation. In contrast, IL‐7 induces development of a population of T cells that produce large amounts of IL‐4. Growth in IL‐7 also increases IL‐2‐induced production of interferon (IFN)‐γ and IL‐10 production. IL‐7‐induced IL‐4 production is not inhibited by neutralizing antibodies to IL‐4 on its receptor. This implies that IL‐7 acts directly to induce Th2 subset development and not by up‐regulating either production of IL‐4 during culture or expression of the IL‐4 receptor. Moreover, IL‐7 potentiates the effects of CD28 co‐stimulation on both naive CD4+cell proliferation and subsequent IL‐4 production. Following primary stimulation, CD4+cells lose expression of the IL‐7 receptor, resulting in IL‐7 unresponsiveness. This work reveals a novel role for IL‐7 in theprimaryactivation of CD4+cells. We propose that in conjunction with CD28 co‐stimulation, IL‐7 induces theinitialexpression of IL‐4 production and that IL‐4 acts subsequently to expa
ISSN:0014-2980
DOI:10.1002/eji.1830270309
出版商:WILEY‐VCH Verlag GmbH
年代:1997
数据来源: WILEY
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9. |
Prevention of experimental autoimmune uveoretinitis by monoclonal antibody to interleukin‐12 |
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European Journal of Immunology,
Volume 27,
Issue 3,
1997,
Page 641-646
Hidetoshi Yokoi,
Kazunori Kato,
Takeshi Kezuka,
Jun‐Ichi Sakai,
Masahiko Usui,
Hideo Yagita,
Ko Okumura,
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摘要:
AbstractExperimental autoimmune uveoretinitis (EAU) induced by immunization with interphotoreceptor retinoid‐binding protein (IRBP), a retinal self antigen, has been regarded to be a typical T helper type 1 (Th1)‐mediated inflammatory disease. In this study, we examined the effect of a neutralizing monoclonal antibody (mAb) to interleukin‐12 (IL‐12), which has been known to play a critical role in the Th1 differentiation, on the development of EAU. While 9 of 13 control mice developed EAU by the immunization with IRBP, none of 12 mice developed EAU when given anti‐IL‐12 mAb 1 day before immunization. These mice did not develop EAU even after a rechallenge with IRBP on day 30, indicating that a protective mechanism had been established by the anti‐IL‐12 treatment. The proliferative response of splenocytes to IRBPin vitrowas not significantly impaired, but the production of IL‐2 and IFN‐γ was greatly reduced by the anti‐IL‐12 treatment. Moreover, production of IL‐5 and expression of IL‐4 mRNA were increased by the anti‐IL‐12 treatment. Consistently, IgG2a anti‐IRBP serum antibodies were decreased and IgG1 were increased. Administration of a neutralizing anti‐IL‐4 mAb at the time of IRBP rechallenge reversed the protection established by the anti‐IL‐12 treatment at the primary immunization. These results indicate that the anti‐IL‐12 treatment at the IRBP priming not only prevented the development of pathogenic Th1 cells, but also induced suppressive Th2 cells that protect the animal
ISSN:0014-2980
DOI:10.1002/eji.1830270310
出版商:WILEY‐VCH Verlag GmbH
年代:1997
数据来源: WILEY
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10. |
Interferon‐γ and interleukin‐4 regulate T cell interleukin‐12 responsiveness through the differential modulation of high‐affinity interleukin‐12 receptor expression |
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European Journal of Immunology,
Volume 27,
Issue 3,
1997,
Page 647-652
Jared A. Gollob,
Hiroshi Kawasaki,
Jerome Ritz,
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摘要:
AbstractInterferon‐γ (IFN‐γ) and interleukin‐4 (IL‐4) are mutually antagonistic cytokines that stimulate CD4+T cells to develop into either Th1 or Th2 cells. One feature of Th2 differentiation in mice is the loss of IL‐12‐induced Jak2 and Stat4 activation, which is accompanied by the inability to produce IFN‐γ in response to IL‐12. In this report, we show that freshly isolated human T cells activated with phytohemagglutinin (PHA) in the presence of IL‐4 exhibit a greatly diminished response to IL‐12, whereas the IL‐12 response of T cells activated with PHA plus IFN‐γ is enhanced. Radiolabeled IL‐12 binding studies demonstrate that the impairment of T cell IL‐12 responsiveness by IL‐4 is associated with the down‐regulation of high‐affinity IL‐12 receptor expression. In contrast, the enhancement of IL‐12 responsiveness by IFN‐γ is associated with the up‐regulation of high‐affinity IL‐12 receptor expression. Through the use of a newly synthesized neutralizing antibody to the low‐affinity IL‐12 receptor β subunit (IL‐12Rβ), we show that neither IL‐4 nor IFN‐γ affect the expression of IL‐12Rβ, which we determine to be one of at least two low‐affinity subunits required for high‐affinity IL‐12 binding. These findings suggest that IL‐4 and IFN‐γ exert opposite effects on T cell IL‐12 responsiveness by differentially modulating the expression of low‐affinity IL‐12 receptor subunits that are distinct from IL‐12Rβ and required, together with IL‐12Rβ, for high‐affinity IL‐12 binding and IL‐12 responsiveness. This provides a basis for understanding the interplay between different cytokines at the level of cytokine recep
ISSN:0014-2980
DOI:10.1002/eji.1830270311
出版商:WILEY‐VCH Verlag GmbH
年代:1997
数据来源: WILEY
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