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T cell tolerance to Mlsa encoded antigens in T cell receptor V beta 8.1 chain transgenic mice. 总被引:15,自引:3,他引:12
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H Pircher T W Mak R Lang W Ballhausen E Rüedi H Hengartner R M Zinkernagel K Bürki 《The EMBO journal》1989,8(3):719-727
To study T cell tolerance, transgenic mice were generated that expressed the Mlsa-reactive T cell receptor (TCR) beta chain V beta 8.1 (cDNA) under the control of the H-2Kb promoter/immunoglobulin heavy chain enhancer on approximately 90% of peripheral T cells. In transgenic mice bearing Mlsa, thymocytes expressing the TCR at a high density were deleted and the percentage of Thy 1.2+ lymph node cells was reduced. The CD4/CD8 ratio of mature T cells was reversed in Mlsa and Mlsb transgenic mice independent of the H-2. RNA analysis and immunofluorescence with TCR V beta-specific antibodies revealed that expression of endogenous TCR beta genes was suppressed. Both Mlsa and Mlsb TCR beta chain transgenic mice mounted a T-cell-dependent IgG response against viral antigens, whereas the capacity to generate alloreactive and virus-specific cytotoxic T cells was impaired in TCR beta chain transgenic Mlsa, but not in transgenic Mlsb mice. 相似文献
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Cutting edge: CCR7+ and CCR7- memory T cells do not differ in immediate effector cell function 总被引:10,自引:0,他引:10
Unsoeld H Krautwald S Voehringer D Kunzendorf U Pircher H 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(2):638-641
It has been proposed that expression of the chemokine receptor CCR7 represents a defining factor for nonpolarized central (CCR7(+)) and polarized effector memory (CCR7(-)) T cells. In this study, we have tested this hypothesis using in vivo-activated T cells from P14 and SMARTA TCR-transgenic (tg) mice specific for MHC class I- and II-restricted epitopes of the lymphocytic choriomeningitis virus (LCMV) glycoprotein. CCR7 cell surface expression on TCR-tg cells was monitored with a CC chemokine ligand 19-Ig fusion protein. CC chemokine ligand 19-Ig staining separated TCR-tg cells activated by LCMV infection into CCR7(-) and CCR7(+) effector/memory T cell populations. Nonetheless, both T cell populations isolated from spleen and liver produced identical amounts of IFN-gamma after short-term Ag stimulation. Furthermore, CCR7(+) and CCR7(-) CD8 TCR-tg cells from LCMV-infected mice exhibited similar lytic activity against LCMV peptide-coated target cells. These results question the proposed concept of differential effector cell function of CCR7(+) and CCR7(-) memory T cells. 相似文献
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CD40 ligation in the presence of self-reactive CD8 T cells leads to severe immunopathology 总被引:2,自引:0,他引:2
Roth E Schwartzkopff J Pircher H 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(10):5124-5129
Previous work has shown that stimulation of APCs via CD40 strongly influences the outcome of a CD8 T cell response. In this study, we examined the effect of CD40 ligation on peripheral tolerance induction of self-reactive CD8 T cells in an adoptive transfer model. Naive CD8 T cells from TCR-transgenic (tg) mice specific for the gp33 epitope of lymphocytic choriomeningitis virus were tolerized when transferred into H8-tg mice expressing the gp33 epitope under the control of a MHC class I promoter. However, if the H8 recipient mice were treated with agonistic anti-CD40 Abs, TCR-tg cells vigorously proliferated, and induced destruction of lymphoid organs and hepatitis. Break of peripheral tolerance induction was B cell independent and did not require CD28/B7 interactions. These findings provide further in vivo evidence for the crucial role of the activation state of the APC in peripheral tolerance induction and suggest the need for caution in systemically activating APC via CD40 ligation in the presence of self-reactive T cells. 相似文献
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Prévost-Blondel A Roth E Rosenthal FM Pircher H 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(7):3645-3651
The role of perforin, IFN-gamma, and TNF-alpha in anti-tumor CD8 T cell immunity was examined in a new tumor model using a CD8 T cell epitope (GP33) derived from lymphocytic choriomeningitis virus as a tumor-associated Ag. In contrast with parental 3LL-A9 (A9) Lewis lung carcinoma cells that progressively grow in C57BL/6 mice, s.c. injection of GP33-transfected A9GP33 tumor cells induced a protective GP33-specific CD8 T cell response that led to complete tumor cell elimination. Tumor regression was dependent on perforin, IFN-gamma, or TNF-alpha, because A9GP33 tumors developed in mice deficient in one of these genes. A9GP33 tumors arising in perforin- and IFN-gamma-deficient mice represented GP33 Ag-loss variants, demonstrating that GP33-specific CD8 T cells from these mice were able to exert an Ag selection pressure. In contrast, tumor cells growing in TNF-alpha knock-out mice still expressed the tumor-associated GP33 peptide despite the presence of activated GP33-specific CD8 T cells. These findings provide evidence for a crucial role of TNF-alpha in A9 tumor cell elimination by CD8 T cells in vivo. 相似文献
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Wirth S van den Broek M Frossard CP Hügin AW Leblond I Pircher H Hauser C 《Cellular immunology》2000,202(1):13-22
Effector T cells secreting type 1 and/or type 2 lymphokines (Tc1, Tc0, Tc2) were generated in vitro from CD8(+) T cells of mice with a transgenic TCR recognizing lymphocytic choriomeningitis virus (LCMV) glycoprotein to compare their effector function in vitro and in vivo. Tc1, Tc2, and Tc0 showed similar Fas- and perforin-mediated cytotoxicity in vitro. Upon adoptive transfer, Tc2 and Tc0 effectors were less efficient than Tc1 at controlling LCMV or recombinant vaccinia virus expressing the LCMV glycoprotein in vivo. Tc2 and Tc0 had decreased surface VLA-4 density and deficient activation-induced LFA-1/ICAM-1-dependent homotypic adhesion in vitro. Therefore, the reduced antiviral activity in vivo of Tc2 and Tc0 compared with Tc1 is not due to reduced cytotoxic activity or IFN-gamma secretion but may be explained by defective homing to the target organ due to decreased expression and/or lower activity of adhesion molecules. 相似文献
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Schwartzkopff S Gründemann C Schweier O Rosshart S Karjalainen KE Becker KF Pircher H 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(2):1022-1029
The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK cells and memory T cells in man and mice. Cadherins were recently identified as ligands for mouse KLRG1 but ligands for human KLRG1 have not yet been defined. In this study, we first demonstrate that human E-cadherin is a ligand for human KLRG1. This finding is remarkable because human and mouse KLRG1 show only an intermediate degree of homology (57% aa identity). In addition, we show that E-cadherin, expressed on K562 target cells, inhibited polyclonal human NK cells. Inhibition of NK cell function was observed consistently in three independent functional assays but the extent of inhibition was modest and required high expression of E-cadherin on target cells. E-cadherin function is often inactivated during development of human carcinomas and splice-site mutations resulting in in-frame loss of exon 8 or 9 occur frequently in diffuse type gastric carcinomas. Our experiments further revealed that interaction of human KLRG1 to E-cadherin was susceptible to these tumor-associated mutations and that KLRG1(+) NK cells were triggered more easily by K562 target cells carrying these mutations in comparison to target cells expressing wild-type E-cadherin. These results also indicate that the E-cadherin binding sites important for homophilic interaction are also involved in KLRG1 binding. Taken together, these data demonstrate that the main adhesion molecule of epithelial tissue, E-cadherin, is involved in regulation of NK cells in both humans and mice. 相似文献
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Ester B. M. Remmerswaal Paul L. Klarenbeek Nuno L. Alves Marieke E. Doorenspleet Barbera D. C. van Schaik Rebecca E. E. Esveldt Mirza M. Idu Ester M. M. van Leeuwen Nelly van der Bom-Baylon Antoine H. C. van Kampen Sven D. Koch Hanspeter Pircher Frederike J. Bemelman Anja ten Brinke Frank Baas Ineke J. M. ten Berge Rene A.W. van Lier Niek de Vries 《Journal of virology》2015,89(1):568-580
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Pircher P Chomez P Yu F Vennström B Larsson L 《American journal of physiology. Regulatory, integrative and comparative physiology》2005,288(2):R482-R490
The rev-erbAalpha orphan protein belongs to the steroid nuclear receptor superfamily. No ligand has been identified for this protein, and little is known of its function in development or physiology. In this study, we focus on 1) the distribution of the rev-erbAalpha protein in adult fast- and slow-twitch skeletal muscles and muscle fibers and 2) how the rev-erbAalpha protein influences myosin heavy chain (MyHC) isoform expression in mice heterozygous (+/-) and homozygous (-/-) for a rev-erbAalpha protein null allele. In the fast-twitch extensor digitorum longus muscle, rev-erbAalpha protein expression was linked to muscle fiber type; however, MyHC isoform expression did not differ between wild-type, +/-, or -/- mice. In the slow-twitch soleus muscle, the link between rev-erbAalpha protein and MyHC isoform expression was more complex than in the extensor digitorum longus. Here, a significantly higher relative amount of the beta/slow (type I) MyHC isoform was observed in both rev-erbAalpha -/- and +/- mice vs. that shown in wild-type controls. A role for the ratio of thyroid hormone receptor proteins alpha1 to alpha2 in modulating MyHC isoform expression can be ruled out because no differences were seen in MyHC isoform expression between thyroid hormone receptor alpha2-deficient mice (heterozygous and homozygous) and wild-type mice. Therefore, our data are compatible with the rev-erbAalpha protein playing an important role in the regulation of skeletal muscle MyHC isoform expression. 相似文献
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Gründemann C Bauer M Schweier O von Oppen N Lässing U Saudan P Becker KF Karp K Hanke T Bachmann MF Pircher H 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(3):1311-1315
The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK cells and by T cells. In both humans and mice, KLRG1 identifies Ag-experienced T cells that are impaired in their proliferative capacity but are capable of performing effector functions. In this study, we identified E-cadherin as a ligand for murine KLRG1 by using fluorescently labeled, soluble tetrameric complexes of the extracellular domain of the murine KLRG1 molecule as staining reagents in expression cloning. Ectopic expression of E-cadherin in B16.BL6 target cells did not affect cell-mediated lysis by lymphokine-activated NK cells and by CD8 T cells but inhibited Ag-induced proliferation and induction of cytolytic activity of CD8 T cells. E-cadherin is expressed by normal epithelial cells, Langerhans cells, and keratinocytes and is usually down-regulated on metastatic cancer cells. KLRG1 ligation by E-cadherin in healthy tissue may thus exert an inhibitory effect on primed T cells. 相似文献