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TEC-/- BTK-/- double mutant T cells exhibit severely impaired T cell activitity. RLK-/-ITK-/- double mutant celles exhibit severely imparired Th2 responses. Grb2(+/-) mice disrupt T cell signaling networks and development. Dendric cells and macrophages of MEK3 deficient mice have impaired IL12 production. Bam32(-/-) B cell develop normally but have impaired T-independent antibody responses in vivo. T-cell and B-cell of RAP1A deficient mice impair integrin-mediated cell adhesion. T-cell of WASP deficient mice impair the proliferaction and antigen receptor cap formation in response to anti-CD3zeta stimulation. T-cell of SHB defective mice impair the phosphorylation of LAT and consequently the activation of MAP kinase pathways. B-cell of 3BP2 (-/-) deficient mice have defective in proliferation, cell cycle progression, PLC-gamma2 phosphorylation, calcium mobilization, NF-ATp dephosphorylation, and Erk and Jnk activation in response to BCR ligation. B-cell of Vav2(-/-) deficient mice are defective in the ability to switch immunoglobulin class. T-cell of Vav1(-/-) deficient mice exhibit impaired antigen receptor signaling. Vav1(-/-)Vav2(-/-) mice exhibit greatly reduced the mature B-cells. Vav-1-/-Vav-2-/- B cells were unresponsive to BCR-driven proliferation in vitro and to thymus-indepen-dent antigen in vivo. Fyn-deficient mice exhibit a remarkably specific lymphoid defect thymocytes are refractile to stimulation through the TCR with mitogen or antigen. Lck-deficient mice show a pronounced thymic atrophy, with a dramatic reduction in the double-positive (CD4+CD8+) thymocyte population. T cell from mice deficient in LCK is required for normal signal transduction through the TCR. T cells from mice deficient in SLAP-130/Fyb show markedly impaired proliferation. B cell of chicken deficient ITK reduce IP3 generation and phospholipase C gamma 2 tyrosine phosphorylation. T cell of mice deficient ITK reduce IP3 generation and phospholipase C gamma 1 tyrosine phosphorylation. T cell of mice deficient ITK have failure of Th2 development. Mice deficient in ITK have reduced proliferative responses to MHC stimulation and to anti-TCR cross-linking Mutations in Btk cause X-linked immunodeficiency. Gads(GRAP2) has a role in thymocyte proliferaction for maturation of T-cells. Gads(GRAP2) has a role for homeostatic proliferaction in B cells. Grap negatively regulates T-cell proliferation. Gab2 is a substrate of ZAP-70 and functions as a switch molecule toward inhibition of TCR signal transuduction. B cell signaling causes tyrosine phosphorylation of Gab1, and in turn SHP2 bind to Gab1 Gab1 phosophorylation potentiate the phosphorylation of Akt, PI3K-dependent response. RasGRP1 mediates Ras activation following TCR stimulatioin. RasGRP1 and RasGRP3 induces RAS activation in B-cell to response to T-cell stimulation. Grb2-hSos1-PLCgamma1-p36/p38-ZAP70 complexes localize in the vicinity of TCR-zeta Gads(Grap2) plays an important role in T-cell signaling via its association with SLP-76 and LAT. Lck is required for normal signal transduction through the TCR. ZAP-70 plays crucial roles in T-cell activation and development. Syk triggers cellular activation in T-cell. TEC-/- BTK-/- double mutant T cells exhibit severely impaired T cell activitity. 1 J Exp Med. 2000 Dec 4;192(11) 1611-24. Severe B cell deficiency in mice lacking the tec kinase family members Tec and Btk. Ellmeier W, Jung S, Sunshine MJ, Hatam F, Xu Y, Baltimore D, Mano H, Littman DR. Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine. wilfried.ellmeier@univie.ac.at The cytoplasmic protein tyrosine kinase Tec has been proposed to have important functions in hematopoiesis and lymphocyte signal transduction. Here we show that Tec-deficient mice developed normally and had no major phenotypic alterations of the immune system. To reveal potential compensatory roles of other Tec kinases such as Bruton's tyrosine kinase (Btk), Tec/Btk double-deficient mice were generated. These mice exhibited a block at the B220(+)CD43(+) stage of B cell development and displayed a severe reduction of peripheral B cell numbers, particularly immunoglobulin (Ig)M(lo)IgD(hi) B cells. Although Tec/Btk(null) mice were able to form germinal centers, the response to T cell-dependent antigens was impaired. Thus, Tec and Btk together have an important role both during B cell development and in the generation and/or function of the peripheral B cell pool. The ability of Tec to compensate for Btk may also explain phenotypic differences in X-linked immunodeficiency (xid) mice compared with human X-linked agammaglobulinemia (XLA) patients. Publication Types Research Support, Non-U.S. Gov't PMID 11104803 [PubMed - indexed for MEDLINE] RLK-/-ITK-/- double mutant celles exhibit severely imparired Th2 responses. 1 Nat Immunol. 2001 Dec;2(12) 1183-8. Mutation of Tec family kinases alters T helper cell differentiation. Schaeffer EM, Yap GS, Lewis CM, Czar MJ, McVicar DW, Cheever AW, Sher A, Schwartzberg PL. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. The Tec kinases Rlk and Itk are critical for full T cell receptor (TCR)-induced activation of phospholipase C-gamma and mitogen-activated protein kinase. We show here that the mutation of Rlk and Itk impaired activation of the transcription factors NFAT and AP-1 and production of both T helper type 1 (TH1) and TH2 cytokines. Consistent with these biochemical defects, Itk-/- mice did not generate effective TH2 responses when challenged with Schistosoma mansoni eggs. Paradoxically, the more severely impaired Rlk-/-Itk-/- mice were able to mount a TH2 response and produced TH2 cytokines in response to this challenge. In addition, Rlk-/-Itk-/- cells showed impaired TCR-induced repression of the TH2-inducing transcription factor GATA-3, suggesting a potential mechanism for TH2 development in these hyporesponsive cells. Thus, mutations that affect Tec kinases lead to complex alterations in CD4+ TH cell differentiation. Publication Types Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. PMID 11702066 [PubMed - indexed for MEDLINE] Grb2(+/-) mice disrupt T cell signaling networks and development. 1 Nat Immunol. 2001 Jan;2(1) 29-36. Disruption of T cell signaling networks and development by Grb2 haploid insufficiency. Gong Q, Cheng AM, Akk AM, Alberola-Ila J, Gong G, Pawson T, Chan AC. Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA. The developmental processes of positive and negative selection in the thymus shape the T cell antigen receptor (TCR) repertoire and require the integration of multiple signaling networks. These networks involve the efficient assembly of macromolecular complexes and are mediated by multimodular adaptor proteins that permit the functional integration of distinct signaling molecules. We show here that decreased expression of the adaptor protein Grb2 in Grb2+/- mice weakens TCR-induced c-Jun N-terminal kinase (JNK) and p38, but not extracellular signal-regulated kinase (ERK), activation. In turn, this selective effect decreases the ability of thymocytes to undergo negative, but not positive, selection. We also show that there are differences in the signaling thresholds of the three mitogen-activated protein kinase (MAPK) families. These differences may provide a mechanism by which quantitative differences in signal strength can alter the balance of downstream signaling pathways to induce the qualitatively distinct biological outcomes of proliferation, differentiation or apoptosis. PMID 11135575 [PubMed - indexed for MEDLINE] Dendric cells and macrophages of MEK3 deficient mice have impaired IL12 production. 1 EMBO J. 1999 Apr 1;18(7) 1845-57. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. Lu HT, Yang DD, Wysk M, Gatti E, Mellman I, Davis RJ, Flavell RA. Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. The p38 mitogen-activated protein kinase (MAPK) pathway, like the c-Jun N-terminal kinase (JNK) MAPK pathway, is activated in response to cellular stress and inflammation and is involved in many fundamental biological processes. To study the role of the p38 MAPK pathway in vivo, we have used homologous recombination in mice to inactivate the Mkk3 gene, one of the two specific MAPK kinases (MAPKKs) that activate p38 MAPK. Mkk3(-/-) mice were viable and fertile; however, they were defective in interleukin-12 (IL-12) production by macrophages and dendritic cells. Interferon-gamma production following immunization with protein antigens and in vitro differentiation of naive T cells is greatly reduced, suggesting an impaired type I cytokine immune response. The effect of the p38 MAPK pathway on IL-12 expression is at least partly transcriptional, since inhibition of this pathway blocks IL-12 p40 promoter activity in macrophage cell lines and IL-12 p40 mRNA is reduced in MKK3-deficient mice. We conclude that the p38 MAP kinase, activated through MKK3, is required for the production of inflammatory cytokines by both antigen-presenting cells and CD4(+) T cells. PMID 10202148 [PubMed - indexed for MEDLINE] Bam32(-/-) B cell develop normally but have impaired T-independent antibody responses in vivo. 1 Immunity. 2003 Oct;19(4) 621-32. Bam32 links the B cell receptor to ERK and JNK and mediates B cell proliferation but not survival. Han A, Saijo K, Mecklenbrauker I, Tarakhovsky A, Nussenzweig MC. Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021, USA. Bam32 is an adaptor protein recruited to the plasma membrane upon B cell receptor (BCR) crosslinking in a phosphoinositol 3-kinase (PI3K)-dependent manner; however, its physiologic function is unclear. To determine its physiologic function, we produced Bam32-deficient mice. Bam32(-/-) B cells develop normally but have impaired T-independent antibody responses in vivo and diminished responses to BCR crosslinking in vitro. Biochemical analysis revealed that Bam32 acts in a novel pathway leading from the BCR to MAPK/ERK Kinases (MEK1/2), MAPK/ERK Kinase Kinase-1 (MEKK1), extracellular signal-regulated kinase (ERK), and c-jun NH2-terminal kinase (JNK), but not p38 mitogen-activated protein kinase (p38). This pathway appears to be initiated by hematopoietic progenitor kinase-1 (HPK1), which interacts directly with Bam32, and differs from all previously characterized BCR signaling pathways in that it is required for normal BCR-mediated proliferation but not for B cell survival. PMID 14563325 [PubMed - indexed for MEDLINE] T-cell and B-cell of RAP1A deficient mice impair integrin-mediated cell adhesion. 1 Mol Cell Biol. 2006 Jan;26(2) 643-53. Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion. Duchniewicz M, Zemojtel T, Kolanczyk M, Grossmann S, Scheele JS, Zwartkruis FJ. Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany. Studies in tissue culture cells have demonstrated a role for the Ras-like GTPase Rap1 in the regulation of integrin-mediated cell-matrix and cadherin-mediated cell-cell contacts. To analyze the function of Rap1 in vivo, we have disrupted the Rap1A gene by homologous recombination. Mice homozygous for the deletion allele are viable and fertile. However, primary hematopoietic cells isolated from spleen or thymus have a diminished adhesive capacity on ICAM and fibronectin substrates. In addition, polarization of T cells from Rap1-/- cells after CD3 stimulation was impaired compared to that of wild-type cells. Despite this, these defects did not result in hematopoietic or cell homing abnormalities. Although it is possible that the relatively mild phenotype is a consequence of functional complementation by the Rap1B gene, our genetic studies confirm a role for Rap1A in the regulation of integrins. PMID 16382154 [PubMed - indexed for MEDLINE] T-cell of WASP deficient mice impair the proliferaction and antigen receptor cap formation in response to anti-CD3zeta stimulation. 1 Immunity. 1998 Jul;9(1) 81-91. Wiskott-Aldrich syndrome protein-deficient mice reveal a role for WASP in T but not B cell activation. Snapper SB, Rosen FS, Mizoguchi E, Cohen P, Khan W, Liu CH, Hagemann TL, Kwan SP, Ferrini R, Davidson L, Bhan AK, Alt FW. Howard Hughes Medical Institute, Children's Hospital, Boston, Massachusetts 02115, USA. The Wiskott-Aldrich syndrome (WAS) is a human X-linked immunodeficiency resulting from mutations in a gene (WASP) encoding a cytoplasmic protein implicated in regulating the actin cytoskeleton. To elucidate WASP function, we disrupted the WASP gene in mice by gene-targeted mutation. WASP-deficient mice showed apparently normal lymphocyte development, normal serum immunoglobulin levels, and the capacity to respond to both T-dependent and T-independent type II antigens. However, these mice did have decreased peripheral blood lymphocyte and platelet numbers and developed chronic colitis. Moreover, purified WASP-deficient T cells showed markedly impaired proliferation and antigen receptor cap formation in response to anti-CD3epsilon stimulation. Yet, purified WASP-deficient B cells showed normal responses to anti-Ig stimulation. We discuss the implications of our findings regarding WASP function in receptor signaling and cytoskeletal reorganization in T and B cells and compare the effects of WASP deficiency in mice and humans. PMID 9697838 [PubMed - indexed for MEDLINE] T-cell of SHB defective mice impair the phosphorylation of LAT and consequently the activation of MAP kinase pathways. 9 Sep 24;274(39) 28050-7. Requirement of the Src homology 2 domain protein Shb for T cell receptor-dependent activation of the interleukin-2 gene nuclear factor for activation of T cells element in Jurkat T cells. Lindholm CK, Gylfe E, Zhang W, Samelson LE, Welsh M. Department of Medical Cell Biology, Box 571, Biomedicum, Uppsala University, S-75123 Uppsala, Sweden. Stimulation of the T cell antigen receptor (TCR) induces tyrosine phosphorylation of numerous intracellular proteins. We have recently investigated the role of the adaptor protein Shb in the early events of T cell signaling and observed that Shb associates with Grb2, linker for activation of T cells (LAT) and the TCR zeta-chain in Jurkat cells. We now report that Shb also associates with phospholipase C-gamma1 (PLC-gamma1) in these cells. Overexpression of Src homology 2 domain defective Shb caused diminished phosphorylation of LAT and consequently the activation of mitogen-activated protein kinases was decreased upon TCR stimulation. In addition, the Shb mutant also blocked phosphorylation of PLC-gamma1 and the increase in cytoplasmic Ca(2+) following TCR stimulation. Nuclear factor for activation of T cells is a major target for Ras and calcium signaling pathways in T cells following TCR stimulation, and the overexpression of the mutant Shb prevented TCR-dependent activation of the nuclear factor for activation of T cells. Consequently, endogenous interleukin-2 production was decreased under these conditions. The results indicate a role for Shb as a link between the TCR and downstream signaling events involving LAT and PLC-gamma1 and resulting in the activation of transcription of the interleukin-2 gene. PMID 10488157 [PubMed - indexed for MEDLINE] B-cell of 3BP2 (-/-) deficient mice have defective in proliferation, cell cycle progression, PLC-gamma2 phosphorylation, calcium mobilization, NF-ATp dephosphorylation, and Erk and Jnk activation in response to BCR ligation. 1 Mol Cell Biol. 2006 Jul;26(14) 5214-25. 3BP2 deficiency impairs the response of B cells, but not T cells, to antigen receptor ligation. de la Fuente MA, Kumar L, Lu B, Geha RS. Division of Immunology, Children's Hospital, 300 Longwood Ave., Boston, MA 02115, USA. The adapter protein 3BP2 is expressed in lymphocytes; binds to Syk/ZAP-70, Vav, and phospholipase C-gamma (PLC-gamma); and is thought to be important for interleukin-2 gene transcription in T cells. To define the role of 3BP2 in lymphocyte development and function, we generated 3BP2-deficient mice. T-cell development, proliferation, cytokine secretion, and signaling in response to T-cell receptor (TCR) ligation were all normal in 3BP2(-/-) mice. 3BP2(-/-) mice had increased accumulation of pre-B cells in the bone marrow and a block in the progression of transitional B cells in the spleen from the T1 to the T2 stage, but normal numbers of mature B cells. B-cell proliferation, cell cycle progression, PLC-gamma2 phosphorylation, calcium mobilization, NF-ATp dephosphorylation, and Erk and Jnk activation in response to B-cell receptor (BCR) ligation were all impaired. These results suggest that 3BP2 is important for BCR, but not for TCR signaling. PMID 16809760 [PubMed - indexed for MEDLINE] B-cell of Vav2(-/-) deficient mice are defective in the ability to switch immunoglobulin class. 1 Nat Immunol. 2001 Jun;2(6) 542-7. Comment in Nat Immunol. 2001 Jun;2(6) 482-4. Signal transduction through Vav-2 participates in humoral immune responses and B cell maturation. Doody GM, Bell SE, Vigorito E, Clayton E, McAdam S, Tooze R, Fernandez C, Lee IJ, Turner M. Laboratory of Lymphocyte Signaling and Development, Molecular Immunology Programme, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK. B and T lymphocytes develop normally in mice lacking the guanine nucleotide exchange factor Vav-2. However, the immune responses to type II thymus-independent antigen as well as the primary response to thymus-dependent (TD) antigen are defective. Vav-2-deficient mice are also defective in their ability to switch immunoglobulin class, form germinal centers and generate secondary immune responses to TD antigens. Mice lacking both Vav-1 and Vav-2 contain reduced numbers of B lymphocytes and display a maturational block in the development of mature B cells. B cells from Vav-1(-/-)Vav-2(-/-) mice respond poorly to antigen receptor triggering, both in terms of proliferation and calcium release. These studies show the importance of Vav-2 in humoral immune responses and B cell maturation. PMID 11376342 [PubMed - indexed for MEDLINE] T-cell of Vav1(-/-) deficient mice exhibit impaired antigen receptor signaling. 1 Nature. 1995 Mar 30;374(6521) 474-7. Defective T-cell receptor signalling and positive selection of Vav-deficient CD4+ CD8+ thymocytes. Fischer KD, Zmuldzinas A, Gardner S, Barbacid M, Bernstein A, Guidos C. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. During lymphocyte development, cellular proliferation and positive and negative selection events ensure the production of T and B lymphocytes bearing highly diverse, but self-tolerant, repertoires of antigen receptors. These processes are initiated when engagement of growth-factor receptors, or the T and B lymphocyte antigen receptors, induces tyrosine phosphorylation of specific SH2- and SH3-domain-containing cytoplasmic proteins, including Vav. Here we show that vav-/- embryonic stem cells generate only limited numbers of immature and mature T and B lymphocytes in the RAG-2 blastocyst complementation assay. Furthermore, Vav-deficient T lymphocytes showed severely impaired antigen receptor signalling. Finally, we demonstrate that Vav-dependent signalling pathways regulate maturation, but not CD4/CD8 lineage commitment, during T-cell-receptor-mediated positive selection of immature CD4+ CD8+ precursors into mature CD4+ CD8- or CD4- CD8+ T cells. PMID 7700360 [PubMed - indexed for MEDLINE] Vav1(-/-)Vav2(-/-) mice exhibit greatly reduced the mature B-cells. Vav-1-/-Vav-2-/- B cells were unresponsive to BCR-driven proliferation in vitro and to thymus-indepen-dent antigen in vivo. 1 Nat Immunol. 2001 Jun;2(6) 548-55. Comment in Nat Immunol. 2001 Jun;2(6) 482-4. Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling. Tedford K, Nitschke L, Girkontaite I, Charlesworth A, Chan G, Sakk V, Barbacid M, Fischer KD. Abteilung Physiologische Chemie, Universitat Ulm, Albert-Einstein-Allee 11, D-89069 Ulm, Germany. Vav-1 and Vav-2 are closely related Dbl-homology GTP exchange factors (GEFs) for Rho GTPases. Mutation of Vav-1 disrupts T cell development and T cell antigen receptor-induced activation, but has comparatively little effect on B cells. We found that combined deletion of both Vav-1 and Vav-2 in mice resulted in a marked reduction in mature B lymphocyte numbers. Vav-1(-/-)Vav-2(-/-) B cells were unresponsive to B cell antigen receptor (BCR)-driven proliferation in vitro and to thymus-independent antigen in vivo. BCR-stimulated intracellular calcium mobilization was greatly impaired in Vav-1(-/-)Vav-2(-/-) B cells. These findings establish a role for Vav-2 in BCR calcium signaling and reveal that the Vav family of GEFs is critical to B cell development and function. PMID 11376343 [PubMed - indexed for MEDLINE] Fyn-deficient mice exhibit a remarkably specific lymphoid defect thymocytes are refractile to stimulation through the TCR with mitogen or antigen. 1 Cell. 1992 Sep 4;70(5) 751-63. Defective T cell receptor signaling in mice lacking the thymic isoform of p59fyn. Appleby MW, Gross JA, Cooke MP, Levin SD, Qian X, Perlmutter RM. Howard Hughes Medical Institute, Department of Immunology, University of Washington, Seattle 98195. Considerable evidence supports the hypothesis that the nonreceptor protein tyrosine kinase p59fyn participates in signal transduction from the T cell receptor (TCR). To examine this hypothesis in detail, we have produced mice that lack the thymic isoform of p59fyn but retain expression of the brain isoform of the protein. fynTnull mice exhibit a remarkably specific lymphoid defect thymocytes are refractile to stimulation through the TCR with mitogen or antigen, while peripheral T cells, following what appears to be a normal maturation sequence, reacquire significant signaling capabilities. These data confirm that p59fynT plays a pivotal role in TCR signal transduction and demonstrate that additional developmentally regulated signaling components also contribute to TCR-induced lymphocyte activation. PMID 1516132 [PubMed - indexed for MEDLINE] Lck-deficient mice show a pronounced thymic atrophy, with a dramatic reduction in the double-positive (CD4+CD8+) thymocyte population. 1 Nature. 1992 May 14;357(6374) 161-4. Comment in Nature. 1993 Jan 21;361(6409) 213. Profound block in thymocyte development in mice lacking p56lck. Molina TJ, Kishihara K, Siderovski DP, van Ewijk W, Narendran A, Timms E, Wakeham A, Paige CJ, Hartmann KU, Veillette A, et al. Ontario Cancer Institute, University of Toronto, Canada. The protein Lck (p56lck) has a relative molecular mass of 56,000 and belongs to the Src family of tyrosine kinases. It is expressed exclusively in lymphoid cells, predominantly in thymocytes and peripheral T cells. Lck associates specifically with the cytoplasmic domains of both CD4 and CD8 T-cell surface glycoproteins and interacts with the beta-chain of the interleukin-2 receptor, which implicates Lck activity in signal transduction during thymocyte ontogeny and activation of mature T cells. Here we generate an lck null mutation by homologous recombination in embryonic stem cells to evaluate the role of p56lck in T-cell development and activation. Lck-deficient mice show a pronounced thymic atrophy, with a dramatic reduction in the double-positive (CD4+CD8+) thymocyte population. Mature, single-positive thymocytes are not detectable in these mice and there are only very few peripheral T cells. These results illustrate the crucial role of this T-cell-specific tyrosine kinase in the thymocyte development. PMID 1579166 [PubMed - indexed for MEDLINE] T cell from mice deficient in LCK is required for normal signal transduction through the TCR. 1 Cell. 1992 Aug 21;70(4) 585-93. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Straus DB, Weiss A. Howard Hughes Medical Institute, Department of Medicine, University of California, San Francisco 94143. Signaling through the T cell antigen receptor (TCR) results both in rapid increases in tyrosine phosphorylation on a number of proteins and in the activation of the phosphatidylinositol pathway. It is not clear how stimulation of the TCR leads to these signaling events. Mutants of the Jurkat T cell line have been previously isolated that fail to show increases in calcium following receptor stimulation. Analysis of one of these mutants, JCaM1, which is defective in the induction of tyrosine phosphorylation, revealed a defect in the expression of functional lck tyrosine kinase. The lack of lck activity was caused in part by a splicing defect. Expression of the lck cDNA in JCaM1 restores the ability of the cell to respond to TCR stimulation. These results indicate that lck is required for normal signal transduction through the TCR. PMID 1505025 [PubMed - indexed for MEDLINE] T cells from mice deficient in SLAP-130/Fyb show markedly impaired proliferation. 1 Science. 2001 Sep 21;293(5538) 2263-5. Coupling of the TCR to integrin activation by Slap-130/Fyb. Peterson EJ, Woods ML, Dmowski SA, Derimanov G, Jordan MS, Wu JN, Myung PS, Liu QH, Pribila JT, Freedman BD, Shimizu Y, Koretzky GA. The Abramson Family Cancer Research Institute, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. SLAP-130/Fyb (SLP-76-associated phosphoprotein or Fyn-binding protein; also known as Fyb/Slap) is a hematopoietic-specific adapter, which associates with and modulates function of SH2-containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76). T cells from mice lacking SLAP-130/Fyb show markedly impaired proliferation following CD3 engagement. In addition, the T cell receptor (TCR) in SLAP-130/Fyb mutant cells fails to enhance integrin-dependent adhesion. Although TCR-induced actin polymerization is normal, TCR-stimulated clustering of the integrin LFA-1 is defective in SLAP-130/Fyb-deficient cells. These data indicate that SLAP-130/Fyb is important for coupling TCR-mediated actin cytoskeletal rearrangement with activation of integrin function, and for T cells to respond fully to activating signals. PMID 11567141 [PubMed - indexed for MEDLINE] B cell of chicken deficient ITK reduce IP3 generation and phospholipase C gamma 2 tyrosine phosphorylation. 1 J Exp Med. 1996 Jul 1;184(1) 31-40. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2. Takata M, Kurosaki T. Department of Oncology and Immunology, Wyeth-Ayerst Research, Pearl River, New York 10965, USA. Defects in the gene encoding Bruton's tyrosine kinase (Btk) result in a disease called X-linked agammaglobulinemia, in which there is a profound decrease of mature B cells due to a block in B cell development. Recent studies have shown that Btk is tyrosine phosphorylated and activated upon B cell antigen receptor (BCR) stimulation. To elucidate the functions of this kinase, we examined BCR signaling of DT40 B cells deficient in Btk. Tyrosine phosphorylation of phospholipase C (PLC)-gamma 2 upon receptor stimulation was significantly reduced in the mutant cells, leading to the loss of both BCR-coupled phosphatidylinositol hydrolysis and calcium mobilization. Pleckstrin homology and Src-homology 2 domains of Btk were required for PLC-gamma 2 activation. Since Syk is also required for the BCR-induced PLC-gamma 2 activation, our findings indicate that PLC-gamma 2 activation is regulated by Btk and Syk through their concerted actions. PMID 8691147 [PubMed - indexed for MEDLINE] T cell of mice deficient ITK reduce IP3 generation and phospholipase C gamma 1 tyrosine phosphorylation. 1 J Exp Med. 1998 May 18;187(10) 1721-7. T cell receptor-initiated calcium release is uncoupled from capacitative calcium entry in Itk-deficient T cells. Liu KQ, Bunnell SC, Gurniak CB, Berg LJ. Program of Immunology, Division of Medical Sciences, Harvard University, Boston, Massachusetts 02115, USA. Itk, a Tec family tyrosine kinase, plays an important but as yet undefined role in T cell receptor (TCR) signaling. Here we show that T cells from Itk-deficient mice have a TCR-proximal signaling defect, resulting in defective interleukin 2 secretion. Upon TCR stimulation, Itk-/- T cells release normal amounts of calcium from intracellular stores, but fail to open plasma membrane calcium channels. Since thapsigargin-induced store depletion triggers normal calcium entry in Itk-/- T cells, an impaired biochemical link between store depletion and channel opening is unlikely to be responsible for this defect. Biochemical studies indicate that TCR-induced inositol 1,4,5 tris-phosphate (IP3) generation and phospholipase C gamma1 tyrosine phosphorylation are substantially reduced in Itk-/- T cells. In contrast, TCR-zeta and ZAP-70 are phosphorylated normally, suggesting that Itk functions downstream of, or in parallel to, ZAP-70 to facilitate TCR-induced IP3 production. These findings support a model in which quantitative differences in cytosolic IP3 trigger distinct responses, and in which only high concentrations of IP3 trigger the influx of extracellular calcium. PMID 9584150 [PubMed - indexed for MEDLINE] T cell of mice deficient ITK have failure of Th2 development. 1 Immunity. 1999 Oct;11(4) 399-409. Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. Fowell DJ, Shinkai K, Liao XC, Beebe AM, Coffman RL, Littman DR, Locksley RM. Department of Medicine, University of California San Francisco 94143, USA. Naive Itk-deficient CD4+ T cells were unable to establish stable IL-4 production, even when primed in Th2-inducing conditions. In contrast, IFNgamma production was little affected. Failure to express IL-4 occurred even among cells that had gone through multiple cell divisions and was associated with a delay in the kinetics and magnitude of NFATc nuclear localization. IL-4 production was restored genetically by retroviral reconstitution of Itk or biochemically by augmenting the calcium flux with ionomycin. In vivo, Itk-deficient mice were unable to establish functional Th2 cells. Development of protective Th1 cells was unimpeded. These data define a nonredundant role for Itk in modulating signals from the TCR/CD28 pathways that are specific for the establishment of stable IL-4 but not IFNgamma expression. PMID 10549622 [PubMed - indexed for MEDLINE] Mice deficient in ITK have reduced proliferative responses to MHC stimulation and to anti-TCR cross-linking 1 Immunity. 1995 Dec;3(6) 757-69. Altered T cell receptor signaling and disrupted T cell development in mice lacking Itk. Liao XC, Littman DR. Department of Microbiology and Immunology, University of California, San Francisco 94143-0414, USA. Itk is a T cell protein tyrosine kinase (PTK) that, along with Btk and Tec, belongs to a family of cytoplasmic PTKs with N-terminal pleckstrin homology domains. Btk plays a critical role in B lymphocyte development. To determine whether Itk has an analogous role in T lymphocytes, we used gene targeting to prepare mice lacking expression of Itk. Such animals had decreased numbers of mature thymocytes, an effect most clearly observed in mice expressing T cell receptor (TCR) transgenes. Mature T cells from Itk-deficient mice had reduced proliferative responses to allogeneic MHC stimulation and to anti-TCR cross-linking, but responded normally to stimulation with phorbol ester plus ionomycin or with IL-2. These results provide genetic evidence that Itk is involved in T cell development and also suggest that Itk has an important role in proximal events in TCR-mediated signaling pathways. PMID 8777721 [PubMed - indexed for MEDLINE] Mutations in Btk cause X-linked immunodeficiency. 1 Semin Immunol. 1998 Aug;10(4) 309-16. Btk function in B cell development and response. Satterthwaite AB, Li Z, Witte ON. Department of Microbiology and Molecular Genetics, University of California, Los Angeles 90095-1662, USA. Mutations in Bruton's tyrosine kinase (Btk) result in the B cell immunodeficiencies XLA in humans and Xid in mice. Both the maintenance of peripheral B cell numbers and their response to B cell antigen receptor (BCR) crosslinking depend on Btk. Btk integrates signals from multiple cell surface receptors, including BCR and G-protein coupled receptors. These Btk dependent signals control B cell proliferation and survival by mediating Ca2+ flux, activating JNK and p38 and inducing cell cycle regulatory genes. Publication Types Review PMID 9695187 [PubMed - indexed for MEDLINE] Gads(GRAP2) has a role in thymocyte proliferaction for maturation of T-cells. 1 Science. 2001 Mar 9;291(5510) 1987-91. Requirement for the SLP-76 adaptor GADS in T cell development. Yoder J, Pham C, Iizuka YM, Kanagawa O, Liu SK, McGlade J, Cheng AM. Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110, USA. GADS is an adaptor protein implicated in CD3 signaling because of its ability to link SLP-76 to LAT. A GADS-deficient mouse was generated by gene targeting, and the function of GADS in T cell development and activation was examined. GADS- CD4-CD8- thymocytes exhibited a severe block in proliferation but still differentiated into mature T cells. GADS- thymocytes failed to respond to CD3 cross-linking in vivo and were impaired in positive and negative selection. Immunoprecipitation experiments revealed that the association between SLP-76 and LAT was uncoupled in GADS- thymocytes. These observations indicate that GADS is a critical adaptor for CD3 signaling. PMID 11239162 [PubMed - indexed for MEDLINE] Gads(GRAP2) has a role for homeostatic proliferaction in B cells. 1 Eur J Immunol. 2005 Apr;35(4) 1184-92. Expression and function of the adaptor protein Gads in murine B cells. Yankee TM, Draves KE, Clark EA. Department of Immunology, University of Washington, Seattle, USA. tyankee@kumc.edu Nearly all hematopoietic receptors are dependent on adaptor proteins for the activation of downstream signaling pathways. The Gads adaptor protein is expressed in many hematopoietic tissues, including bone marrow, lymph node, and spleen. Using intracellular staining, we detected Gads protein in a number cells, including B cells, T cells, NK cells, monocytes, and plasmacytoid DC, but not in macrophages, neutrophils, or monocyte-derived DC. In the B cell compartment, Gads was first expressed after immature B cells leave the bone marrow and was down-regulated after B cell antigen receptor (BCR) ligation. Female Gads(-/-) mice had increased numbers of splenic B cells, as compared to female Gads(+/+) mice, suggesting a role for Gads in B cell homeostasis. Although B cell production and turnover of splenic B cell subsets appeared normal in Gads(-/-) mice, homeostatic proliferation was significantly impaired in Gads(-/-) B cells. Whereas BCR ligation can induce apoptosis in wild-type transitional stage 1 (T1) B cells, Gads(-/-) T1 B cells were resistant to BCR-induced apoptosis. Gads(-/-) B cells also showed increased BCR-mediated calcium mobilization. We conclude that Gads may have a negative regulatory role in signaling through survival pathways, and is necessary for normal homeostatic proliferation in B cells. PMID 15761845 [PubMed - indexed for MEDLINE] Grap negatively regulates T-cell proliferation. 1 Mol Cell Biol. 2002 May;22(10) 3230-6. Grap negatively regulates T-cell receptor-elicited lymphocyte proliferation and interleukin-2 induction. Shen R, Ouyang YB, Qu CK, Alonso A, Sperzel L, Mustelin T, Kaplan MH, Feng GS. Program in Signal Transduction Research, The Burnham Institute, La Jolla, California 92037, USA. Grb-2-related adaptor protein (Grap) is a Grb2-like SH3-SH2-SH3 adaptor protein with expression restricted to lymphoid tissues. Grap(-/-) lymphocytes isolated from targeted Grap-deficient mice exhibited enhanced proliferation, interleukin-2 production, and c-fos induction in response to mitogenic T-cell receptor (TCR) stimulation, compared to wild-type cells. Ectopic expression of Grap led to a suppression of Elk-1-directed transcription induced by the Ras/Erk pathway, without having effects on gene expression mediated by Jnk and p38 mitogen-activated protein kinases. Together, these data suggest that Grap, unlike Grb2, acts as a negative regulator of TCR-stimulated intracellular signaling by downregulating signal relay through the Ras/Erk pathway. PMID 11971956 [PubMed - indexed for MEDLINE] Gab2 is a substrate of ZAP-70 and functions as a switch molecule toward inhibition of TCR signal transuduction. 1 J Biol Chem. 2001 Nov 30;276(48) 45175-83. Epub 2001 Sep 25. Docking protein Gab2 is phosphorylated by ZAP-70 and negatively regulates T cell receptor signaling by recruitment of inhibitory molecules. Yamasaki S, Nishida K, Hibi M, Sakuma M, Shiina R, Takeuchi A, Ohnishi H, Hirano T, Saito T. Molecular Genetics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. To maintain various T cell responses and immune equilibrium, activation signals triggered by T cell antigen receptor (TCR) must be regulated by inhibitory signals. Gab2, an adaptor protein of the insulin receptor substrate-1 family, has been shown to be involved in the downstream signaling from cytokine receptors. We investigated the functional role of Gab2 in TCR-mediated signal transduction. Gab2 was phosphorylated by ZAP-70 and co-precipitated with phosphoproteins, such as ZAP-70, LAT, and CD3zeta, upon TCR stimulation. Overexpression of Gab2 in Jurkat cells or antigen-specific T cell hybridomas resulted in the inhibition of NF-AT activation, interleukin-2 production, and tyrosine phosphorylation. The structure-function relationship of Gab2 was analyzed by mutants of Gab2. The Gab2 mutants lacking SHP-2-binding sites mostly abrogated the inhibitory activity of Gab2, but its inhibitory function was restored by fusing to active SHP-2 as a chimeric protein. A mutant with defective phosphatidylinositol 3-kinase binding capacity also impaired the inhibitory activity, and the pleckstrin homology domain-deletion mutant revealed a crucial function of the pleckstrin homology domain for localization to the plasma membrane. These results suggest that Gab2 is a substrate of ZAP-70 and functions as a switch molecule toward inhibition of TCR signal transduction by mediating the recruitment of inhibitory molecules to the TCR signaling complex. PMID 11572860 [PubMed - indexed for MEDLINE] B cell signaling causes tyrosine phosphorylation of Gab1, and in turn SHP2 bind to Gab1 Gab1 phosophorylation potentiate the phosphorylation of Akt, PI3K-dependent response. 1 J Biol Chem. 2001 Apr 13;276(15) 12257-65. Epub 2001 Jan 22. The Gab1 docking protein links the b cell antigen receptor to the phosphatidylinositol 3-kinase/Akt signaling pathway and to the SHP2 tyrosine phosphatase. Ingham RJ, Santos L, Dang-Lawson M, Holgado-Madruga M, Dudek P, Maroun CR, Wong AJ, Matsuuchi L, Gold MR. Departments of Microbiology and Immunology and Zoology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. B cell antigen receptor (BCR) signaling causes tyrosine phosphorylation of the Gab1 docking protein. This allows phosphatidylinositol 3-kinase (PI3K) and the SHP2 tyrosine phosphatase to bind to Gab1. In this report, we tested the hypothesis that Gab1 acts as an amplifier of PI3K- and SHP2-dependent signaling in B lymphocytes. By overexpressing Gab1 in the WEHI-231 B cell line, we found that Gab1 can potentiate BCR-induced phosphorylation of Akt, a PI3K-dependent response. Gab1 expression also increased BCR-induced tyrosine phosphorylation of SHP2 as well as the binding of Grb2 to SHP2. We show that the pleckstrin homology (PH) domain of Gab1 is required for BCR-induced phosphorylation of Gab1 and for Gab1 participation in BCR signaling. Moreover, using confocal microscopy, we show that BCR ligation can induce the translocation of Gab1 from the cytosol to the plasma membrane and that this requires the Gab1 PH domain as well as PI3K activity. These findings are consistent with a model in which the binding of the Gab1 PH domain to PI3K-derived lipids brings Gab1 to the plasma membrane, where it can be tyrosine-phosphorylated and then act as an amplifier of BCR signaling. PMID 11278704 [PubMed - indexed for MEDLINE] RasGRP1 mediates Ras activation following TCR stimulatioin. RasGRP1 and RasGRP3 induces RAS activation in B-cell to response to T-cell stimulation. 1 Immunol Lett. 2006 May 15;105(1) 77-82. Epub 2006 Feb 20. The role of RasGRPs in regulation of lymphocyte proliferation. Coughlin JJ, Stang SL, Dower NA, Stone JC. Department of Biochemistry, University of Alberta, Edmonton, Alta., Canada T6G 2H7. RasGRP1 links TCR signaling to Ras in T cells, while both RasGRP1 and RasGRP3 link BCR signaling to Ras in B cells. T cells deficient in RasGRP1 have defective proliferative responses as do B cells deficient in both RasGRP1 and RasGRP3, confirming the importance of Ras activation in lymphocyte proliferation. While aged Rasgrp1-/- mice develop late-onset autoimmunity characterized by splenomegaly and the presence of anti-nuclear antibodies (ANA), the additional loss of RasGRP3 expression inhibits this phenotype. We show here that the autoimmunity in Rasgrp1-/- mice is T cell dependent. Compared to wildtype, Rasgrp1-/- T cells induce greater in vitro B cell proliferation that is due, at least in part, to increased production of interleukin-4 (IL-4). Rasgrp1 Rasgrp3 double mutant B cells are less responsive to this T cell stimulation. The reduced double mutant B cell proliferative response was paralleled by decreased induction of cyclin D2 upon stimulation with IL-4 and anti-IgM. Taken together these results suggest that double mutant mice fail to generate autoimmunity due to their decreased B cell cyclin D2 accumulation, and thus proliferation, in response to the elevated levels of IL-4 produced by mutant T cells. PMID 16530850 [PubMed - indexed for MEDLINE] Grb2-hSos1-PLCgamma1-p36/p38-ZAP70 complexes localize in the vicinity of TCR-zeta 1 J Biol Chem. 1995 Aug 4;270(31) 18428-36. Ligation of the T-cell antigen receptor (TCR) induces association of hSos1, ZAP-70, phospholipase C-gamma 1, and other phosphoproteins with Grb2 and the zeta-chain of the TCR. Nel AE, Gupta S, Lee L, Ledbetter JA, Kanner SB. Department of Medicine, UCLA School of Medicine 90024, USA. Signaling by the T-cell antigen receptor (TCR) involves both phospholipase C (PLC)-gamma 1 and p21ras activation. While failing to induce Shc/Grb2 association, ligation of the TCR/CD3 receptor in Jurkat T-cells induced hSos1-Grb2 complexes. In addition to hSos1, Grb2 participates in the formation of a tyrosine phosphoprotein complex that includes 145-, 95-, 70-, 54-, and 36-38-kDa proteins. p145 was identified as PLC-gamma 1 and p70 as the protein tyrosine kinase, ZAP-70. Although of the same molecular weight, p95 was not recognized by an anti-serum to p95 Vav. The SH2 domains of Grb2 and PLC-gamma 1 were required for the formation of this protein complex. In anti-CD3-treated cells, Grb2 redistributed from the cytosol to a particulate cell compartment along with p36/p38, ZAP-70, and PLC-gamma 1. Part of the Grb2 complex associated with the particulate compartment could be extracted with Nonidet P-40, while the rest was Nonidet P-40 insoluble. In both the detergent-soluble and -insoluble fractions, Grb2 coimmunoprecipitated with the zeta-chain of the TCR. Taken together, these results indicate that anti-CD3 induces Grb2-hSos1-PLC-gamma 1-p36/p38-ZAP70 complexes, which localize in the vicinity of TCR-zeta. PMID 7629168 [PubMed - indexed for MEDLINE] Gads(Grap2) plays an important role in T-cell signaling via its association with SLP-76 and LAT. 1 Curr Biol. 1999 Jan 28;9(2) 67-75. The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Liu SK, Fang N, Koretzky GA, McGlade CJ. Department of Medical Biophysics, University of Toronto, The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Research Institute, 555 University Ave, Toronto, Ontario M5G 1X8, Canada. BACKGROUND The adaptor protein Gads is a Grb2-related protein originally identified on the basis of its interaction with the tyrosine-phosphorylated form of the docking protein Shc. Gads protein expression is restricted to hematopoietic tissues and cell lines. Gads contains a Src homology 2 (SH2) domain, which has previously been shown to have a similar binding specificity to that of Grb2. Gads also possesses two SH3 domains, but these have a distinct binding specificity to those of Grb2, as Gads does not bind to known Grb2 SH3 domain targets. Here, we investigated whether Gads is involved in T-cell signaling. RESULTS We found that Gads is highly expressed in T cells and that the SLP-76 adaptor protein is a major Gads-associated protein in vivo. The constitutive interaction between Gads and SLP-76 was mediated by the carboxy-terminal SH3 domain of Gads and a 20 amino-acid proline-rich region in SLP-76. Gads also coimmunoprecipitated the tyrosine-phosphorylated form of the linker for activated T cells (LAT) adaptor protein following cross-linking of the T-cell receptor; this interaction was mediated by the Gads SH2 domain. Overexpression of Gads and SLP-76 resulted in a synergistic augmentation of T-cell signaling, as measured by activation of nuclear factor of activated T cells (NFAT), and this cooperation required a functional Gads SH2 domain. CONCLUSIONS These results demonstrate that Gads plays an important role in T-cell signaling via its association with SLP-76 and LAT. Gads may promote cross-talk between the LAT and SLP-76 signaling complexes, thereby coupling membrane-proximal events to downstream signaling pathways. PMID 10021361 [PubMed - indexed for MEDLINE] Lck is required for normal signal transduction through the TCR. 1 Cell. 1992 Aug 21;70(4) 585-93. Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor. Straus DB, Weiss A. Howard Hughes Medical Institute, Department of Medicine, University of California, San Francisco 94143. Signaling through the T cell antigen receptor (TCR) results both in rapid increases in tyrosine phosphorylation on a number of proteins and in the activation of the phosphatidylinositol pathway. It is not clear how stimulation of the TCR leads to these signaling events. Mutants of the Jurkat T cell line have been previously isolated that fail to show increases in calcium following receptor stimulation. Analysis of one of these mutants, JCaM1, which is defective in the induction of tyrosine phosphorylation, revealed a defect in the expression of functional lck tyrosine kinase. The lack of lck activity was caused in part by a splicing defect. Expression of the lck cDNA in JCaM1 restores the ability of the cell to respond to TCR stimulation. These results indicate that lck is required for normal signal transduction through the TCR. PMID 1505025 [PubMed - indexed for MEDLINE] ZAP-70 plays crucial roles in T-cell activation and development. Syk triggers cellular activation in T-cell. 1 Mol Cell Biol. 1998 Mar;18(3) 1388-99. Genetic evidence for differential coupling of Syk family kinases to the T-cell receptor reconstitution studies in a ZAP-70-deficient Jurkat T-cell line. Williams BL, Schreiber KL, Zhang W, Wange RL, Samelson LE, Leibson PJ, Abraham RT. Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA. T-cell antigen receptor (TCR) engagement activates multiple protein tyrosine kinases (PTKs), including the Src family member, Lck, and the Syk-related PTK, ZAP-70. Studies in ZAP-70-deficient humans have demonstrated that ZAP-70 plays crucial roles in T-cell activation and development. However, progress toward a detailed understanding of the regulation and function of ZAP-70 during TCR signaling has been hampered by the lack of a suitable T-cell model for biochemical and genetic analyses. In this report, we describe the isolation and phenotypic characterization of a Syk- and ZAP-70-negative somatic mutant derived from the Jurkat T-cell line. The P116 cell line displays severe defects in TCR-induced signaling functions, including protein tyrosine phosphorylation, intracellular Ca2+ mobilization, and interleukin-2 promoter-driven transcription. These signaling defects were fully reversed by reintroduction of catalytically active versions of either Syk or ZAP-70 into the P116 cells. However, in contrast to ZAP-70 expression, Syk expression triggered a significant degree of cellular activation in the absence of TCR ligation. Transfection experiments with ZAP-70-Syk chimeric proteins indicated that both the amino-terminal regulatory regions and the carboxy-terminal catalytic domains of Syk and ZAP-70 contribute to the distinctive functional properties of these PTKs. These studies underscore the crucial role of ZAP-70 in TCR signaling and offer a powerful genetic model for further analyses of ZAP-70 regulation and function in T cells. PMID 9488454 [PubMed - indexed for MEDLINE]
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目標３００ genes for database issue Knock-Out Database BKT CBL-B FYB Fyk ITK GAB1 GAB2 GAB3 GRAP GRAP2(GADS) GRB2 LCK Rap1A RasGRP1 RasGRP2 SHC1, ShcA SOS1 SOS2 VAV1 VAV2 WASP 3BP2 BKT Mice deficient in BKT elicit X-linked immunodeficienceSatterthwaite AB et al 1998 Semin Immunol CBL-B CBL-B null mice have enhanced long-term memory and show an enhancement in short-term plasticity. Tan DP et al 2006 Proc Natl Acad Sci U S A FYB T-cell from mice deficient in FYB show markedly impaired proliferaction.Peterson EJ et al 2001 Science Fyk T-cell from mice deficient in FYK exhibit a remarkably specific lymphoid defect thymocytes are refractile to stimulation through the TCR with mitogen or antigen.Appleby MW et al 1992 Cell ITK Mice deficient in ITK have reduced proliferative responses to MHC stimulation and anti-TCR cross-linking.Liao XC et al 1995 Immunity GAB1 Mice deficient in GAB1 die at the early phase of development with multiple defects in heart, placenta, liver, spleen and muscle development.Itoh M et al 2000 Mol Cell Biol GAB2 no detectable defects in normal mouse development, hematopoiesis, or immune system function.Sarmay G et al 2006 Immuno Lett GAB3 no detectable defects in normal mouse development, hematopoiesis, or immune system function.Seiffert M et al 2003 Mol Cell Biol GRAP Mice deficient in Grap(-/-) enhance proliferation.Shen R et al 2002 Mol Cell Biol GRAP2(GADS) Thymocytes deficient in GRAP2(-/-) are blocked in proliferaction during maturation of T-cell.Yoder J et al 2001 Science B-cells deficient in GRAP2(-/-) impaire homeostatic proliferation.Yankee TM et al Eur J Immunol GRB2 Mice deficient in GRB2 die at the early phase of development.Cheng AM et al 1998 Cell LCK Lck-deficient mice show a pronounced thymic atrophy, with a dramatic reduction in the double-positive (CD4+CD8+) thymocyte population. Molina et al 1992 Nature Rap1A T cells and B cells of RAP1 deficient mice impair integrin-mediated cell adhesion.Duchniewicz M et al 2006 Mol Cell Biol RasGRP1 T cells deficient in RasGRP1 have defective proliferative responses. late-onset lymphoproliferation autoimmunityCoughlin JJ et al 2006 Immunol Lett B cell deficient in RasGRP2 and RasGRP1 have defective proliferative responses.Coughlin JJ et al 2006 Immunol Lett RasGRP2 B cell deficient in RasGRP2 and RasGRP1 have defective proliferative responses.Coughlin JJ et al 2006 Immunol Lett Coughlin JJ et al 2005 J Immunol SHC1, ShcA Mice deficient in SHC1 die at day 11.5Lai KM and Pawson T 2000 Genes Dev Mice deficient in SHC1 fail to produce IL-2 because of impaired MAP kinase activation.Iwashima M et al 2002 Proc Natl Acad Sci U S A SOS1 Mice deficient in SOS1 die at the early phase of development.Wang DZ et al 1997 Genes Dev. SOS2 No detectable defects in normal mouse development, growth, and fertility.Esteban LM et al 2000 Proc Natl Acad Sci U S A VAV1 Mice deficient in VAV1 and VAV2 (-/-,-/-) reduce mature B cells.Tedford K et al 2001 Nat Immunol T-cell of mice deficient in VAV1 (-/-) exhibit impaired antigen receptor signaling.Fischer KD et al 1995 Nature VAV2 Mice deficient in VAV1 and VAV2 (-/-,-/-) reduce mature B cells.Tedford K et al 2001 Nat Immunol B cell of mice deficient in VAV2 are defective in the ablity to switch immunoglobulin class.Doody GM et al 2001 Nature WASP T-cell of mice deficient in WASP impair proliferation and antigen receptor cap formation in response to anti-CD3zeta stimulation.Snapper SB et al 1998 Immunity 3BP2 B-cell from deficient in 3BP2 impaire proliferation, cell cycle progression, PLC-gamma2 phosphorylation, calcium mobilization, NF-ATp dephosphorylation, and Erk and Jnk activation in response to BCR ligation.de la Fuente MA et al 2006 Mol Cell Biol
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シークレット・ナンバーズ サークル：ぴずやの独房 Number Track Name Arranger Lyrics Vocal Original Works Original Tune Length 01 カレイドスコープ Pizuya's Cell 普透明度 普透明度 東方天空璋 秘匿されたフォーシーズンズ [05 08] 02 Infinite Butterfly Pizuya's Cell 普透明度 普透明度 東方天空璋 希望の星は青霄に昇る [04 12] 03 ホワイトディスタンス Pizuya's Cell rudder-k 普透明度 東方天空璋 幻想のホワイトトラベラー [04 21] 04 エレクトリックエンカウンター Pizuya's Cell rudder-k 普透明度 東方天空璋 山奥のエンカウンター [04 23] 05 Crazy Clumsy Circus Pizuya's Cell 普透明度 普透明度 東方天空璋 クレイジーバックダンサーズ [02 52] 06 Divine beast Pizuya's Cell rudder-k 普透明度 東方天空璋 一対の神獣 [04 24] 07 カレイドスコープ -off vox- Pizuya's Cell - - 東方天空璋 秘匿されたフォーシーズンズ [05 08] 08 Infinite Butterfly -off vox- Pizuya's Cell - - 東方天空璋 希望の星は青霄に昇る [04 11] 09 Crazy Clumsy Circus -off vox- Pizuya's Cell - - 東方天空璋 クレイジーバックダンサーズ [02 52] 詳細 コミックマーケット93?(2017/12/29)にて頒布 イベント価格：1,000円 ショップ価格：1,430円 Guest 普透明度（√8 BEAT） rudder-k（scorefreq） レビュー
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表のセルに文字を書き入れる Putcell 2016.03.26 putcell.cdy Putcell("c0r0","c2r1","lt","abc"); Putcell(2,3,"c","xyz"); 表のセルに文字を書き入れる Putcellexpr("c0r0","c2r1","lt","abc"); Putcellexpr(2,3,"c","\sin x"); 表のセルに数式を書き入れる #ref error ：ご指定のファイルが見つかりません。ファイル名を確認して、再度指定してください。 (title=) putcell.zip xLst=[30,30,30]; yLst=[10,10,10,10]; rmvL=[]; Tabledata("",xLst,yLst,rmvL); ／／ リストで指定した横と縦の幅を持つ表を表示する． Putcell("c0r0","c1r1","l","a"); ／／ c0r0 と c1r1 を対角線とするセルの左側(left)に文字を書き入れる． Putcellexpr("c0r0","c1r1","r","a"); ／／ Putcellexpr だと数式モードになる． Putcell(1,2,"t","x"); Putcellexpr(1,2,"b","x^2"); ／／ 左から1番目, 上から2番目のセルに文字を書き入れる． Putcell(2,3,"tl","tl"); Putcell(2,3,"tr","tr"); Putcell(2,3,"bl","bl"); Putcell(2,3,"br","br"); Putcell(2,3,"c","c"); ／／ tが上(top)，bが下(bottom)，lが左(left)，rが右(right)，cが中心(center) Putcell("c2r2","c3r4","c","CENTER"); ／／ c2r2 と c3r4 を対角線とするセルの中心(center)に文字を書き入れる．
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セルを指定して出力 Cell 指定のデータを出力 サンプル ソース ?php // ライブラリを読み込み require_once("./fpdf17/mbfpdf.php"); // インスタンスを生成 //$fpdf = new MBFPDF("P", "mm", "A4");// 向き、単位、サイズ指定 $fpdf = new MBFPDF("L", "mm", "A4");// //$fpdf = new MBFPDF("P", "mm", "A5");// //$fpdf = new MBFPDF("L", "mm", "Letter");// //$fpdf = new MBFPDF("L", "mm", array(100, 120));// $fpdf- AddMBFont(GOTHIC, "SJIS"); // ページを追加 $fpdf- AddPage(); // フォントを設定 $fpdf- SetFont(GOTHIC, B , 16); // Cellのパラメータ // 出力時にポインタが出力後の部分へ割り当てられる // 1 幅 // 2 高さ // 3 文字列 // 4 罫線エリア(0 なし、１ 全体、"L" 左のみ、"R" 右のみ、"T" 上のみ、"B" 下のみ // 5 改行（0 改行しない、1 次行へ、2 改行するがX座標はそのまま // 6 文字列位置("L" 左寄せ、"R" 右寄せ、"C" 中央寄せ // 7 // 文字を出力 $fpdf- Cell(100, 10, この文字を出力する ); $fpdf- Cell(100, 30, 罫線付きデータ（全体） , "1", 1, C ); // 一度改行 $fpdf- Ln(5); $fpdf- Cell(100, 10, 罫線付きデータ（上） , "T", 0, C ); $fpdf- Cell(100, 10, 罫線付きデータ（右） , "R", 1, C ); $fpdf- Ln(10); $fpdf- Cell(100, 10, 罫線付きデータ（左） , "L", 0, C ); $fpdf- Cell(100, 10, 罫線付きデータ（下） , "B", 1, C ); // 一度改行 $fpdf- Ln(5); // 文字列出力後に改行位置修正 $fpdf- Cell(80, 10, 改行できるかテスト ); $fpdf- Cell(80, 10, 次行の先頭へ移動 , 0, 1); $fpdf- Cell(80, 10, 次行の先頭である ); $fpdf- Cell(80, 10, 改行後のX位置が先頭にならない , 0, 2); $fpdf- Cell(80, 10, 改行できるかテスト , 0, 1); $fpdf- Ln(5); // 文字列出力時にテキスト位置修正 $fpdf- Cell(80, 10, これは左寄せ , 1, 1, "L"); $fpdf- Cell(80, 10, これは右寄せ , 1, 1, "R"); $fpdf- Cell(80, 10, これは中央寄せ , 1, 1, "C"); // 一度改行 $fpdf- Ln(5); // 塗りつぶし指定 $fpdf- SetFillColor(0xFF, 0xFF, 0x00); // 塗りつぶし $fpdf- Cell(80, 10, 塗りつぶし , 1, 1, "L", true); // 一度改行 $fpdf- Ln(5); // リンク追加 $fpdf- Cell(80, 10, クリックするとジャンプします , 1, 0, "L", false, "http //localhost/sample/sample04.php"); // PDFを出力 $fpdf- Output() ? イメージ
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領域のカナタVIIICELL (りょういきのカナタ エイトセル) 基本情報 アーティスト Dr.Laintrigger Demo feat. 夢眠ネム 配信日 2018/05/23 ジャンル ボーカロイド 原曲 － 解禁方法 解禁条件なし BPM 180 難易度 Ｓ３／Ｎ６／Ｈ１０ 特徴 高速コースNORMAL以上はアドリブ注意 アップデートに伴う特記事項 2018/07/02NORMAL特定箇所にて異常な形のスライドが出現しないように修正。 【アップデート年表へ戻る】 【トップページへ戻る】
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序曲 第１幕 N° 1 – 導入部 【バルドゥッチ】 テレーザ！テレーザ！彼女はどこだ？ テレーザ！ （気付いて）窓のところか！ 禁じておったろう！ 聞いていないのか？ （彼女は窓から離れる） 空気を入れ替えるにはあまりに美しい時なのだ！ ずっと前から呼んでおったのだぞ 教皇がわしをお待ちなのだ わしの杖を！ わしの手袋を！わしの短剣を！そしてその書類ケースだ！ 全く聖人も天使も呪われておるぞ！ 実際 非常に奇妙なことだ 教皇さまがこうして悩ませになるのは この財務官を夜も朝も あのチェッリーニ フィレンツェ人 怠惰な放蕩者めのことでな！ いったいなぜわれらの教皇さまは トスカーナの彫刻家を呼んできたのか あなたさまには彫刻家フィエラモスカがいるというのに 仕事をさせるのなら... 彼はぶつぶつ言いながら去る 【テレーザ】 やっと出て行った 良かったわ... ああ！一息つける ふーっ！何て大変なの！本当にえらい目にあったわ 仮面の合唱 【チェッリーニ,フランチェスコ,ベルナルディーノと仮面の人々】 （舞台裏で） ラララララ 深き淵より！ カーニバルの父は 埋めるのだ 今夜 彼の息子のひとりを！ 深き淵より！ 【テレーザ】 神さま！あれはあの人かしら？ 【チェッリーニ,フランチェスコ,ベルナルディーノと仮面の人々】 ああ 偉大な子らよ 行儀良くあれ！ ああ 偉大な子らよ すべての年齢の すべての身分の 男も女も 泣いてはならぬ カーニバルの月曜の魂を飲み干せ！ N° 2 – アリア 【テレーザ】 美しい花！ （彼女は花束を拾い上げる） 手紙だわ！ （読む） チェッリーニ！ 狂ってるわ！何でなの！ここに来るって！ 今夜に ああ！神さま！でも私の父は 出かけている タイミングはちょうどいいわ どうしましょう？ カヴァティーナ 愛と義務の間で 若い心は大いに嘆かなければいけないの 心が望むことを 心は恐れて 希望さえも退ける いつも非難するふりをして 目を持っていても見ないようにする どうして どうしてそんなことができるの？ 愛と義務の間で．．． 私があなた方の歳になったら 愛する両親よ もっと賢くなれているでしょう だけど１７歳では それは無理なことなのです 本当に無理なのです！ ああ！すぐに私の番がきて 私がおばあさんになったら そのときはどうぞ良いようにしてください 愛することはつらいわ！ 私があなた方の歳になったら．．． N° 3 - デュオとトリオ 【テレーザ】 （激しく動揺しながら） チェッリーニ！... 【チェッリーニ】 テレーザ！私の前から逃げないでくれ！ 【テレーザ】 チェッリーニ あなたのそばに私はいられないわ 【チェッリーニ】 （悲しみと焦りが入り混じって） ああ！その言語は私を殺す！ 【テレーザ】 物音が！ 【チェッリーニ】 心配しないで！ 【テレーザ】 私はもうだめ！ 行って！ 【チェッリーニ】 あの騒ぎは何でもありません 私の名誉にかけて！ あれは陽気なカーニバルが外で歓声を上げているのです 窓の外に放っておいてください 派手な浮かれ騒ぎをしているのを さあ落ち着いて テレーザ あなたの恐怖を静めてください トリオ 【チェッリーニ】 ああテレーザ 私の命よりもずっと愛しているあなた テレーザ！私は今知ったのです こうして遠く離れていると 悲しみと孤独で 私の魂は希望を失うということが 【テレーザ】 ああ！あなたの愛は愚かなこと チェッリーニ 無駄で望みなき苦しみなのです！ あなたは一生私を忘れなければならないのです あなたにはもう会えないのですから 【フィエラモスカ】 （手に巨大な花束を持って つま先立ちで歩いてくる） むりやり門をこじ開けることではない ドアの鍵を壊すことでもない 乙女の心を得るには つま先立ちで歩くことしかないのだ 【チェッリーニ】 嫌です 聖人たちにかけて 聖母さまにかけても！... 【フィエラモスカ】 何と！チェッリーニが！ あそこに隠れよう 【チェッリーニ】 私は信じられないのです おおわがテレーザ 愛があなたを委ねるであろうなどということが あのフィエラモスカの腕に！ 【テレーザ】 ああ！私を守護天使が守って下さいます この恥辱やこの邪悪さから 私は感じています ええ 私は死んでしまうでしょう もし結婚することになれば フィエラモスカと 【フィエラモスカ】 ああ！私に声を出して話す勇気があれば！ ああ！私に一言でも発する勇気があれば！ 【チェッリーニ】 分かったよ テレーザ 私の愛する人よ 聖人の名にかけて 私は知ったのだ こうして遠く離れていると 悲しみと孤独で 私の魂は希望を失うということが 【テレーザ】 けれど あなたの愛は チェッリーニ 愚かなこと 無駄で望みなき苦しみなのです！ このこれ以上あなたの恋する人を呼び出さないでください いいえ あなたにはもう会えないのですから 【チェッリーニ】 （怒って） フィエラモスカめ！ 【テレーザ】 （怒って） フィエラモスカ！何てひどい人！ 【テレーザ】 誰？私があいつの妻に？...私は望むわ それよりも百回のつらい死の方を 【フィエラモスカ】 もしこの手に剣を持っていたならば！ 【チェッリーニ】 ああ！死ぬなんて 親愛なる妹よ あなたは何を言うのです？ そんな残酷なことを考えないで おお私のテレーザ！ いいえ 別の道を行きましょう 花咲く芝の道を 恐れることはありません 愛し合う心には 【テレーザ】 他の道って それは？ 私に何も隠さないで！ 【チェッリーニ】 逆らったりしないで 聞いてください！ 【テレーザ】 もっと小声で話して！ 【チェッリーニ】 （小声で） 明日の夜 カーニバルの火曜日... 【テレーザ】 （小声で） 明日の夜 カーニバルの火曜日... 【フィエラモスカ】 明日 カーニバルの火曜日... 【チェッリーニ】 ああ 決して間違えないで 【テレーザ】 ええ 決して間違えないわ 【フィエラモスカ】 ああ 絶対見逃さないぞ 【チェッリーニ】 コロンナ広場に来てください... 【テレーザ】 コロンナ広場に... 【フィエラモスカ】 コロンナ広場に... 【チェッリーニ】 われらの老カッサンドロが ... 【テレーザ】 われらの老カッサンドロが ... 【フィエラモスカ】 カッサンドロが ... 【チェッリーニ】 ローマの人々のため 上演するのです 新しいオペラを！ 【フィエラモスカ】 新しいオペラを！ 【チェッリーニ】 そこで 夢中にさせている間に 彼の一座が笑わせている間に 心の底からあなたの父上を あなたを... 【テレーザ】 私を... 【フィエラモスカ】 ああ！ 【チェッリーニ】 あなたは腕を取るのです... 【テレーザ】 私が腕を取るの... 【フィエラモスカ】 彼女が腕を取る... 【チェッリーニ】 茶色の服を着た修道士の... 【テレーザ】 茶色の服を着た修道士の... 【フィエラモスカ】 彼女が腕を取るのだ 茶色の服を着た修道士の... 【チェッリーニ】 それから白衣の告解僧の 【テレーザ】 それから白衣の告解僧の 【フィエラモスカ】 それから白衣の告解僧の 【チェッリーニ】 一人はあなたの恋人です... 【テレーザ】 あなたが 本当に？ 【フィエラモスカ】 奴か 【チェッリーニ】 そしてもうひとりは私の弟子 【テレーザ】 あなたの弟子？ 【フィエラモスカ】 奴の弟子か... 【チェッリーニ】 そして私はあなたを連れ去る... 【テレーザ】 彼は私を連れ去る！ 【フィエラモスカ】 彼女を連れ去る！ 【チェッリーニ】 そして二人で急いで 私たちはフィレンツェに行く... 【テレーザ】 フィレンツェに！ 【フィエラモスカ】 フィレンツェに！ 【チェッリーニ】 幸せな日々のために 【チェッリーニ、テレーザ】 そして急いでフィレンツェへ 希望に満ちた心で 私たちは一緒に出発します 【フィエラモスカ】 ふたりだけで 【テレーザ】 おおチェッリーニ そんなことができるの このように私の父を残して それは天を傷つけてることではないの？ 【チェッリーニ】 天を傷つける いや 私は思う あなたの父の方がずっと罪深いと 娘のテレーザに望むのだから 花のような娘を 萎れ 色あせさせようというのだから 修道院の暗闇の中で あるいはフィエラモスカの腕の中で 【テレーザ】 フィエラモスカ！フィエラモスカ！ 【フィエラモスカ】 おお財務官殿！あなたがここにおられれば！ 【テレーザ】 ああ！それは本当ね 私の憎しみが強すぎて この魂を支配しているの 私のお友達 私たちはお願いしましょう 明日 明日の夜！ 【チェッリーニ】 明日の夜お会いしましょう！ 【フィエラモスカ】 明日の夜お会いしましょう！ 【チェッリーニ】 (小声で） それでは時間と場所を間違わないように 繰り返しましょうか？ 【テレーザ】 （声を出して） ええ そうしましょう 声を出して？ 【チェッリーニ】 （小声で） 小声で 小声で話して！ 明日の夜 カーニバルの火曜日... 【テレーザ】 （小声で） 明日の夜 カーニバルの火曜日... 【フィエラモスカ】 明日の夜 カーニバルの火曜日... 【チェッリーニ】 ああ 決して間違えないで 【テレーザ】 ええ 決して間違えないわ 【フィエラモスカ】 ああ 絶対見逃さないぞ 【チェッリーニ】 コロンナ広場に来てください... 【テレーザ】 コロンナ広場に... 【フィエラモスカ】 コロンナ広場に... 【チェッリーニ】 われらの老カッサンドロが ... 【テレーザ】 われらの老カッサンドロが ... 【フィエラモスカ】 われらの老カッサンドロが ... 【チェッリーニ】 ローマの人々のため 上演するのです 新しいオペラを 【テレーザ】 新しいオペラを上演する 【フィエラモスカ】 新しいオペラを上演する 【チェッリーニ】 そこで 夢中にさせている間に 彼の一座が笑わせている間に 心の底からあなたの父上を あなたを... 【テレーザ】 私を... 【フィエラモスカ】 そうか... 【チェッリーニ】 あなたは腕を取るのです... 【テレーザ】 私が腕を取るの... 【フィエラモスカ】 彼女が腕を取る... 【チェッリーニ】 茶色の服を着た修道士の... 【テレーザ】 茶色の服を着た修道士の... 【フィエラモスカ】 彼女が腕を取る... 茶色の服を着た修道士の... 【チェッリーニ】 それから白衣の告解僧の 【テレーザ】 それから白衣の告解僧の 【フィエラモスカ】 それから白衣の告解僧の 【チェッリーニ】 一人はあなたの恋人です... 【テレーザ】 あなたが？ 分かったわ 【フィエラモスカ】 奴か 【チェッリーニ】 そしてもうひとりは私の弟子 【テレーザ】 彼の弟子... 【フィエラモスカ】 奴の弟子か... 【チェッリーニ】 そして私はあなたを連れ去る... 【テレーザ】 彼は私を連れ去る！ 【フィエラモスカ】 連れ去るのか！良かろう！ 【チェッリーニ】 そして二人で急いで 私たちはフィレンツェに行く... 【テレーザ】 フィレンツェに！ 【フィエラモスカ】 フィレンツェに！ 【チェッリーニ】 幸せな日々のために 【テレーザ】 幸せな日々のために 【フィエラモスカ】 幸せに暮らす！ 【三人全員で】 そして急いでフィレンツェへ 希望に満ちた心で 私たち／彼らは一緒に出発します 【チェッリーニ】 大切な愛の約束！ 陶酔に満ちた時！ 私の心の中であなたは甘美だ！ 愛よ お前の翼の下で 見守っておくれ 私の美しい人が この約束をきちんと守ってくれるかどうか 【フィエラモスカ】 ああ！裏切り女め！ 不実なあばずれめ！ 覚えているがいい 【テレーザ】 優しき御母 永遠の処女よ 跪いて希います 私の反抗的な声をお許しください そして静めてください 父の怒りを！ 【チェッリーニとテレーザ】 そう 永遠の死？ 私たちはきっと間違っている！ 若さがいったい そんなところに港を見つけるだろうか 愛が私たちに用意しているというのに 甘美な未来を？ さあ 頭を切り替えて 愛を呼び寄せよう 新しい岸辺に向かって さあ 向かって行こう！ 愛は翼を持っている 嫉妬から逃げ出すための ああ！一緒に行こう こんなところからは逃げ出すのだ ここを去り 他の土地で 幸せな日を過ごそう！ 【チェッリーニとテレーザ】 そう 急いでフィレンツェへ 希望に満ちた心で 私たちは一緒に出発します 【フィエラモスカ】 ああ！裏切り女め！ 不実なあばずれめ！ 覚えているがいい 私の憎しみが 永遠の嘆きへと 変えてやるのだ ひどい女め お前の甘い企てをな！ この甘美な企みを阻止してやるぞ この魅惑の約束を邪魔してやるぞ！ 【チェッリーニ、テレーザ、フィエラモスカ】 明日の夜に会いましょう！ 【チェッリーニ】 （小声で） コロンナ広場で... 【テレーザ】 （小声で） シーッ！ 【チェッリーニ】 劇場の近くに... 【テレーザ】 シーッ！ 【チェッリーニ】 白衣の修道士... 【テレーザ】 ええ 私はそこに行くわ！ 【フィエラモスカ】 良かろう 我々はそこに行こう！ 【チェッリーニとテレーザ】 希望に満ちて... 【３人全員】 明日会いましょう！ ダイアローグ 【テレーザ】 たいへん もうだめだわ お父さまが帰ってきたじゃないの... 【チェッリーニ】 本当に？ 【テレーザ】 お父さまがここに！ 【フィエラモスカ】 （テレーザの部屋のドアを閉じて） フェレットのように私はここに隠れよう チェッリーニは驚いて走り テレーザの部屋のドアを開くそぶりを見せるが 彼女はそれを止めるので チェッリーニは手当たり次第にドアに近づく バルドゥッチがドアを開けたのでチェッリーニはその裏に隠れる バルドゥッチは娘がまだ起きていたことに驚き ドアを閉めるのを忘れる 【バルドゥッチ】 なぜ 娘よ こんな時間にまだこの部屋にいるのだ？ もう真夜中の時を打つ頃だぞ 【テレーザ】 お父さま 男が... 【バルドゥッチ】 男が我が家の中に！ 【テレーザ】 男です 私がベッドに行くときに 大きな音がして！ 【バルドゥッチ】 男がここに 愛しい娘よ 男か！ 急いで灯りを！テレーザ わしがぶっ飛ばしてやる 強盗め 夜盗め （彼はテレーザの部屋に入る） 【テレーザ】 （あわててチェッリーニに） 父がここにいないうちに チェッリーニ 急いで逃げて 【チェッリーニ】 （急いで小声で） ありがとう 私の守護天使よ 明日の夜に 明日また！ （彼は去る） 【テレーザ】 恐怖で心臓がドキドキするわ 【バルドゥッチ】 （部屋の中から） ああ 悪党め 掴まえたぞ！ 【テレーザ】 まあ！何て物音！ 私の部屋の中に誰か入っていたのかしら？ 【バルドゥッチ】 ついて来い 道化者め さもなくば殺すぞ！ （舞台の上にフィエラモスカを引きずり出す） 何だ お前ではないか？ 【テレーザ】 （驚いて） 予想外の獲物だわ！ 【フィエラモスカ】 泥棒ではありません... 【バルドゥッチ】 もっと悪いわい！ 琥珀色で覆われた寝室の泥棒め！ 答えなさい わが婿どのよ 何のために娘の部屋に隠れておったのじゃ？ 【テレーザ】 ええ なぜあなたは私の部屋に隠れていたの？ 【フィエラモスカ】 それは、簡単です （愛想良く） あなたのところに行きたいと思って... 【バルドゥッチ】 呪われた厚かましさじゃ！ 【フィエラモスカ】 しかしバルドゥッチ様 あなたにお話ししたいことが... 【バルドゥッチ】 いい加減にせい！ N° 4 – 終曲 【バルドゥッチとテレーザ】 来てください 近所の人や召使いたちよ！ ガエターナ！ フォルナリーナ！カタリーナ！ ペトロニッラ！スコラスティカ！ ここに ここに 【フィエラモスカ】 聞いてください 騒ぐのを止めて！ 【近所の人々】 ノックしてるのは隣人たちですよ 何の物音です 何の騒ぎです？ 【バルドゥッチ】 助けに来てください 放蕩者が 大胆な女たらしが 私の娘のところに！突然押し入ったのです 放蕩者を狩りに来てください！ 【フィエラモスカ】 私は放蕩者ではありません 大胆な女たらしでもない もう一度言います 私は違います... 【バルドゥッチとテレーザ】 ああ！今は十分注意して あなたが女たちの手に落ちるでしょうから 【バルドゥッチ】 女性たちの腕だけなのだ 正しい道を示すことができるのは でたらめな趣味を持つ連中や 心ない 無法な ブレーキの利かない連中に 【フィエラモスカ】 （驚いて） 女性の手でだって...何という運命だ！ 私はバッカスの巫女たちの獲物にされたオルフェウスなのか？ 【合唱】 ああ！道楽者の先生 ああ！放蕩者め！ あたしたちはあんたに教えてあげるよ 誘惑者さん あたしたちの名誉に敬意を払うことをね あんたにゃ 水浴びしてもらわにゃならないね この庭でそれを訓練するんだよ 明日まで浸けといてやるよ 大きな池の噴水の下に！ ひっくり返しましょう 美人たちの手で ああ！放蕩者 あんたにゃ 水浴びしてもらわにゃならないね！ ああ！道楽者 あたしたちはあんたをしっかり捕まえてやるよ！ ああ！ 【テレーザとバルドゥッチ】 はい 素晴らしい 明日まで 大きな池の噴水の下に！ ひっくり返せ そう それはとても良い ああ！放蕩者！ ああ！裏切り者！ああ！面白い、 お前には最高の水浴びをしてもらおうか ああ！ 【フィエラモスカ】 何！どうして？私が？何てことだ！ 明日まで 大きな池の噴水の下に！ 恐ろしいことだ！ 何てひどい女たちだ！... どうやって彼女たちの手から抜け出せるのか ああ！ （奥のドアを通って逃げ出す） Ouverture ACTE PREMIER N° 1 – Introduction BALDUCCI Teresa! Teresa! Où peut-elle être? Teresa! (l’apercevant) à la fenêtre! Je l’ai pourtant bien défendu! N’avez-vous donc pas entendu? Elle quitte la fenêtre Pour prendre l’air l’heure est fort belle! Depuis un siècle que j’appelle, Le Pape m’attend, mon bâton! Mes gants! ma dague! et ce carton! C’est à damner un saint, un ange! En vérité, c’est bien étrange Que le Pape ainsi dérange Un trésorier, soir et matin, Pour Cellini, ce Florentin, Ce paresseux, ce libertin! Aussi pourquoi, notre Saint-Père, Prendre en Toscane un ciseleur, Quand vous aviez Fieramosca, votre sculpteur, Dont c’est l’affaire... Il sort en grommelant TERESA Enfin il est sorti tout de bon... Ah! je respire; Ouf! quel ennui! c’était un vrai martyre. Chœur de masques CELLINI, FRANCESCO, BERNARDINO et MASQUES dans la coulisse La la la la la De profundis! Carnaval père Enterre Ce soir un de ses fils! De profundis! TERESA Dieu! serait-ce lui? CELLINI, FRANCESCO, BERNARDINO et MASQUES Ô grands enfants Soyez bien sages! Ô grands enfants De tous les âges, De tous les rangs, Hommes ni femmes ne pleurez pas, Buvez à l’âme de Lundi gras! N° 2 – Air TERESA Les belles fleurs! Elle ramasse un bouquet un billet! Elle lit Cellini! Quelle imprudence! eh quoi! venir ici! Ce soir même, ah! grand Dieu! mais mon père Est bien loin, et l’instant est propice, que faire? Cavatine Entre l’amour et le devoir Un jeune cœur est bien à plaindre, Ce qu’il désire il doit le craindre, Et repousser même l’espoir. Se condamner à toujours feindre, Avoir des yeux et ne point voir, Comment, comment le pouvoir? Entre l’amour et le devoir, etc. Quand j’aurai votre âge, Mes chers parents, Il sera temps ’être plus sage, Mais à dix-sept ans Ce serait dommage Vraiment bien dommage! Oh! dès qu’à mon tour Je serai grand-mère Alors laissez faire! Malheur à l’amour! Ah! quand j’aurai votre âge, etc. N° 3 – Duo et trio TERESA avec la plus vive agitation Cellini!... CELLINI Teresa! Ne fuyez pas ma vue! TERESA Cellini, près de vous je ne puis pas rester. CELLINI avec un chagrin mêlé d’impatience Ah! ce langage me tue! TERESA Du bruit! CELLINI Rassurez-vous! TERESA Je suis perdue! Partez! CELLINI Ce bruit n’est rien, sur mon honneur! C’est le gai carnaval qui dehors parle en maître. Laissez-le sous votre fenêtre Agiter son grelot moqueur, Et calmez, Teresa, calmez votre frayeur. Trio CELLINI Ô Teresa, vous que j’aime plus que ma vie, Teresa! je viens savoir Si loin de vous, triste et bannie, Mon âme doit perdre l’espoir. TERESA Las! votre amour n’est que folie, Cellini, un vain tourment et sans espoir! Il faut m’oublier pour la vie Car je ne dois plus vous revoir. FIERAMOSCA entrant sur la pointe du pied, un énorme bouquet à la main Ce n’est pas en forçant les grilles, En jetant bas portes, verrous, Que l’on gagne le cœur des filles; Mais en marchant à pas de loup. CELLINI Non, par les saints, par la Madone!... FIERAMOSCA Dieu! Cellini! Cachons-nous là. CELLINI Je ne puis croire, ô ma Teresa, Qu’amour jamais vous abandonne Aux bras de ce Fieramosca! TERESA Ah! me préserve ma patronne De cette honte, de ce malheur, car je sens là Oui, je mourrai, si l’on me donne A ce Fieramosca. FIERAMOSCA Ah! si j’osais parler tout haut! Ah! si j’osais souffler un mot! CELLINI Eh bien donc, Teresa, ma chère vie, Au nom des saints je viens savoir Si loin de vous, triste et bannie, Mon âme doit perdre l’espoir. TERESA Mais votre amour, Cellini, n’est que folie, Un vain tourment et sans le moindre espoir! Ne m’appelez plus votre amie, Non, je ne dois plus vous revoir. CELLINI avec fureur Fieramosca! TERESA avec fureur Fieramosca! Un tel faquin! TERESA Qui? moi, sa femme?... je préfère Cent fois la mort la plus amère. FIERAMOSCA Si j’avais ma rapière en main! CELLINI Ah! mourir, chère belle, Qu’avez-vous dit là? Cette voie est cruelle, Ô ma Teresa! Non, prenons l’autre route Aux gazons fleuris, Que jamais ne redoute Un cœur bien épris. TERESA L’autre route, et laquelle? Ne me cachez rien! CELLINI Ne soyez pas rebelle, Écoutez-moi bien! TERESA Parlez plus bas! CELLIN à voix basse Demain soir, mardi gras... TERESA à voix basse Demain soir, mardi gras... FIERAMOSCA Demain, mardi gras... CELLINI Ah, surtout n’y manquez pas. TERESA Non, je n’y manquerai pas. FIERAMOSCA Non, je n’y manquerai pas. CELLINI Venez Place Colonne... TERESA Place Colonne... FIERAMOSCA Place Colonne... CELLINI Où notre vieux Cassandro... TERESA Où notre vieux Cassandro... FIERAMOSCA Cassandro... CELLINI Au peuple romain donne Un opéra nouveau! FIERAMOSCA Un opéra nouveau! CELLINI Là, tandis qu’en délire Sa troupe fera rire Votre père aux éclats, Vous... TERESA Moi... FIERAMOSCA Ah! CELLINI Vous saisirez le bras... TERESA Je saisirai le bras... FIERAMOSCA Elle prendra le bras... CELLINI D’un moine en robe brune... TERESA D’un moine en robe brune... FIERAMOSCA Elle prendra le bras D’un moine en robe brune... CELLINI Et d’un pénitent blanc. TERESA Et d’un pénitent blanc. FIERAMOSCA Et d’un pénitent blanc. CELLINI L’un sera votre amant... TERESA Vous, vraiment? FIERAMOSCA Lui. CELLINI Et l’autre mon élève. TERESA Votre élève? FIERAMOSCA Son élève... CELLINI Alors je vous enlève... TERESA Il m’enlève! FIERAMOSCA Il l’enlève! CELLINI Et vite tous les deux Nous allons à Florence... TERESA A Florence! FIERAMOSCA A Florence! CELLINI Couler des jours heureux. CELLINI, TERESA Et vite pour Florence, Le cœur plein d’espérance, Nous partons tous les deux. FIERAMOSCA Tous les deux. TERESA Ô Cellini, se peut-il faire Que je laisse ainsi mon père; N’est-ce pas blesser les cieux? CELLINI Offenser le ciel, non, je pense, Votre père bien plus l’offense En voulant que sa Teresa, Comme une fleur, tombe et s’altère Dans l’ombre d’un couvent austère, Ou la main d’un Fieramosca. TERESA Fieramosca! Fieramosca! FIERAMOSCA Ô trésorier! que n’es-tu là! TERESA Ah! c’en est fait, ma haine est trop forte; Dans mon âme elle l’emporte. Mon ami, prenons espoir, A demain, à demain soir! CELLINI A demain soir! FIERAMOSCA A demain soir! CELLINI à demi-voix Faut-il redire encore l’heure et le lieu de notre rendez-vous? TERESA à haute voix Oui, je viendrai, disons-nous? CELLINI à voix basse Plus bas, parlez plus bas! Demain soir, mardi gras... TERESA à voix basse Demain soir, mardi gras... FIERAMOSCA Demain soir mardi gras... CELLINI Ah, surtout n’y manquez pas. TERESA Non, je n’y manquerai pas. FIERAMOSCA Non, je n’y manquerai pas. CELLINI Venez Place Colonne... TERESA Place Colonne... FIERAMOSCA Place Colonne... CELLINI Où notre vieux Cassandro... TERESA Où notre vieux Cassandro... FIERAMOSCA Où notre vieux Cassandro... CELLINI Au peuple romain donne Un opéra nouveau. TERESA Donne un opéra nouveau. FIERAMOSCA Donne un opéra nouveau. CELLINI Là, tandis qu’en délire Sa troupe fera rire Votre père aux éclats, Vous... TERESA Moi... FIERAMOSCA Oui... CELLINI Vous saisirez le bras... TERESA Je saisirai le bras... FIERAMOSCA Elle prendra le bras... CELLINI D’un moine en robe brune... TERESA D’un moine en robe brune... FIERAMOSCA Elle prendra le bras D’un moine en robe brune... CELLINI Et d’un pénitent blanc. TERESA Et d un pénitent blanc. FIERAMOSCA Et d’un pénitent blanc. CELLINI L’un sera votre amant... TERESA Vous? j’entends. FIERAMOSCA Lui. CELLINI Et l’autre mon élève. TERESA Son élève... FIERAMOSCA Son élève... CELLINI Alors je vous enlève... TERESA Il m’enlève! FIERAMOSCA Il l’enlève! Bien! CELLINI Et vite tous les deux Nous allons à Florence... TERESA A Florence! FIERAMOSCA A Florence! CELLINI Couler des jours heureux. TERESA Couler des jours heureux. FIERAMOSCA Vivre heureux! TOUS LES TROIS Et vite pour Florence, Le cœur plein d’espérance, Nous partons / Ils partent tous les deux. CELLINI Chère et tendre promesse! Ô moments pleins d’ivresse! Pour mon cœur que vous êtes doux! Amour, sous ton aile Garde, garde ma belle Fidèle à son rendez-vous. FIERAMOSCA Ah! femelle traîtresse! Perfide tigresse! Prenez garde à vous. TERESA Mère de tendresse, Vierge que sans cesse J’implore à genoux, Pardonne à ma voix rebelle, Et viens calmer celle D’un père en courroux! CELLINI et TERESA Oui, la mort éternelle? Nous aurions bien tort! La jeunesse doit-elle Chercher là le port, Quand l’amour nous apprête Un doux avenir? Ne tournons point la tête, Laissons-le venir. Vers des rives nouvelles, Vite, éloignons-nous! Les amours ont des ailes Pour fuir les jaloux. Ah ! partons tous les deux, Fuyons loin de ces lieux, Partons et sous d’autres cieux Allons couler des jours heureux! CELLINI et TERESA Oui, soudain pour Florence, Le cœur plein d’espérance, Nous partons tous les deux. FIERAMOSCA Ah! femelle traîtresse! Perfide tigresse! Prenez garde à vous. Ma haine, en plainte éternelle Changera, cruelle, Vos projets si doux! Je saurai déjouer des projets si doux, Je saurai déranger ce charmant rendez-vous! CELLINI, TERESA, FIERAMOSCA A demain soir! CELLINI à voix basse Place Colonne... TERESA à voix basse Chut! CELLINI Près du théâtre... TERESA Chut! CELLINI Un moine blanc... TERESA Oui, j’y serai! FIERAMOSCA Bien. Nous y serons ! CELLINI ET TERESA Espérons... TOUS LES TROIS A demain ! Dialogue TERESA Ciel, nous sommes perdus, c’est le pas de mon père... CELLINI Êtes-vous sûre? TERESA Le voici! FIERAMOSCA renfermant sur lui la porte de la chambre de Teresa Comme un furet, moi, je me cache ici. Cellini courant effaré fait le geste d’ouvrir la chambre de Teresa, qui lui défend d’y entrer; Cellini se jette à tout hasard à côté de la porte d’entrée au moment où Balducci va ouvrir. La porte en s’ouvrant cache Cellini, et Balducci, surpris de voir sa fille encor levée, oublie de la refermer BALDUCCI Eh quoi, ma fille, encor dans la salle à cette heure? Il va bientôt sonner minuit. TERESA Mon père, un homme... BALDUCCI Un homme en ma demeure! TERESA Un homme, quand j’allais me coucher, un grand bruit! BALDUCCI Un homme ici, ma chère fille, un homme! Vite, un flambeau! Teresa, que j’assomme Ce brigand, ce voleur de nuit. Il entre dans la chambre de Teresa TERESA à Cellini rapidement Profitez du départ de mon père, Cellini, fuyez soudain. CELLINI rapidement à voix basse Merci, mon ange tutélaire, A demain soir, à demain ! Il sort TERESA De frayeur je me sens toute émue. BALDUCCI de l’intérieur de la chambre Ah, brigand, je te tiens! TERESA Dieu! quel bruit! Dans ma chambre on s’était introduit? BALDUCCI Suis-moi, drôle, ou si non, je te tue! Il traîne Fieramosca sur la scène Quoi, c’est vous? TERESA vivement Ô capture imprévue! FIERAMOSCA Ce n’est point un voleur... BALDUCCI C’est bien pis! Un larron de boudoir, couvert d’ambre! Répondez ça, monsieur le beau-fils, Qu’étiez-vous venu faire en sa chambre? TERESA Oui, pourquoi vous cacher dans ma chambre? FIERAMOSCA C’est bien simple, d’un air aimable Chez vous je venais en visite... BALDUCCI Impudence maudite! FIERAMOSCA Mais, messer Balducci, je vous dis... BALDUCCI C’est fini! N° 4 – Final BALDUCCI ET TERESA A nous, voisines et servantes! Gaetana! Fornarina! Catarina! Petronilla! Scolastica! A nous, à nous FIERAMOSCA Écoutez-moi, cessez ce train! LES VOISINES On s’assomme chez le voisin; Quel est ce bruit, pourquoi ce train? BALDUCCI A mon secours, un libertin, Un coureur de femmes galantes Est chez ma fille! entrez soudain, Venez chasser ce libertin! FIERAMOSCA Je ne suis point un libertin, Un coureur de femmes galantes. Encore un coup, je ne suis point...etc. BALDUCCI et TERESA Ah ! maintenant, gare à tes reins, Tu vas tomber en bonnes mains. BALDUCCI Ce n’est que le bras féminin Qui peut montrer le droit chemin Aux gens de mœurs extravagantes, Aux gens sans cœur, sans loi, ni frein. FIERAMOSCA épouvanté Aux mains des femmes... quel destin! Suis-je Orphée en proie aux Bacchantes? CHŒUR Ah! maître drôle, ah! libertin! Nous allons t’apprendre, suborneur Les respects dus à notre honneur Tu vas prendre un bain. Entraînons-le dans le jardin Et mettons-le jusqu’à demain Sous le jet d’eau du grand bassin! Tombez dessus, à belles mains Ah! libertin, Tu vas prendre un bain! Ah! drôle, nous t’attraperons bien! Ah! TERESA et BALDUCCI Oui, très bien, jusqu’à demain Sous le jet d’eau du grand bassin! Tombez dessus, oui c’est très bien, Ah! libertin! Ah! traître! ah! drôle, Tu vas prendre un fameux bain Ah! FIERAMOSCA Quoi! qui? moi? grand Dieu! Jusqu’à demain Sous le jet d’eau du grand bassin! C’est une horreur! Quelles mégères!... Comment sortir de leurs mains Ah! Il s’échappe par la porte du fond この日本語テキストは、 クリエイティブ・コモンズ・ライセンス の下でライセンスされています。@ 藤井宏行 Berlioz,Hector/Benvenuto Cellini/II
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