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Studies on the mechanisms of the maturation of germinal center B cells.

Research Project

Project/Area Number 05404024
Research Category

Grant-in-Aid for General Scientific Research (A)

Allocation TypeSingle-year Grants
Research Field Immunology
Research InstitutionThe University of Tokyo

Principal Investigator

TAKATSU Kiyoshi  The University of Tokyo, Inst.Med.Sci., Professor, 医科学研究所, 教授 (10107055)

Co-Investigator(Kenkyū-buntansha) KIKUCHI Yuji  The University of Tokyo, Inst.Med.Sci., Research Associate, 医科学研究所, 助手 (60262078)
KINASHI Tatsuo  The University of Tokyo, Inst.Med.Sci., Research Associate, 医科学研究所, 助手 (30202039)
TAKAKI Satoshi  The University of Tokyo, Inst.Med.Sci., Research Associate, 医科学研究所, 助手 (10242116)
HITOSHI Yasumichi  The University of Tokyo, Inst.Med.Sci., Research Associate, 医科学研究所, 助手 (10222241)
KATAGIRI Takutya  The University of Tokyo, Inst.Med.Sci., Research Associate, 医科学研究所, 助手 (70126100)
刈米 アイ  東京大学, 医科学研究所, 教務職員 (50114450)
Project Period (FY) 1993 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥28,400,000 (Direct Cost: ¥28,400,000)
Fiscal Year 1995: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 1994: ¥9,600,000 (Direct Cost: ¥9,600,000)
Fiscal Year 1993: ¥13,900,000 (Direct Cost: ¥13,900,000)
KeywordsGerminal center / B cells / B cell maturation / Cytokine / Cytokine receptor / CD38 / CD40 / Btk / D40 / 増殖.分化 / サイトカイン レセプター / Ig-アイソタイプ変換 / 接着分子
Research Abstract

In a T-cell dependent immune response, antigen-activated B cells switch their IgH chain expression and hypermutate their VH and VL regions to improve the affinity of its antibodies. This maturation processes are believed to occur in the germinal center. To understand the role of the germinal center for B cell maturation and cellular interactions in germinal centers, we carried out immunohistochemical and functional analysis of germinal center B cell.
(1) We found that some of germinal center B cells in light zone, marginal zone and mantle zone express CD38. IL-5Ralpha positive B cells were localized in light zone and some of them appear to co-express CD38.
(2) IL-4 and IL-5 in the presence of anti-CD40 mAb induced semi-purified GB B cells to differentiate into antigen specific IgG1 antibody-secreting cells. FACS analysis revealed that stimulation of semi-purified GB B cells with IL-4 and anti-CD40 mAb enhanced expression of IL-5Ralpha.
(3) CD38 ligation on B cells induced proliferation, IgM secretion, and tyrosine phosphorylation of Bruton's tyrosine kinase (Btk) in B cells from wild-type mice but not in B cells from XID mice. CD38 ligation can cynergistically acts with IL-5 to enhance B-cell proliferation, Blimp-1 gene expression, and IgM production. Flow cytometry analysis revealed that CD38 ligation enhanced the expression of the IL-5Ralpha on B cells.
(4) Mutational analysis using substitution mutants of IL-5Ralpha revealed that one of the proline residues, particularly Pro352 or Pro355, in the membrane proximal proline-rich sequence (Pro352-Pro353-X-Pro355) of the cytoplasmic domain of IL-5Ralpha is required for cell proliferation and for activation of JAKs/STAT5 pathway.

Report

(4 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • 1993 Annual Research Report
  • Research Products

    (38 results)

All Other

All Publications (38 results)

  • [Publications] Koike,M. et al.: "Defect of IL-5-receptor-mediated signaling in B cells of X-linked immunodeficient mice" Int. Immunol.7. 21-30 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Li,T. et al.: "Activation of Bruton's tyrosine kinase(Btk)by a point mutation in its pleckstrin homology(PH)domain" Immunity. 2. 451-460 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kinashi,T. et al.: "Receptor tyrosine kinase stimulates cell-matrix adhesion by phosphatidylinositol 3 kinase and phospholipase Cγ1 pathway" Blood. 86. 2086-2090 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Takatsu,K.et al.: "Interleukin-5 receptor and CD5-positive B cells" Methods. 8. 45-59 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kikuchi,Y. et al.: "CD38 ligation induces tyrosine phosphorylation of Bruton tyrosine kinase and enhanced expression of interleukin 5 receptor α" Proc. Natl. Acad. Sci. USA. 92. 11814-11818 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Kouro,T. et al.: "Critical residues of cytoplasmic domain of the IL-5 receptor α and its function in IL-5-mediated activation of JAK kinases and STAT5" Int. Immunol.8. 237-245 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Takatsu,K.: "Interleukin-5 as a B cell growth and differentiation factor" John Wiley & Sons(印刷中), (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Takatsu,K.: "Interleukin5 and Its Receptor System:From Genes to Disease" Landes Publishing Inc.(印刷中), (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] M.Koike et al.: "Defect of IL-5-receptor-mediated signaling in B cells of X-linked immunodeficient (XID) mice." Int.Immunol.7. 21-30 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Li et al.: "Activation of Bruton's tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain." Immunity. 2. 451-460 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Kinashi et al.: "Receptor tyrosine kinase stimulates cell-matrix adhesion by phosphatidylinositol 3 kinase and phospholipase C-gamma1 pathways." Blood. 86. 2086-2090 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K.Takatsu et al.: "Interleukin-5 receptor and CD5-positive B cells." Methods. 8. 45-59 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Y.Kikuchi et al.: "CD38 ligation induces tyrosine phosphorylation of Bruton tyrosine kinase and enhanced expression of interleukin-5 receptor alpha chain : Synergistic effects with interleukin 5." Proc.Natl.Acad.Sci.USA.92. 11814-11818 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] T.Kouro et al.: "Critical residues of cytoplasmic domain of the IL-5 receptor alpha chain and its function in IL-5-mediated activation of JAK kinase and STAT5." Int.Immunol.8. 237-245 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K.Takats: Interleukin-5 (IL-5) as a B cell growth and differentiation factor. In "Cytokine Regulation of Immunoglobulin Synthesis and Class Switching". John Wiley & Sons.England (in press), (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] K.Takatsu: Interleukin-5 and Its Receptor System : From Genes to Diseases.Landes Publishing Inc., TX (in press), (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Koike,M et al: "Defect of IL-5-receptor-mediated signaling in B cells of X-linked immunodeficient mice" Int.Immunol.7. 21-30 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Li,T.et al.: "Activation of Bruton′s tyrosine kinase (BtK) by a point mutation in its pleckstrin homelogy (PH) domain" Immunity. 2. 451-460 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] kinashi,T.et al.: "Receptor tyrosine kinase stimulates cell-matrix adhesion by phosphatidy linositol 3 kinasc and phospholipase c-γ1 pathways." Blood. 86. 2086-2090 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takatsu,K.et al.: "Interleukin-5 receptor and CD5-positive Bolls" Methods. 8. 45-59 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] kikuchi,Y.et al.: "CD38 ligation induces tyrosine phosphorylation of Bruton tyrosine kinase and enhanced expression of interleukln-5 receptor a cain" Proc.Natl.Acad.Sci.USA.92. 11814-11818 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Kouro,T.et al.: "Critical residues of cytoplasmic of the IL-5 receptor a chain and its function in IL-5-mediated activation of JAK kinase and STAT5" Int.Immunol.(印刷中). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takatsu,K.: "Interleukin-5 (IL-5) as a Ball growth and differentiation facter" John Wiley & Sons(印刷中), (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takatsu,K.: "Interleukin-5 and Its Receptor System:From Genes to Diseases" Landes.Publishing Inc(印刷中), (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] M.Koike 他: "IL-5 and its receptor-which role do they play in the immune system." International Archives Allergy and Immuruslogy. 104. 1-9 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] T.Fukuda 他: "Detection of interleukin-5 messenger RNA and interlenkin-5 protein in bronchial biopsies from asthma by in situ hybridization." Journal of Allergy and Clinical Immurology. 94. 584-593 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] K.Takatsu 他: "Interleukir-5 and its receptor system in the immune system and inflammstion." Advanus in Immurology. 57. 145-190 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] S.Takaki 他: "Critical cytoplasmic domain of the IL-5R α chain and its function in IL-5-mediated gronth Signal transduction" Journal of Experimental Medicine. 12. 7404-7413 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] I.Akutsu: "Passive administration of anti-IL-5-antibody into chronically ovadbumin-sensitized guinea pigs indmus suppression of eosinophilia" Immunslogy Letters. (印刷中). (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] 高津 聖志: "IL-5とアレルギー疾患" アレルギー. 43. 1229-1239 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] K.Takatsu: "Advanres in Cell and Molecular Biology of Membranes and Organelles" JAI Press-, 236 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] S.Takaki: "Reconstitution of the functional receptors for murine and human interleukin 5" Journal of Experimental Medicine. 177. 1523-1529 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Y.Hitoshi: "Delayed progression of a murine retrovirus induced acquired immunodeficiency syndrome in X-linked immunodeficient mice" Journal of Experimental Medicine. 177. 621-626 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] S.Katoh: "Maintainance of CD5^+ B cells at an early developmental stage by interleukin-5:evidence from immunoglobulin gene usage in IL-5 transgenic mice" DNA and cell Biology. 12. 481-491 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Y.Hitoshi: "Interleukin 5 receptor positive B cells,but not eosinophils are functionally and numerically influenced in the mice carrying X-linked immune defect." International Immunology. 5. 1183-1190 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] S.Mita: "Comparative analysis of Kinetic finding,internalization and degradation of IL-5 receptors of high- and low-affinity" Journal of Immunology. 151. 6924-6932 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Y.Kikuchi: "Biochemical and functional characterization of soluble form of IL-5 receptor α(sIL-5Rα):development of ELISA system for detection of sIL-5Rα." Journal of Immunological Methods. 167. 289-298 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] K.Takatsu: "Advances in Immunology" Academic Press(印刷中), (1994)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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