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2001 Fiscal Year Final Research Report Summary

Isolation of PD-1 ligands and their application for immunosuppression

Research Project

Project/Area Number 12557030
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Immunology
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

HONJO Tasuku  Kyoto Univ., Dept. of Med. Chem., Professor, 医学研究科, 教授 (80090504)

Co-Investigator(Kenkyū-buntansha) SHINOHARA Takashi  Kyoto Univ., Dept. of Med. Chem., Lecturer, 医学研究科, 助手 (30322770)
Project Period (FY) 2000 – 2001
KeywordsAutoimmunity / PD-1 / PD-L1 / PD-L2 / SHP-2
Research Abstract

PD-1 -deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identified PD-1 ligand 1 and 2 (PD-L1 and PD-L2) as ligands for PD-1 by computer-based homology search. Both ligands are expressed on nonlymphoid tissues, such as heart or liver. Engagement of PD-1 by PD-1 ligands leads to the inhibition of T cell receptor mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-ligands are expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon, and activated human and murine dendritic cells. Therefore, the relative levels of inhibitory PD-1 ligands and costimulatory B7-1/B7-2 signals on antigen presenting cells may determine the extent of lymphocyte activation and consequently the threshold between tolerance and autoimmunity.
In addition, we … More also generated chimeric molecules composed of the IgG Fc receptor type IIB extracellular region and the PD-1 cytoplasmic region and expressed them in a B lymphoma cell line, IIA1.6. Coligation of the cytoplasmic region of PD-1 with the B cell receptor (BCR) in IIA1.6 transformants inhibited BCR-mediated growth retardation, and tyrosine phosphorylation of effector molecules, including Ig beta, Syk, phospholipase C-gamma 2 and ERK1/2. Mutagenesis studies indicated that these inhibitory effects do not require the N-terminal tyrosine in the immunoreceptor tyrosine-based inhibitory motif-like sequence, but do require the other tyrosine residue in the C-terminal tail. This tyrosine was phosphorylated and recruited src homology 2-domain-containing tyrosine phosphatase 2 (SHP-2) on cologation of PD-1 with BCR. These results show that PD-1 can inhibit BCR signaling by recruiting SHP-2 to its phosphotyrosine and dephosphorylating key signal transducers of BCR signaling.
Taken together, we identified two PD-1 ligands and showed that the inhibitory signal of PD-1 is mediated by SHP-2. Less

  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Freeman, G.J. et al.: "Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation"J. Exp. Med.. 192. 1027-1034 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Latchman, Y. et al.: "PD-L2 is a second ligand for PD-1 and inhibits T cell activation"Nat. Immunol.. 2. 261-268 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nishimura, H. et al.: "PD-1 : an inhibitory immunoreceptor involved in peripheral tolerance"Trends Immunol.. 22. 265-268 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Okazaki, T. et al.: "PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting Src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine"Proc. Natl. Acad. Sci. USA. 98. 13866-13871 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Carter, L. et al.: "PD-1 : PD-L inhibitory pathway affects both CD-4(+) and CDS(+) T cells and is overcome by IL-2"Eur. J. Immunol.. 32. 634-643 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 1. Freeman, G.J. et al.: "Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation"J. Exp. Med.. 192. 1027-1034 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Latchman, Y et al.: "PD-L2 is a second ligand for PD-1 and inhibits T cell acitivation."Nat. Immumol.. 2. 261-268 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nishimura, H et al.: "PD-1 an inhibitory immunoreceptor involved in peripheral tolerance"Trendo Immunal. 22. 265-268 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okazaki, T. et al.: "PD-1 immunoreceptor inhibits B cell receptor mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine"Proc. Natl. Acad. Sci. USA. 98. 13866-13871 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Carter, L. et al.: "PD-1: PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2"Eur. J. Immunol.. 32. 634-643 (2002)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2003-09-17  

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