Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Tacrolimus Differentially Regulates the Proliferation of Conventional and Regulatory CD4+ T Cells

  • Kogina, Kazue (Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo) ;
  • Shoda, Hirofumi (Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo) ;
  • Yamaguchi, Yumi (Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo) ;
  • Tsuno, Nelson H (Department of Transfusion Medicine, Graduate School of Medicine, The University of Tokyo) ;
  • Takahashi, Koki (Department of Transfusion Medicine, Graduate School of Medicine, The University of Tokyo) ;
  • Fujio, Keishi (Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo) ;
  • Yamamoto, Kazuhiko (Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo)
  • Received : 2009.06.24
  • Accepted : 2009.07.02
  • Published : 2009.08.31
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Abstract

Tacrolimus is a widely used T cell targeted immunosuppressive drug, known as a calcineurin inhibitor. However, the exact pharmacological effects of tacrolimus on $CD4^+$ T cells have yet to be elucidated. This study investigated the effects of tacrolimus on $CD4^+$ T cell subsets. Mouse or human $CD4^+$ T cells were cultured with immobilized anti-CD3/CD28 antibodies in the presence of tacrolimus. The cell division of $CD4^+$ T cells was analyzed using a flow cytometer according to the expression of Foxp3. The gene expression patterns of tacrolimus-exposed T cells were examined by quantitative PCR. In the case of conventional $CD4^+$ T cells (Tconv cells), tacrolimus inhibited T cell receptor stimulation-induced cell division. In contrast, the cell division of regulatory $CD4^+$ T cells (Treg cells) was even promoted in the presence of tacrolimus, especially in humans. Tacrolimus did not promote conversion of Tconv to Treg cells in mice. Furthermore, tacrolimus modified the expression levels of Foxp3-regulated T cell receptor signal related-genes, PTPN22 and Itk, in human Treg cells. Immunosuppressive effect of tacrolimus may be attributed to the relatively enhanced proliferation of Treg cells in association with altered gene expression levels of TCR signaling molecules.

Keywords

Acknowledgement

Supported by : Japan Society for the Promotion of Science, Ministry of Health, Labour and Welfare of Japan, Ministry of Education, Culture, Sports, Science and Technology of Japan

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