title: Tacrolimus differentially regulates the proliferation of conventional and regulatory CD4(+) T cells.
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.
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Kogina
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Shoda
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Nelson H
authors.initials: NH
authors.lastname: Tsuno
authors.forename: Koki
authors.initials: K
authors.lastname: Takahashi
authors.forename: Keishi
authors.initials: K
authors.lastname: Fujio
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D011505:Protein-Tyrosine Kinases; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D016559:Tacrolimus