LY294002 and rapamycin co-operate to inhibit T-cell proliferation

Authors

  • Elaine M Breslin,

    1. Infection and Immunity, Wales College of Medicine, Cardiff University, Henry Wellcome Research Building, Heath Park, Cardiff CF14 XX
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  • Paul C White,

    1. Infection and Immunity, Wales College of Medicine, Cardiff University, Henry Wellcome Research Building, Heath Park, Cardiff CF14 XX
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  • Angharad M Shore,

    1. Infection and Immunity, Wales College of Medicine, Cardiff University, Henry Wellcome Research Building, Heath Park, Cardiff CF14 XX
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  • Mathew Clement,

    1. Infection and Immunity, Wales College of Medicine, Cardiff University, Henry Wellcome Research Building, Heath Park, Cardiff CF14 XX
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  • Paul Brennan

    Corresponding author
    1. Infection and Immunity, Wales College of Medicine, Cardiff University, Henry Wellcome Research Building, Heath Park, Cardiff CF14 XX
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Infection and Immunity, Wales College of Medicine, Cardiff University, Henry Wellcome Research Building, Heath Park, Cardiff CF14 XX. E-mail: brennanp@cardiff.ac.uk

Abstract

  • 1T-cell proliferation is critical for mounting an effective adaptive immune response. It is regulated by signals through the T-cell receptor, through co-stimulation and through cytokines such as interleukin-2 (IL-2). Phosphatidylinositol 3-kinase (PI3K) lies downstream of each of these pathways and has been directly implicated in the regulation of lymphocyte proliferation.
  • 2In this study, we have shown that PI3K regulates cyclin D2 and cyclin D3, the first cell cycle proteins induced in T-cell proliferation, transcriptionally and post-transcriptionally. In T-lymphoblasts, LY294002, a PI3K inhibitor, prevents the induction of both D-type cyclin mRNA and protein, while rapamycin inhibits the induction of protein. Rapamycin inhibits mammalian target of rapamycin (mTOR), which lies downstream of PI3K.
  • 3Furthermore, our data show that the combination of LY294002 and rapamycin results in a co-operative inhibition of T-cell proliferation. This co-operation occurs in Kit225 cells stimulated with IL-2, and also in resting peripheral blood lymphocytes stimulated with antibodies to the T-cell receptor in the presence and absence of antibodies to CD28.
  • 4These data indicate that PI3K regulates T-cell proliferation in response to diverse stimuli, and suggest that combinations of inhibitors, perhaps isoform-selective, may be useful as alternative immunosuppressive therapies.

British Journal of Pharmacology (2005) 144, 791–800. doi:10.1038/sj.bjp.0706061

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