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  • Title: CD28 confers CD4+ T cells with resistance to cyclosporin A and tacrolimus but to different degrees.
    Author: Kawai H, Yagyu F, Terada A, Matsunaga T, Inobe M.
    Journal: Asian Pac J Allergy Immunol; 2024 Sep; 42(3):298-304. PubMed ID: 33638630.
    Abstract:
    BACKGROUND: Cyclosporin A (CSA) and tacrolimus (TAC) suppress T-cell activation and subsequent proliferation by inhibiting calcineurin. Though they have the same target, CSA and TAC have quite different molecular structures, indicating quantitative and/or qualitative differences in their effects. OBJECTIVE: CD28 is a costimulatory molecule that enhances T-cell activation. It has also been shown to attenuate calcineurin inhibitors. In this study, we compared the CD28-mediated resistance of CD4+ T cells to those calcineurin inhibitors and tried to predict CD28's impact on infectious diseases. METHODS: CD4+ T-cell proliferation was induced with anti-CD3 mAb in the presence or absence of anti-CD28 mAb in vitro. CSA or TAC was added at various concentrations, and the half-maximal inhibitory concentration on CD4+ T-cell proliferation was determined. Effects of lipopolysaccharide (LPS) on dendritic cells (DCs) and CD4+ T-cell proliferation were also evaluated in vitro. RESULTS: Anti-CD28 mAb conferred CD4+ T cells with resistance to both CSA and TAC, and CD28's effect on the latter was approximately twice that on the former. LPS induced expression of CD28 ligands CD80/86 on DCs. The addition of LPS to culture containing DCs seemed to make CD4+ T cells slightly resistant to TAC but not to CSA. However, its effect on the former was very weak under our experimental conditions. CONCLUSIONS: CD28 attenuated TAC more strongly than CSA. Although LPS did not demonstrate strong enough resistance in our in vitro model, TAC might maintain a better antibacterial immune response than CSA in clinical use.
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