CD28 confers CD4+ T cells with resistance to cyclosporin A and tacrolimus but to different degrees

Hiroyuki Kawai, Fumiko Yagyu, Aki Terada, Tsukasa Matsunaga, Manabu Inobe

Laboratory of Human Molecular Genetics, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan

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.
Conclusion: 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.
Key words: Cyclosporin A, Tacrolimus, Calcineurin inhibitor, CD28, T-cell activation