Roscovitine suppresses CD4+ T cells and T cell-mediated experimental uveitis

Zili Zhang, Qi Liu, Konstantin S. Leskov, Xiumei Wu, Jie Duan, Gary L. Zhang, Mark Hall, James T. Rosenbaum

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background: T cells are essential for the development of uveitis and other autoimmune diseases. After initial activation, CD4+ lymphocytes express the co-stimulatory molecule OX40 that plays an important role in T cell proliferation. Cyclin dependent kinase 2 (CdK2) plays a pivotal role in the cell cycle transition from G1 to S phase. In addition, recent research has implicated CdK2 in T cell activation. Thus, we sought to test the immunosuppressive effect of roscovitine, a potent CdK2 inhibitor, on CD4+ T cell activation, proliferation, and function. Design and Methods: Mouse CD4+ T cells were activated by anti-CD3 and anti-CD28 antibodies. The expression of OX40, CD44, and CdK2 were analyzed by flow cytometry. In addition, cell cycle progression and apoptosis of control and roscovitine-treated T lymphocytes were measured by BrdU incorporation and annexin V assay, respectively. Furthermore, the immunoregulatory effect of roscovitine was evaluated in both ovalbumin-induced uveitis and experimental autoimmune uveitis (EAU) models. Results: In this study, we found that T cell activation induced OX40 expression. Cell cycle analysis showed that more CD4+OX40+ cells entered S phase than OX40- T cells. Concurrently, CD4+OX40+ cells had a higher level of CdK2 expression. Roscovitine treatment blocked activated CD4+ cells from entering S phase. In addition, roscovitine not only reduced the viability of CD4+ lymphocytes but also suppressed T cell activation and cytokine production. Finally, roscovitine significantly attenuated the severity of T cell-dependent, OX40-enhanced uveitis. Conclusion: These results implicate CdK2 in OX40-augmented T cell response and expansion. Furthermore, this study suggests that roscovitine is a novel, promising, therapeutic agent for treating T cell-mediated diseases such as uveitis.

Original languageEnglish (US)
Article numbere81154
JournalPloS one
Volume8
Issue number11
DOIs
StatePublished - Nov 18 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Zhang, Z., Liu, Q., Leskov, K. S., Wu, X., Duan, J., Zhang, G. L., Hall, M., & Rosenbaum, J. T. (2013). Roscovitine suppresses CD4+ T cells and T cell-mediated experimental uveitis. PloS one, 8(11), [e81154]. https://doi.org/10.1371/journal.pone.0081154