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 (Jim) Rosenbaum

Research output: Contribution to journalArticle

4 Citations (Scopus)

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

Fingerprint

T-cells
Uveitis
T-lymphocytes
Cyclin-Dependent Kinase 2
T-Lymphocytes
cyclin-dependent kinase
Chemical activation
S Phase
interphase
cell cycle
Cell Cycle
Lymphocytes
Cells
roscovitine
lymphocytes
Cell Proliferation
immunosuppressive agents
Flow cytometry
autoimmune diseases
Annexin A5

ASJC Scopus subject areas

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

Cite this

Roscovitine suppresses CD4+ T cells and T cell-mediated experimental uveitis. / Zhang, Zili; Liu, Qi; Leskov, Konstantin S.; Wu, Xiumei; Duan, Jie; Zhang, Gary L.; Hall, Mark; Rosenbaum, James (Jim).

In: PLoS One, Vol. 8, No. 11, e81154, 18.11.2013.

Research output: Contribution to journalArticle

Zhang, Z, Liu, Q, Leskov, KS, Wu, X, Duan, J, Zhang, GL, Hall, M & Rosenbaum, JJ 2013, 'Roscovitine suppresses CD4+ T cells and T cell-mediated experimental uveitis', PLoS One, vol. 8, no. 11, e81154. https://doi.org/10.1371/journal.pone.0081154
Zhang Z, Liu Q, Leskov KS, Wu X, Duan J, Zhang GL et al. Roscovitine suppresses CD4+ T cells and T cell-mediated experimental uveitis. PLoS One. 2013 Nov 18;8(11). e81154. https://doi.org/10.1371/journal.pone.0081154
Zhang, Zili ; Liu, Qi ; Leskov, Konstantin S. ; Wu, Xiumei ; Duan, Jie ; Zhang, Gary L. ; Hall, Mark ; Rosenbaum, James (Jim). / Roscovitine suppresses CD4+ T cells and T cell-mediated experimental uveitis. In: PLoS One. 2013 ; Vol. 8, No. 11.
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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.",
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AU - Zhang, Gary L.

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AB - 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.

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