Cell cycle arrest induced by engagement of B7-H4 on Epstein-Barr virus-positive B-cell lymphoma cell lines

Ga Bin Park, Hyunkeun Song, Yeong Seok Kim, Minjung Sung, Jeoung W. Ryu, Hyun Kyung Lee, Dae Ho Cho, Daejin Kim, Wang J. Lee, Dae Y. Hur

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Abstract

Summary B7-H4 is a recently discovered B7 family member that has inhibitory effects on T-cell immunity. However, the reverse signalling mechanism of the B7-H4-expressing cells remains unclear. Previous work has shown that B7-H4 expression was enhanced on B cells following Epstein-Barr virus (EBV) infection, and engagement of cell-surface-expressed B7-H4 induces cell death of EBV-transformed B cells. Here we found that B7-H4 was constitutively expressed on EBV-positive lymphoma cells, Raji and IM-9 cells, but was not expressed on EBV-negative lymphoma cells (Ramos). Engagement of B7-H4 significantly reduced cell growth of Raji and IM-9 cells and resulted in cell cycle arrest at G0-G1 phase in a dose- and time-dependent manner. To clarify the mechanism of cell cycle arrest via activation of B7-H4, cell cycle regulatory factors were examined by reverse transcription-polymerase chain reaction and immunoblotting. We found that B7-H4 triggered down-regulation of CDK4/6 and up-regulation of p21 expression at both protein and RNA levels. Furthermore, CDK2 and cyclin E/D expression was down-regulated by B7-H4 triggering. Additionally, the down-regulation of phospho-AKT and phospho-cyclin E were clearly detected in B7-H4-activated Raji cells, but the phosphorylation of p53 was constitutively maintained. These results indicate that B7-H4-mediated signalling on EBV-positive B-cell lymphoma cells modulates the cell cycle through down-regulation of the AKT pathway. Consequently, B7-H4 may be a new potential target for use in EBV-positive lymphoma therapy.

Original languageEnglish
Pages (from-to)360-368
Number of pages9
JournalImmunology
Volume128
Issue number3
DOIs
Publication statusPublished - 2009 Nov 1
Externally publishedYes

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Keywords

  • Apoptosis
  • B cells
  • B7-H4
  • Cancer
  • Cell cycle
  • Costimulation
  • Epstein-Barr virus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Park, G. B., Song, H., Kim, Y. S., Sung, M., Ryu, J. W., Lee, H. K., Cho, D. H., Kim, D., Lee, W. J., & Hur, D. Y. (2009). Cell cycle arrest induced by engagement of B7-H4 on Epstein-Barr virus-positive B-cell lymphoma cell lines. Immunology, 128(3), 360-368. https://doi.org/10.1111/j.1365-2567.2009.03111.x