4-1BB enhances CD8+ T cell expansion by regulating cell cycle progression through changes in expression of cyclins D and E and cyclin-dependent kinase inhibitor p27kip1

Eur J Immunol. 2003 Aug;33(8):2133-41. doi: 10.1002/eji.200323996.


The T cell costimulatory receptor 4-1BB enhances cell cycle progression and proliferation of CD8(+) T cells in both an IL-2-dependent and -independent manner. In these studies, 4-1BB costimulation was shown to increase cyclin D2, D3, and E expression, and concomitantly down-regulate the expression of the cyclin-dependent kinase inhibitor p27(kip1). 4-1BB increases cyclin D2 transcription via mitogen-activated/extracellular signal-regulated kinase-1/2 and LY294002-sensitive phosphatidylinositol 3-kinase (PI3K) signaling pathways. In addition, 4-1BB up-regulates cyclin D2 translation via PI3K/Akt/mammalian target of rapamycin (mTOR) pathways, presumably triggered by IL-2/IL-2 receptor ligation. The enhanced cyclin D2 and D3 expression initiates up-regulation of cyclin E expression and down-regulation of p27(kip1). Our results suggest a role for cyclin D2, D3, and E, and p27(kip1) proteins in the 4-1BB-mediated cell cycle progression of CD8(+) T cells in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD
  • CD8-Positive T-Lymphocytes / cytology*
  • CD8-Positive T-Lymphocytes / physiology*
  • Cell Cycle
  • Cell Cycle Proteins / genetics*
  • Cell Division
  • Cross-Linking Reagents
  • Cyclin D2
  • Cyclin D3
  • Cyclin E / genetics
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclins / genetics*
  • Gene Expression
  • In Vitro Techniques
  • Interleukin-2 / pharmacology
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Inbred BALB C
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Nerve Growth Factor / physiology*
  • Receptors, Tumor Necrosis Factor / physiology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Suppressor Proteins / genetics*


  • Antigens, CD
  • Ccnd2 protein, mouse
  • Ccnd3 protein, mouse
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • Cross-Linking Reagents
  • Cyclin D2
  • Cyclin D3
  • Cyclin E
  • Cyclins
  • Interleukin-2
  • RNA, Messenger
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27