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.
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.
Lee
Hyeon-Woo
HW
Immunomodulation Research Center, University of Ulsan, Ulsan, Korea.
Nam
Kyung-Ok
KO
Park
Su-Jung
SJ
Kwon
Byoung S
BS
D000818:Animals; D015703:Antigens, CD; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics*; D002455:Cell Division; D003432:Cross-Linking Reagents; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000235:genetics*; D015870:Gene Expression; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D015703:Antigens, CD; C486196:Ccnd2 protein, mouse; C534697:Ccnd3 protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D003432:Cross-Linking Reagents; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E; D016213:Cyclins; D007376:Interleukin-2; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505715:Tnfrsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27