IL-7 promotes T cell proliferation through destabilization of p27Kip1.
Interleukin (IL)-7 is required for survival and homeostatic proliferation of T lymphocytes. The survival effect of IL-7 is primarily through regulation of Bcl-2 family members; however, the proliferative mechanism is unclear. It has not been determined whether the IL-7 receptor actually delivers a proliferative signal or whether, by promoting survival, proliferation results from signals other than the IL-7 receptor. We show that in an IL-7-dependent T cell line, cells protected from apoptosis nevertheless underwent cell cycle arrest after IL-7 withdrawal. This arrest was accompanied by up-regulation of the cyclin-dependent kinase inhibitor p27Kip1 through a posttranslational mechanism. Overexpression of p27Kip1 induced G1 arrest in the presence of IL-7, whereas knockdown of p27Kip1 by small interfering RNA promoted S phase entry after IL-7 withdrawal. CD4 or CD8 T cells transferred into IL-7-deficient hosts underwent G1 arrest, whereas 27Kip1-deficient T cells underwent proliferation. We observed that IL-7 withdrawal activated protein kinase C (PKC)theta and that inhibition of PKCtheta with a pharmacological inhibitor completely blocked the rise of p27Kip1 and rescued cells from G1 arrest. The conventional pathway to breakdown of p27Kip1 is mediated by S phase kinase-associated protein 2; however, our evidence suggests that PKCtheta acts via a distinct, unknown pathway inducing G1 arrest after IL-7 withdrawal from T cells. Hence, IL-7 maintains T cell proliferation through a novel pathway of p27Kip1 regulation.
Li
Wen Qing
WQ
Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Frederick, MD 21702, USA.
Jiang
Qiong
Q
Aleem
Eiman
E
Kaldis
Philipp
P
Khaled
Annette R
AR
Durum
Scott K
SK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000276:immunology; D034741:RNA, Small Interfering / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
C493961:Cdkn1b protein, mouse; D004791:Enzyme Inhibitors; D015851:Interleukin-7; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011493:Protein Kinase C