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.
Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Frederick, MD 21702, USA.
Wen Qing
WQ
Li
Qiong
Q
Jiang
Eiman
E
Aleem
Philipp
P
Kaldis
Annette R
AR
Khaled
Scott K
SK
Durum
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