Cytokine-stimulated T lymphocyte proliferation is regulated by p27Kip1.
T lymphocyte growth is regulated by the cyclin-dependent kinase inhibitor p27(Kip1). Mice deficient in p27(Kip1) have increased proliferative responses to multiple cytokines, including IL-2, IL-4, and IL-12, but not to anti-CD3. In the absence of p27(Kip1), T cells proliferate faster than control cells, as evidenced by increased [(3)H]thymidine uptake, increased cell growth and division, and an increased number of cells in S phase. Importantly, this regulation is specific for p27(Kip1) in T cells, because hyperproliferation of T cells from mice deficient in p21(Cip1/Waf1) was not observed. In vivo, there is an expansion of activated/memory CD4(+) cells in p27(Kip1)-deficient mice before and after immunization. Furthermore, Ag-stimulated spleen cells from immunized p27(Kip1)-deficient mice demonstrated increased proliferative responses to IL-2 and increased secretion of IFN-gamma. Although IL-4 stimulated proliferative responses are diminished in Stat6-deficient T cells, activated T cells from mice doubly deficient in both p27(Kip1) and Stat6 recover normal proliferative responses to IL-4. Together, these data firmly support a role for p27(Kip1) as a negative regulator of cytokine-stimulated T cell growth.
Zhang
S
S
Department of Microbiology and Immunology and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Lawless
V A
VA
Kaplan
M H
MH
D000276:Adjuvants, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D006131:Growth Inhibitors / Q000502:physiology; D006433:Hemocyanins / Q000008:administration & dosage / Q000276:immunology; D007106:Immune Sera / Q000494:pharmacology; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics; D025521:Tumor Suppressor Proteins
D000276:Adjuvants, Immunologic; D000941:Antigens; D017252:CD3 Complex; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016207:Cytokines; D006131:Growth Inhibitors; D007106:Immune Sera; D008869:Microtubule-Associated Proteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin