Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adjuvants, Immunologic / deficiency
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / physiology*
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Animals
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Antigens / administration & dosage
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Antigens / immunology
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CD3 Complex / immunology
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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Cell Cycle Proteins*
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclins / physiology
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Cytokines / antagonists & inhibitors
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Cytokines / physiology*
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Growth Inhibitors / physiology
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Hemocyanins / administration & dosage
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Hemocyanins / immunology
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Immune Sera / pharmacology
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Immunologic Memory / genetics
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Immunologic Memory / immunology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Microtubule-Associated Proteins / deficiency
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / physiology*
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STAT6 Transcription Factor
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Signal Transduction / genetics
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Signal Transduction / immunology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Tumor Suppressor Proteins*
Substances
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Adjuvants, Immunologic
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Antigens
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CD3 Complex
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Cdkn1a protein, mouse
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Cytokines
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Growth Inhibitors
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Immune Sera
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Microtubule-Associated Proteins
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STAT6 Transcription Factor
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Stat6 protein, mouse
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Trans-Activators
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Hemocyanins
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keyhole-limpet hemocyanin