Abstract
The cyclin-dependent kinase inhibitor p27(Kip1) is a critical regulator of T cell proliferation. To further examine the relationship of T cell proliferation and differentiation, we examined the ability of T cells deficient in p27(Kip1) to differentiate into Th subsets. We observed increased Th2 differentiation in p27(Kip1)-deficient cultures. In addition to increases in CD4(+) and CD8(+) T cells, there is a similar increase in gamma delta T cells in p27(Kip1)-deficient mice compared with wild-type mice. The increase in Th2 differentiation is correlated to an increase of IL-4 secretion by CD4(+)DX5(+)TCR alpha beta(+)CD62L(low) T cells but not to increased expansion of differentiating Th2 cells. While STAT4- and STAT6-deficient T cells have diminished proliferative responses to IL-12 and IL-4, respectively, proliferative responses are increased in T cells doubly deficient in p27(Kip1) and STAT4 or STAT6. In contrast, the increased proliferation and differentiative capacity of p27(Kip1)-deficient T cells has no effect on the ability of STAT4/p27(Kip1)- or STAT6/p27(Kip1)-deficient CD4(+) cells to differentiate into Th1 or Th2 cells, respectively. Thus, while p27(Kip1) regulates the expansion and homeostasis of several T cell subsets, it does not affect the differentiation of Th subsets.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CD4 Antigens / biosynthesis
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Division / genetics
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Cell Division / immunology
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / metabolism
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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Enzyme Inhibitors / pharmacology
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Homeostasis / genetics
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Homeostasis / immunology*
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Immunophenotyping
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Interleukin-4 / biosynthesis
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Interleukin-4 / metabolism
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Lymphocyte Activation / genetics
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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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Receptors, Antigen, T-Cell, gamma-delta / biosynthesis
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STAT4 Transcription Factor
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STAT6 Transcription Factor
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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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T-Lymphocyte Subsets / physiology*
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Th2 Cells / cytology
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Th2 Cells / immunology
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Th2 Cells / metabolism
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Trans-Activators / deficiency
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Trans-Activators / genetics
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
Substances
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CD4 Antigens
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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DNA-Binding Proteins
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Enzyme Inhibitors
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Receptors, Antigen, T-Cell, gamma-delta
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STAT4 Transcription Factor
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STAT6 Transcription Factor
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Stat4 protein, mouse
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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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Interleukin-4
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Cyclin-Dependent Kinases