Abstract
During T-cell activation, a number of cytokine-activated signaling cascades, including the Jak-STAT, phosphoinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase (MAPK) pathways, play important roles in modulating the expression of target genes and mediating a cellular response. We now report that interleukin 2 (IL-2) and IL-15, but not IL-7, rapidly activate the p90 ribosomal S6 kinases, Rsk1 and Rsk2, in human T lymphocytes. Surprisingly, mouse spleen T cells transduced with either the wild-type or a dominant-negative (DN) Rsk2-expressing retrovirus could not be recovered, in contrast to the normal survival of T cells transduced with retroviruses expressing wild-type or DN mutants of Rsk1 or Rsk3. Examination of Rsk2 knockout (KO) mice revealed normal T-cell development, but these T cells had delayed cell-cycle progression and lower production of IL-2 in response to anti-CD3 and anti-CD28 stimulation in vitro. Moreover, Rsk2 KO mice had defective homeostatic T-cell expansion following sublethal irradiation in vivo, which is known to involve T-cell receptor (TCR), IL-2, and/or IL-15 signals, each of which we demonstrate can rapidly and potently activate Rsk2 in mouse T cells. These results indicate an essential nonredundant role of Rsk2 in T-cell activation.
MeSH terms
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Animals
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CD28 Antigens / genetics
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CD28 Antigens / immunology
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CD3 Complex / genetics
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CD3 Complex / immunology
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Cell Cycle / drug effects
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Cell Cycle / immunology*
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Cell Cycle / radiation effects
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Cell Survival / drug effects
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Cell Survival / genetics
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Cell Survival / immunology
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Cell Survival / radiation effects
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Cells, Cultured
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Enzyme Activation / immunology
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Enzyme Activation / radiation effects
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / immunology
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Genes, Dominant / immunology
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Homeostasis / drug effects
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Homeostasis / genetics
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Homeostasis / immunology
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Homeostasis / radiation effects
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Humans
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Interleukin-15 / genetics
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Interleukin-15 / immunology
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Interleukin-2 / genetics
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Interleukin-2 / immunology
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Janus Kinases / genetics
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Janus Kinases / immunology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Lymphocyte Activation / radiation effects
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / immunology*
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MAP Kinase Signaling System / radiation effects
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Retroviridae
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Ribosomal Protein S6 Kinases, 90-kDa / genetics
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Ribosomal Protein S6 Kinases, 90-kDa / immunology*
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STAT Transcription Factors / genetics
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STAT Transcription Factors / immunology
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Spleen / cytology
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Spleen / immunology*
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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Transduction, Genetic
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Whole-Body Irradiation
Substances
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CD28 Antigens
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CD3 Complex
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IL2 protein, human
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Interleukin-15
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Interleukin-2
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Receptors, Antigen, T-Cell
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STAT Transcription Factors
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Janus Kinases
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RPS6KA1 protein, human
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Ribosomal Protein S6 Kinases, 90-kDa
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Rps6ka1 protein, mouse
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ribosomal protein S6 kinase, 90kDa, polypeptide 3
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Extracellular Signal-Regulated MAP Kinases