In CD28-costimulated human naïve CD4+ T cells, I-κB kinase controls the expression of cell cycle regulatory proteins via interleukin-2-independent mechanisms

Immunology. 2010 Oct;131(2):231-41. doi: 10.1111/j.1365-2567.2010.03297.x.

Abstract

Stimulation of naïve CD4(+) T cells through engagement of the T-cell receptor (TCR) and the CD28 co-receptor initiates cell proliferation which critically depends on interleukin (IL)-2 secretion and subsequent autocrine signalling via the IL-2 receptor. However, several studies indicate that in CD28-costimulated T cells additional IL-2-independent signals are also required for cell proliferation. In this study, using a neutralizing anti-human IL-2 antibody and two selective, structurally unrelated, cell-permeable I-κB kinase (IKK) inhibitors, BMS-345541 and PS-1145, we show that in human naïve CD4(+) T cells stimulated through a short engagement of the TCR and the CD28 co-receptor, IKK controls the expression of the cell cycle regulatory proteins cyclin D3, cyclin E and cyclin-dependent kinase 2 (CDK2) and the stability of the F-box protein S-phase kinase-associated protein 2 (SKP2) and its co-factor CDC28 protein kinase regulatory subunit 1B (CKS1B), through IL-2-independent mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • CD28 Antigens / immunology*
  • CD3 Complex / immunology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism*
  • CDC2-CDC28 Kinases
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation / drug effects
  • Cyclin D3 / genetics
  • Cyclin D3 / metabolism
  • Cyclin E / genetics
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology*
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Proteins / metabolism
  • Imidazoles / pharmacology
  • Interleukin-2 / antagonists & inhibitors
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism*
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / pharmacology
  • Quinoxalines / pharmacology
  • S-Phase Kinase-Associated Proteins / genetics
  • S-Phase Kinase-Associated Proteins / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Up-Regulation / drug effects

Substances

  • 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
  • Antibodies, Monoclonal
  • CCND3 protein, human
  • CCNE1 protein, human
  • CD28 Antigens
  • CD3 Complex
  • CDKN1B protein, human
  • CKS1B protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclin D3
  • Cyclin E
  • Heterocyclic Compounds, 3-Ring
  • I-kappa B Proteins
  • Imidazoles
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Oncogene Proteins
  • PS1145
  • Protein Kinase Inhibitors
  • Pyridines
  • Quinoxalines
  • S-Phase Kinase-Associated Proteins
  • NF-KappaB Inhibitor alpha
  • Cyclin-Dependent Kinase Inhibitor p27
  • I-kappa B Kinase
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases