CD28 induces cell cycle progression by IL-2-independent down-regulation of p27kip1 expression in human peripheral T lymphocytes

Eur J Immunol. 1999 Mar;29(3):789-98. doi: 10.1002/(SICI)1521-4141(199903)29:03<789::AID-IMMU789>3.0.CO;2-5.

Abstract

CD28 is the primary T cell costimulatory receptor, and upon ligation with its ligands, it enhances T cell proliferation and IL-2 synthesis. In this study we examined the role of CD28 in the initial proliferative response and cell cycle entry of T lymphocytes. Stimulation through CD3 alone resulted in a poor proliferative response, while in the presence of CD28 costimulation a strong increase in the number of cells in S-phase could be detected after 48 h of stimulation. CD28 costimulation enhanced expression of cyclin D3 and induced down-regulation of p27kip1 expression. Cross-linking CD28 was much more effective in inducing cyclin D3 expression and in down-regulating p27kip1 expression than addition of IL-2. Blocking experiments, using antibodies that neutralize IL-2 or the IL-2 receptor, showed that the effects induced by CD28 are independent of endogenous IL-2. Moreover, using a variety of immunosuppressants that interfere with IL-2 signaling pathways, we were able to show that IL-2 is not required for cell cycle entry induced by CD28 costimulation. From these experiments it can be concluded that CD28 and IL-2 use different signaling pathways for down-regulation of p27kip1 expression. We hypothesize that costimulation through CD28 is responsible for initial cell cycle entry of T lymphocytes, while IL-2, which is produced after costimulation, might be involved in sustaining proliferation.

MeSH terms

  • CD28 Antigens / biosynthesis*
  • CDC2-CDC28 Kinases*
  • Cell Cycle
  • Cell Cycle Proteins*
  • Cell Line
  • Cyclin D3
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / metabolism
  • Cyclins / biosynthesis
  • Down-Regulation*
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Interleukin-2 / pharmacology
  • Interleukin-2 / physiology*
  • Microtubule-Associated Proteins / biosynthesis*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Retinoblastoma Protein / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism*
  • Tumor Suppressor Proteins*

Substances

  • CCND3 protein, human
  • CD28 Antigens
  • Cell Cycle Proteins
  • Cyclin D3
  • Cyclins
  • Immunosuppressive Agents
  • Interleukin-2
  • Microtubule-Associated Proteins
  • Retinoblastoma Protein
  • Tumor Suppressor Proteins
  • Cyclin-Dependent Kinase Inhibitor p27
  • Protein-Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases