Retinoic acid stimulates the cell cycle machinery in normal T cells: involvement of retinoic acid receptor-mediated IL-2 secretion

J Immunol. 2002 Nov 15;169(10):5555-63. doi: 10.4049/jimmunol.169.10.5555.


The mechanisms whereby vitamin A stimulates the immune system are poorly understood. In the current study, we attempted to elucidate the potential mechanisms of action of all-trans retinoic acid (atRA) on proliferation of human T lymphocytes. We found that physiological levels of atRA potently augmented T cell proliferation when added in combination with common T cell-stimulating agents. This was reflected in a time- and concentration-dependent stimulation of the cell cycle machinery. The presence of atRA led to elevated levels of cyclin D3, -E, and -A, decreased levels of p27(Kip1), increased activity of cyclin-dependent kinase 2, and enhanced phosphorylation of the retinoblastoma protein (pRB). The atRA-mediated changes in the cell cycle machinery were late events, appearing after 20 h of stimulation, indicating that the effects of atRA were indirect. atRA did not alter the expression of the high-affinity IL-2R. However, the level of IL-2 secreted by T cells was strongly enhanced by atRA. rIL-2 was able to substitute for the effects of atRA on the cell cycle machinery and on DNA synthesis, and blocking the IL-2R markedly inhibited atRA-induced cell proliferation and pRB phosphorylation. A retinoic acid receptor (RAR)-selective agonist and 9-cis-RA had the same potency as atRA on T cell proliferation and IL-2 secretion, whereas a retinoid X receptor-selective agonist had only marginal effects. Furthermore, a RAR-selective antagonist completely suppressed T cell proliferation and pRB phosphorylation induced by atRA. Taken together, these results suggest that atRA stimulates the cell cycle machinery and proliferation of normal human T cells by increasing IL-2 secretion through mechanisms involving RARs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / antagonists & inhibitors
  • Adjuvants, Immunologic / metabolism
  • Adjuvants, Immunologic / pharmacology
  • Antibodies, Blocking / pharmacology
  • Benzoates / pharmacology
  • Cell Cycle / drug effects*
  • Cell Cycle / immunology
  • Cell Division / drug effects
  • Cell Division / immunology
  • Cells, Cultured
  • Growth Substances / metabolism
  • Growth Substances / pharmacology*
  • Humans
  • Interleukin-2 / metabolism*
  • Interleukin-2 / pharmacology
  • Lymphocyte Activation / drug effects
  • Phosphorylation / drug effects
  • Receptors, Interleukin-2 / antagonists & inhibitors
  • Receptors, Interleukin-2 / biosynthesis
  • Receptors, Interleukin-2 / immunology
  • Receptors, Retinoic Acid / agonists
  • Receptors, Retinoic Acid / antagonists & inhibitors
  • Receptors, Retinoic Acid / physiology*
  • Recombinant Proteins / pharmacology
  • Retinoblastoma Protein / metabolism
  • Retinoids / pharmacology
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism*
  • Tretinoin / antagonists & inhibitors
  • Tretinoin / metabolism
  • Tretinoin / pharmacology*
  • Up-Regulation / drug effects
  • Up-Regulation / immunology


  • Adjuvants, Immunologic
  • Antibodies, Blocking
  • Benzoates
  • Growth Substances
  • Interleukin-2
  • Receptors, Interleukin-2
  • Receptors, Retinoic Acid
  • Recombinant Proteins
  • Retinoblastoma Protein
  • Retinoids
  • SR 11217
  • Tretinoin
  • 4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid