Survival of activated human T lymphocytes is promoted by retinoic acid via induction of IL-2

Int Immunol. 2004 Mar;16(3):443-53. doi: 10.1093/intimm/dxh048.


At the end of an immune response, most activated T cells spontaneously undergo programmed cell death (apoptosis). In the present study we show that all-trans retinoic acid (atRA), a major vitamin A metabolite, can inhibit the spontaneous apoptosis of activated human T lymphocytes in vitro. Isolated peripheral blood T lymphocytes were activated by 12-O-tetradecanoyl phorbol 13-acetate and cultured for up to 11 days without any further stimuli. With time, a gradual increase in cell death was observed. This spontaneous death of activated T cells was apoptotic, as demonstrated by cell shrinkage, DNA fragmentation and depolarization of the mitochondrial membrane. In the presence of physiological concentrations of atRA, the percentage of T cells exhibiting these apoptotic features was significantly reduced. After 5 days of stimulation, the percentage of TUNEL+ T cells decreased from 28 to 12% in the presence of atRA. The anti-apoptotic effect of atRA was mimicked by the retinoic acid receptor (RAR)-selective agonists 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid and AM-580, and totally abrogated by the RAR-selective antagonist Ro 41-5253. Cytokines of the IL-2 family have been shown to improve the survival of activated T cells. Strikingly, we found that the ability of atRA to inhibit apoptosis was significantly correlated with its ability to increase the production of IL-2. Furthermore, a blocking anti-IL-2 receptor antibody completely abrogated the anti-apoptotic effect of atRA. Together, these results suggest that retinoic acid inhibits spontaneous apoptosis of activated T lymphocytes through a RAR-dependent increase in IL-2 production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Apoptosis / drug effects*
  • Benzoates / metabolism
  • Benzoates / pharmacology
  • Cell Survival
  • Cells, Cultured
  • DNA Fragmentation
  • Flow Cytometry
  • Humans
  • Interleukin-2 / biosynthesis*
  • Lectins, C-Type
  • Lymphocyte Activation
  • Propidium / chemistry
  • Propidium / metabolism
  • Receptors, Retinoic Acid / antagonists & inhibitors
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tetrahydronaphthalenes / metabolism
  • Tetrahydronaphthalenes / pharmacology
  • Tretinoin / metabolism
  • Tretinoin / pharmacology*


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Benzoates
  • CD69 antigen
  • Interleukin-2
  • Lectins, C-Type
  • Receptors, Retinoic Acid
  • Tetrahydronaphthalenes
  • Am 580
  • Re 80
  • Propidium
  • Tretinoin
  • Tetradecanoylphorbol Acetate