Primary human T lymphocytes engineered with a codon-optimized IL-15 gene resist cytokine withdrawal-induced apoptosis and persist long-term in the absence of exogenous cytokine

J Immunol. 2005 Dec 1;175(11):7226-34. doi: 10.4049/jimmunol.175.11.7226.


IL-15 is a common gamma-chain cytokine that has been shown to be more active than IL-2 in several murine cancer immunotherapy models. Although T lymphocytes do not produce IL-15, murine lymphocytes carrying an IL-15 transgene demonstrated superior antitumor activity in the immunotherapy of B16 melanoma. Thus, we sought to investigate the biological impact of constitutive IL-15 expression by human lymphocytes. In this report we describe the generation of a retroviral vector encoding a codon-optimized IL-15 gene. Alternate codon usage significantly enhanced the translational efficiency of this tightly regulated gene in retroviral vector-transduced cells. Activated human CD4+ and CD8+ human lymphocytes expressed IL-15Ralpha and produced high levels of cytokine upon retroviral transduction with the IL-15 vector. IL-15-transduced lymphocytes remained viable for up to 180 days in the absence of exogenous cytokine. IL-15 vector-transduced T cells showed continued proliferation after cytokine withdrawal and resistance to apoptosis while retaining specific Ag recognition. In the setting of adoptive cell transfer, IL-15-transduced lymphocytes may prolong lymphocyte survival in vivo and could potentially enhance antitumor activity.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Apoptosis / immunology
  • Cell Proliferation
  • Codon / genetics
  • Cytokines / immunology
  • Cytokines / metabolism
  • Flow Cytometry
  • Genetic Vectors*
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-15 / biosynthesis*
  • Interleukin-15 / genetics*
  • Lymphocyte Activation / immunology
  • Mice
  • Molecular Sequence Data
  • Protein Biosynthesis
  • Protein Engineering / methods*
  • Retroviridae
  • T-Lymphocytes / immunology*
  • Transduction, Genetic / methods*


  • Codon
  • Cytokines
  • Interleukin-15
  • Interferon-gamma