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

Cary Hsu, Marybeth S. Hughes, Zhili Zheng, Regina B. Bray, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticlepeer-review

Abstract

IL-15 is a common γ-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-15Rα 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.

Original languageEnglish (US)
Pages (from-to)7226-7234
Number of pages9
JournalJournal of Immunology
Volume175
Issue number11
DOIs
StatePublished - Dec 1 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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