Genetic modification of T cells with IL-21 enhances antigen presentation and generation of central memory tumor-specific cytotoxic T-lymphocytes

J Immunother. 2009 Sep;32(7):726-36. doi: 10.1097/CJI.0b013e3181ad4071.


An optimized antigen-presenting cell for tumor immunotherapy should produce a robust antigen specific cytotoxic T lymphocytes (CTL) response to tumor-associated antigens, which can persist in vivo and expand on antigen reencounter. Interleukin (IL)-21 synergizes with other gamma-chain cytokines to enhance the frequency and cytotoxicity of antigen-specific CTL. As T cells themselves may serve as effective antigen-presenting cells (T antigen-presenting cells; TAPC) and may be useful in vivo as cellular vaccines, we examined whether CD8(+) T cells genetically modified to produce IL-21 could induce immune responses to tumor associated antigen peptides in healthy human leukocyte antigen-A2(+) donors. We found that IL-21 modified TAPC enhanced both the proliferation and survival of MART-1 specific CD8(+) T cells, which were enriched by >8-fold over cultures with control nontransgenic TAPC. MART-1-specific CTL produced interferon-gamma in response to cognate peptide antigen and killed primary tumor cells expressing MART-1 in a major histocompatibility complex restricted manner. IL-21 modified TAPC similarly enhanced generation of functional CTL against melanoma antigen gp100 and the B-cell chronic lymphocytic leukemia associated RHAMM antigen. Antigen-specific CTL generated using IL-21 gene-modified TAPC had a central memory phenotype characterized by CD45RA(-), CD44(high), CD27(high), CD28(high), CD62L(high), and IL-7 receptor-alpha(high), contrasting with the terminal effector phenotype of CTL generated in the absence of IL-21. Thus, TAPC stimulation in the presences of IL-21 enhances proliferation of tumor antigen-specific T cells and favors induction of a central memory phenotype, which may improve proliferation, survival, and efficacy of T-cell based therapies for the treatment of cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigen Presentation / immunology*
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Apoptosis / drug effects
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytotoxicity, Immunologic / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Expression
  • Humans
  • Immunologic Memory / immunology
  • Immunophenotyping
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Interleukins / pharmacology
  • K562 Cells
  • Lentivirus / genetics
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • T Cell Transcription Factor 1 / genetics
  • T Cell Transcription Factor 1 / metabolism
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism
  • Transfection


  • Interleukins
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • T Cell Transcription Factor 1
  • TCF7 protein, human
  • interleukin-21