miR-17-92 expression in differentiated T cells - implications for cancer immunotherapy

J Transl Med. 2010 Feb 18;8:17. doi: 10.1186/1479-5876-8-17.

Abstract

Background: Type-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs (miRs) are a large family of small regulatory RNAs that control diverse aspects of cell function, including immune regulation. We identified miRs differentially regulated between type-1 and type-2 T cells, and determined how the expression of such miRs is regulated.

Methods: We performed miR microarray analyses on in vitro differentiated murine T helper type-1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used quantitative RT-PCR to confirm the differential expression levels. We also used WST-1, ELISA, and flow cytometry to evaluate the survival, function and phenotype of cells, respectively. We employed mice transgenic for the identified miRs to determine the biological impact of miR-17-92 expression in T cells.

Results: Our initial miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells when compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT)6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 when compared with cells from non-tumor bearing counterparts. CD4+ T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-gamma production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Human Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD).

Conclusion: The type-2-skewing tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / immunology
  • Cell Differentiation / immunology
  • Humans
  • Immunotherapy / methods*
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interleukin-2 / immunology
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology
  • Jurkat Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs* / genetics
  • MicroRNAs* / immunology
  • Microarray Analysis
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Signal Transduction / immunology
  • Th1 Cells* / cytology
  • Th1 Cells* / immunology
  • Th1 Cells* / physiology
  • Th2 Cells* / cytology
  • Th2 Cells* / immunology
  • Th2 Cells* / physiology

Substances

  • Interleukin-2
  • MicroRNAs
  • Interleukin-4
  • Interferon-gamma