Trans-presentation of IL-15 modulates STAT5 activation and Bcl-6 expression in TH1 cells

Sci Rep. 2015 Oct 26:5:15722. doi: 10.1038/srep15722.

Abstract

During infection, naïve CD4(+) T helper cells differentiate into specialized effector subsets based upon environmental signals propagated by the cytokine milieu. Recently, this paradigm has been complicated by the demonstration that alterations in the cytokine environment can result in varying degrees of plasticity between effector T helper cell populations. Therefore, elucidation of the mechanisms by which cytokines regulate T helper cell differentiation decisions is increasingly important. The gamma common cytokine IL-15 is currently undergoing clinical trials for the treatment of malignancies, due to its well-established role in the regulation of natural killer and CD8(+) T cell immune responses. However, the effect of IL-15 signaling on CD4(+) T cell activity is incompletely understood. One mechanism by which IL-15 activity is conferred is through trans-presentation via the IL-15 receptor alpha subunit. Here, we demonstrate that differentiated TH1 cells are responsive to trans-presented IL-15. Importantly, while trans-presentation of IL-15 results in STAT5 activation and maintenance of the TH1 gene program, IL-15 treatment alone allows for increased Bcl-6 expression and the upregulation of a TFH-like profile. Collectively, these findings describe a novel role for IL-15 in the modulation of CD4(+) T cell responses and provide valuable insight for the use of IL-15 in immunotherapeutic approaches.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / metabolism
  • Interleukin-15 / pharmacology*
  • Interleukin-15 Receptor alpha Subunit / genetics
  • Interleukin-15 Receptor alpha Subunit / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation / drug effects
  • Positive Regulatory Domain I-Binding Factor 1
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-6 / genetics
  • Proto-Oncogene Proteins c-bcl-6 / metabolism*
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction
  • Th1 Cells / cytology
  • Th1 Cells / drug effects*
  • Th1 Cells / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcriptome / drug effects
  • Up-Regulation / drug effects

Substances

  • Interleukin-15
  • Interleukin-15 Receptor alpha Subunit
  • Prdm1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-6
  • Recombinant Proteins
  • STAT5 Transcription Factor
  • Transcription Factors
  • Positive Regulatory Domain I-Binding Factor 1