The IL-15 receptor {alpha} chain cytoplasmic domain is critical for normal IL-15Ralpha function but is not required for trans-presentation

Blood. 2008 Dec 1;112(12):4411-9. doi: 10.1182/blood-2007-03-080697. Epub 2008 Sep 16.

Abstract

IL-15 is critical for natural killer (NK)-cell development and function and for memory CD8(+) T-cell homeostasis. The IL-15 receptor consists of IL-15Ralpha, IL-2Rbeta, and the common cytokine receptor gamma chain (gamma(c)). IL-15Ralpha is known to "trans-present" IL-15 to an IL-2Rbeta/gamma(c) heterodimeric receptor on responding cells to initiate signaling. To investigate the importance of the IL-15Ralpha cytoplasmic domain, we generated a chimeric receptor consisting of the extracellular domain of IL-15Ralpha and intracellular domain of IL-2Ralpha (IL-15Ralpha(ext)/IL-2Ralpha(int)) and examined its function in 32D cells, in knock-in (KI) mice, and in adoptive-transfer experiments. The chimeric protein exhibited decreased cell-surface expression, and KI mice exhibited diminished NK, NKT, and CD8(+) T-cell development and defects in T-cell functional responses. However, 32D cells expressing the chimeric receptor had less IL-15-induced proliferation than wild-type (WT) transfectants with similar levels of IL-15Ralpha expression, indicating a signaling role for the IL-15Ralpha cytoplasmic domain beyond its effect on expression, and demonstrating that the IL-2Ralpha and IL-15Ralpha cytoplasmic domains are functionally distinct. Interestingly, adoptive-transfer experiments indicated that the chimeric IL-15Ralpha(ext)/IL-2Ralpha(int) receptor still supports trans-presentation. These experiments collectively indicate that IL-15Ralpha can act in cis in addition to acting in trans to present IL-15 to responding cells.

Publication types

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

MeSH terms

  • Adoptive Transfer* / veterinary
  • Animals
  • Antigen Presentation / physiology*
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / physiology
  • Cell Proliferation
  • Cells, Cultured
  • Cytoplasm / metabolism
  • Female
  • Interferon-gamma / metabolism
  • Interleukin-15 / metabolism*
  • Interleukin-15 Receptor alpha Subunit / chemistry*
  • Interleukin-15 Receptor alpha Subunit / genetics
  • Interleukin-15 Receptor alpha Subunit / metabolism
  • Interleukin-15 Receptor alpha Subunit / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Natural Killer T-Cells / cytology
  • Natural Killer T-Cells / metabolism
  • Natural Killer T-Cells / physiology
  • Protein Structure, Tertiary / physiology
  • Transfection

Substances

  • Interleukin-15
  • Interleukin-15 Receptor alpha Subunit
  • Interferon-gamma