Rel/NF-kappaB family member RelA regulates NK1.1- to NK1.1+ transition as well as IL-15-induced expansion of NKT cells

Eur J Immunol. 2008 Dec;38(12):3508-19. doi: 10.1002/eji.200737830.

Abstract

Development of NKT cells was shown to depend on lymphotoxin (LT) and IL-15 signaling pathways as well as on cytokine receptor common gamma chain. After positive selection, NKT-cell precursors transit through progressive maturation stages including proliferative expansion within the NK1.1(-) window. The transcription factors that integrate different signaling pathways into different stages of NKT-cell development are not well characterized. Here, we show that the Rel/NF-kappaB family member RelA regulates the NK1.1(-) to NK1.1(+) transition during NKT-cell development. RelA is also required for both IL-15- and IL-7-induced proliferation of CD44(hi)NK1.1(-) NKT-cell precursors. Activation of the invariant NKT-cell receptor induces both IL-15 receptor alpha and gamma chains' expression in an NF-kappaB-dependent manner, suggesting a molecular mechanism by which NF-kappaB regulates NKT-cell development. NF-kappaB also regulates TCR-induced expression of LT-alpha and LT-beta within NKT cells. In contrast to previous reports, however, we show that LT signaling is dispensable for thymic NKT-cell development but is essential for their colonization of peripheral organs such as liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / immunology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Hyaluronan Receptors / immunology
  • Interleukin Receptor Common gamma Subunit / genetics
  • Interleukin Receptor Common gamma Subunit / metabolism
  • Interleukin-15 / pharmacology*
  • Interleukin-15 Receptor alpha Subunit / metabolism
  • Interleukin-7 / pharmacology
  • Ligases / classification
  • Ligases / metabolism*
  • Lymphotoxin-alpha / metabolism
  • Mice
  • NF-kappa B / classification
  • NF-kappa B / metabolism*
  • Natural Killer T-Cells / cytology
  • Natural Killer T-Cells / drug effects
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism*
  • Protein Binding
  • Protein Subunits / metabolism
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / immunology

Substances

  • Hyaluronan Receptors
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-15
  • Interleukin-15 Receptor alpha Subunit
  • Interleukin-7
  • Lymphotoxin-alpha
  • NF-kappa B
  • Protein Subunits
  • Receptors, Antigen, T-Cell
  • Ligases
  • guanosine 3',5'-polyphosphate synthetases