IL-15Rα of radiation-resistant cells is necessary and sufficient for thymic invariant NKT cell survival and functional maturation

J Immunol. 2011 Aug 1;187(3):1235-42. doi: 10.4049/jimmunol.1100270. Epub 2011 Jun 27.

Abstract

The development of invariant NKT (iNKT) cells depends on the thymus. After positive selection by CD4(+)CD8(+)CD1d(+) cortical thymocytes, iNKT cells proceed from CD44(low)NK1.1(-) (stage 1) to CD44(high)NK1.1(-) (stage 2), and then to CD44(high)NK1.1(+) (stage 3) cells. The programming of cytokine production occurs along the three differentiation stages, whereas the acquisition of NK receptors occurs at stage 3. Stage 3 thymic iNKT cells are specifically reduced in Il15ra(-/-) mice. The mechanism underlying this homeostatic deficiency and whether the IL-15 system affects other thymic iNKT cell developmental events remain elusive. In this study, we demonstrate that increased cell death contributed to the reduction of stage 3 cells in Il15ra(-/-) mice, as knockout of Bim restored this population. IL-15-dependent upregulation of Bcl-2 in stage 3 cells affected cell survival, as overexpression of hBcl-2 partially restored stage 3 cells in Il15ra(-/-) mice. Moreover, thymic iNKT cells in Il15ra(-/-) mice were impaired in functional maturation, including the acquisition of Ly49 and NKG2 receptors and the programming of cytokine production. Finally, IL-15Rα expressed by radiation-resistant cells is necessary and sufficient to support the survival as well as the examined maturation events of thymic iNKT cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / genetics
  • Cell Death / immunology
  • Cell Death / radiation effects
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cell Differentiation / radiation effects
  • Cell Survival / genetics
  • Cell Survival / immunology
  • Cell Survival / radiation effects
  • Interleukin-15 Receptor alpha Subunit / biosynthesis
  • Interleukin-15 Receptor alpha Subunit / genetics
  • Interleukin-15 Receptor alpha Subunit / physiology*
  • Lymphocyte Depletion
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Natural Killer T-Cells / cytology
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / radiation effects
  • Radiation Chimera*
  • Thymus Gland / cytology
  • Thymus Gland / immunology
  • Thymus Gland / radiation effects

Substances

  • Interleukin-15 Receptor alpha Subunit