Different NK cell developmental events require different levels of IL-15 trans-presentation

J Immunol. 2011 Aug 1;187(3):1212-21. doi: 10.4049/jimmunol.1100331. Epub 2011 Jun 29.

Abstract

NK cell development requires IL-15, which is "trans-presented" to IL-15Rβγ on NK cells by IL-15Rα on other cells. In this study, we report that different levels of IL-15 trans-presentation are required for different NK cell developmental events to reach full maturation status. Because the IL-15Rα intracellular domain has the capacity to recruit signaling molecules, we generated knockin and transgenic (Tg) mice that lack the intracellular domain to assess the role of the IL-15 trans-presentation level independent of the function of this domain. The level of IL-15Rα on various cells of these mice follows the order WT > Tg6 > knockin > Tg1 ≥ knockout. Bone marrow (BM)-derived dendritic cells prepared from these mice induced Stat5 phosphorylation in NK cells. The level of phospho-Stat5 correlated with the level of IL-15Rα on BMDCs, thus offering the opportunity to study quantitative effects of IL-15 trans-presentation on NK cell development in vivo. We found that NK cell homeostasis, mature NK cell differentiation, and acquisition of Ly49 receptor and effector functions require different levels of IL-15 trans-presentation input to achieve full status. All NK cell developmental events examined were quantitatively regulated by the IL-15Rα level of BM-derived and radiation-resistant accessory cells, but not by IL-15Rα of NK cells. We also found that IL-15Rα of radiation-resistant cells was more potent than IL-15Rα of BM-derived accessory cells in support of stage 2 to stage 3 splenic mNK differentiation. In summary, each examined developmental event required a particular level of IL-15 trans-presentation by accessory cells.

Publication types

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

MeSH terms

  • Animals
  • Antigen Presentation / genetics
  • Antigen Presentation / immunology*
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Female
  • Gene Knock-In Techniques
  • Homeostasis / genetics
  • Homeostasis / immunology
  • Interleukin-15 / metabolism*
  • Interleukin-15 / physiology
  • Interleukin-15 Receptor alpha Subunit / genetics
  • Interleukin-15 Receptor alpha Subunit / metabolism
  • Interleukin-15 Receptor alpha Subunit / physiology
  • Killer Cells, Natural / cytology*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NK Cell Lectin-Like Receptor Subfamily A / metabolism

Substances

  • Interleukin-15
  • Interleukin-15 Receptor alpha Subunit
  • NK Cell Lectin-Like Receptor Subfamily A