In vivo survival and homeostatic proliferation of natural killer cells.
While the specificity and development of natural killer (NK) cells have been intensely studied, little is known about homeostasis of the mature NK population. Here we show that mouse NK cells undergo homeostatic proliferation when transferred into NK-deficient Rag-/- gammaC-/- hosts. Normal NK functional activity is maintained during this process, although there are some changes in NK phenotype. Using cell sorting, we demonstrate that mature (Mac-1hi) NK cells undergo homeostatic proliferation in an NK-deficient environment, yet immature (Mac-1lo) NK cells also proliferate in such hosts. We find that mature NK cells survive but do not proliferate in hosts which possess an endogenous NK pool. However, we go on to show that mature NK survival is critically dependent on interleukin (IL)-15. Surprisingly, NK survival is also compromised after transfer of cells into IL-15Ralpha-/- mice, implying that IL-15 responsiveness by bystander cells is critical for NK maintenance. These data imply that, similar to T cells, homeostasis of the NK pool is much more dynamic than previously appreciated and this may be relevant to manipulation of NK cells for therapeutic purposes.
Prlic
Martin
M
Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
Blazar
Bruce R
BR
Farrar
Michael A
MA
Jameson
Stephen C
SC
D019264:Adoptive Transfer; D000818:Animals; D002455:Cell Division / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007694:Killer Cells, Natural / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology
D004268:DNA-Binding Proteins; C508025:Il15ra protein, mouse; D016177:Macrophage-1 Antigen; C499308:Rag2 protein, mouse; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; C064655:V(D)J recombination activating protein 2