In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells

• Published in: Blood 2002-11, Vol.100 (10), p.3633-3638
• Main Authors: Cooper, Megan A., Bush, Jennifer E., Fehniger, Todd A., VanDeusen, Jeffrey B., Waite, Ross E., Liu, Yang, Aguila, Hector L., Caligiuri, Michael A.
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Biological and medical sciences; Cell Survival - drug effects; Chemotaxis, Leukocyte; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunobiology; Interleukin-15 - genetics; Interleukin-15 - immunology; Interleukin-15 - pharmacology; Killer Cells, Natural - drug effects; Killer Cells, Natural - metabolism; Killer Cells, Natural - transplantation; Mice; Mice, Knockout; Modulation of the immune response (stimulation, suppression); Organ Specificity; Proto-Oncogene Proteins c-bcl-2 - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2001-12-0293

Cellular homeostasis requires a balance between cell production, cell survival, and cell death. Production of natural killer (NK) cells from bone marrow precursor cells requires interleukin 15 (IL-15); however, very little is known about the factors controlling survival of mature NK cells in vivo. Because mice deficient in IL-15 (IL-15−/− mice) fail to develop NK cells, it is not known whether mature NK cells can survive in an environment lacking IL-15. We hypothesized that IL-15 might indeed be required for survival of mature NK cells in vivo. Freshly isolated NK cells labeled with 5-(and-6)-carboxyfluorescein diacetate, succinimidyl ester (CFSE) were adoptively transferred into IL-15−/− mice and littermate control (IL-15+/−) mice. Within 36 hours after transfer, NK cells were detected in both IL-15−/− and IL-15+/− mice; however, significantly more (P < .003) CFSE-positive (CFSE+) NK cells were found in control mice than in IL-15−/− mice. By 5 days, similar numbers of CFSE+ NK cells were still easily detected in IL-15+/− mice, whereas no CFSE+ NK cells survived in IL-15−/− mice. Furthermore, mice with severe combined immunodeficiency treated with the Fab fragment of a blocking antibody recognizing a signaling subunit of the IL-15 receptor, IL-2/15Rβ, had a significant (∼90%) loss of NK cells compared with control mice. Finally, NK cells from Bcl-2 transgenic mice that were adoptively transferred into IL-15−/− mice did survive. These results show conclusively that IL-15 is required for mature NK cell survival in vivo and suggest that IL-15 mediates its effect on NK cell survival by means of Bcl-2.