In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells.
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-2/15Rbeta, had a significant ( approximately 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.
Cooper
Megan A
MA
Department of Internal Medicine, Division of Hematology/Oncology, The James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University, Columbus 43210, USA.
Bush
Jennifer E
JE
Fehniger
Todd A
TA
VanDeusen
Jeffrey B
JB
Waite
Ross E
RE
Liu
Yang
Y
Aguila
Hector L
HL
Caligiuri
Michael A
MA
D019264:Adoptive Transfer; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002634:Chemotaxis, Leukocyte; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism
D019409:Interleukin-15; D019253:Proto-Oncogene Proteins c-bcl-2