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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2001-12-0293.
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Blood, 15 November 2002, Vol. 100, No. 10, pp. 3633-3638
IMMUNOBIOLOGY
In vivo evidence for a dependence on interleukin 15 for
survival of natural killer cells
Megan A. Cooper,
Jennifer
E. Bush,
Todd A. Fehniger,
Jeffrey B. VanDeusen,
Ross E. Waite,
Yang Liu,
Hector L. Aguila, and
Michael
A. Caligiuri
From the Departments of Internal Medicine, Division of
Hematology/Oncology; Veterinary Biosciences; Molecular Virology,
Immunology and Medical Genetics; and Pathology; The James Cancer
Hospital and Comprehensive Cancer Center, The Ohio State University,
Columbus; and the Center for Immunotherapy, University of Connecticut
Health Center, Farmington.
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-2/15R , 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.
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