Chronic lymphocytosis of functionally immature natural killer cells.
BACKGROUND
The development of natural killer (NK) cells in the bone marrow is not well characterized. We recently described a mouse (referred to as an NK cell-deficient [NKD] mouse) with a selective deficiency in NK cells caused by the insertion of a transgene construct into the genetic locus for the basic leucine zipper transcription factor ATF-2. NK cells in this mouse were both phenotypically and functionally immature and accumulated in the bone marrow at a stage at which constitutive NK cell proliferation occurs in wild-type mice.


OBJECTIVE
We hypothesized that excess IL-15 could potentially overcome this developmental block, allowing normal emigration of mature NK cells from the bone marrow to the periphery.


METHODS
Double-transgenic mice were generated by crossing the NKD mice with transgenic mice overexpressing IL-15.


RESULTS
The double-transgenic mice had a dramatic accumulation of phenotypically immature NK cells in the bone marrow and subsequently in the blood, liver, and spleen. NK cells from these double-transgenic mice manifested functional deficits similar to those observed in NK cells from NKD mice, as assessed by decreased cytokine production and cytotoxicity.


CONCLUSIONS
Rather than bypass the observed developmental defect in NKD mice, excess IL-15 drove a massive accumulation of phenotypically and functionally immature NK cells in the bone marrow and periphery.


CONCLUSIONS
We propose that these double-transgenic mice will serve as a murine model of chronic NK cell lymphocytosis in human patients.
French
Anthony R
AR
Division of Pediatric Rheumatology, Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA. french_a@kids.wustl.edu
Kim
Sungjin
S
Fehniger
Todd A
TA
Pratt
Jennifer R
JR
Yang
Liping
L
Song
Yun Jeong
YJ
Caligiuri
Michael A
MA
Yokoyama
Wayne M
WM
D000367:Age Factors; D000818:Animals; D002908:Chronic Disease; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000502:physiology; D007694:Killer Cells, Natural / Q000502:physiology*; D008218:Lymphocytosis / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D019409:Interleukin-15