title: Development of an IL-15-autocrine CD8 T-cell leukemia in IL-15-transgenic mice requires the cis expression of IL-15Rα.
abstract: IL-15 has growth-promoting effects on select lymphoid subsets, including natural killer (NK) cells, NK T cells, intraepithelial lymphocytes (IELs), CD8 T cells, and γδ-T cells. Constitutive expression of murine IL-15 in IL-15-transgenic mice was reported to cause T-NK leukemia. We investigated whether IL-15 expression is sufficient for leukemic transformation using a human IL-15-transgenic (IL-15Tg) mouse model. We noted that 100% of the mice observed over a 2-year period (n > 150) developed fatal expansions of CD8 T cells with NK markers, and determined that these cells expressed IL-15 receptor alpha (IL-15Rα). The expression of IL-15Rα on CD8 T cells appears to be required for uncontrolled aggressive lymphoproliferation, because none of the IL-15Rα(-/-)-IL-15Tg mice that we followed for more than 2 years developed the fatal disease despite controlled expansion of CD8 T cells. In addition, in contrast to IL-15Tg mice, in which leukemia-like CD8 T cells expressed IL-15Rα persistently, acutely activated normal CD8 T cells only transiently expressed IL-15Rα. Inhibition of DNA methylation enabled sustained IL-15Rα expression induced by activation. We present a scenario for IL-15Tg mice in which CD8 T cells that acquire constitutive persistent IL-15Rα expression are at a selective advantage and become founder cells, outgrow other lymphocytes, and lead to the establishment of a leukemia-like condition.
authors.affiliation: Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
authors.forename: Helen
authors.initials: H
authors.lastname: Sabzevari
authors.forename: Song
authors.initials: S
authors.lastname: Fu
authors.forename: Wei
authors.initials: W
authors.lastname: Ju
authors.forename: Michael N
authors.initials: MN
authors.lastname: Petrus
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bamford
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tagaya
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D005816:Genetic Complementation Test; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics* / Q000378:metabolism; D053720:Interleukin-15 Receptor alpha Subunit / Q000235:genetics* / Q000378:metabolism; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation
chemical_list: D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit