title: Nfil3-independent lineage maintenance and antiviral response of natural killer cells.
abstract: Development of the natural killer (NK) cell lineage is dependent on the transcription factor Nfil3 (or E4BP4), which is thought to act downstream of IL-15 signaling. Nfil3-deficient mice lack NK cells, whereas other lymphocyte lineages (B, T, and NKT cells) remain largely intact. We report the appearance of Ly49H-expressing NK cells in Nfil3(-/-) mice infected with mouse cytomegalovirus (MCMV) or recombinant viruses expressing the viral m157 glycoprotein. Nfil3(-/-) NK cells at the peak of antigen-driven expansion were functionally similar to NK cells from infected wild-type mice with respect to IFN-γ production and cytotoxicity, and could comparably produce long-lived memory NK cells that persisted in lymphoid and nonlymphoid tissues for >60 d. We demonstrate that generation and maintenance of NK cell memory is an Nfil3-independent but IL-15-dependent process. Furthermore, specific ablation of Nfil3 in either immature NK cells in the bone marrow or mature peripheral NK cells had no observable effect on NK cell lineage maintenance or homeostasis. Thus, expression of Nfil3 is crucial only early in the development of NK cells, and signals through activating receptors and proinflammatory cytokines during viral infection can bypass the requirement for Nfil3, promoting the proliferation and long-term survival of virus-specific NK cells.
authors.affiliation: Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Firth
authors.forename: Sharline
authors.initials: S
authors.lastname: Madera
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Beaulieu
authors.forename: Georg
authors.initials: G
authors.lastname: Gasteiger
authors.forename: Eliseo F
authors.initials: EF
authors.lastname: Castillo
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Schluns
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rothman
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Sun
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D019070:Cell Lineage; D002469:Cell Separation; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006706:Homeostasis; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology* / Q000821:virology; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000276:immunology; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013629:Tamoxifen / Q000737:chemistry
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D016207:Cytokines; D019409:Interleukin-15; D008024:Ligands; D055650:NK Cell Lectin-Like Receptor Subfamily A; C497441:Nfil3 protein, mouse; D013629:Tamoxifen; D007371:Interferon-gamma