title: Conditional IFNAR1 ablation reveals distinct requirements of Type I IFN signaling for NK cell maturation and tumor surveillance.
abstract: Mice with an impaired Type I interferon (IFN) signaling (IFNAR1- and IFNβ-deficient mice) display an increased susceptibility toward v-ABL-induced B-cell leukemia/lymphoma. The enhanced leukemogenesis in the absence of an intact Type I IFN signaling is caused by alterations within the tumor environment. Deletion of Ifnar1 in tumor cells (as obtained in Ifnar1(f/f) CD19-Cre mice) failed to impact on disease latency or type. In line with this observation, the initial transformation and proliferative capacity of tumor cells were unaltered irrespective of whether the cells expressed IFNAR1 or not. v-ABL-induced leukemogenesis is mainly subjected to natural killer (NK) cell-mediated tumor surveillance. Thus, we concentrated on NK cell functions in IFNAR1 deficient animals. Ifnar1(-/-) NK cells displayed maturation defects as well as an impaired cytolytic activity. When we deleted Ifnar1 selectively in mature NK cells (by crossing Ncr1-iCre mice to Ifnar1(f/f) animals), maturation was not altered. However, NK cells derived from Ifnar1(f/f) Ncr1-iCre mice showed a significant cytolytic defect in vitro against the hematopoietic cell lines YAC-1 and RMA-S, but not against the melanoma cell line B16F10. Interestingly, this defect was not related to an in vivo phenotype as v-ABL-induced leukemogenesis was unaltered in Ifnar1(f/f )Ncr1-iCre compared with Ifnar1(f/f) control mice. Moreover, the ability of Ifnar1(f/f) Ncr1-iCre NK cells to kill B16F10 melanoma cells was unaltered, both in vitro and in vivo. Our data reveal that despite the necessity for Type I IFN in NK cell maturation the expression of IFNAR1 on mature murine NK cells is not required for efficient tumor surveillance.
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research; Vienna, Austria.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Mizutani
authors.forename: Nina
authors.initials: N
authors.lastname: Neugebauer
authors.forename: Eva M
authors.initials: EM
authors.lastname: Putz
authors.forename: Nadine
authors.initials: N
authors.lastname: Moritz
authors.forename: Olivia
authors.initials: O
authors.lastname: Simma
authors.forename: Eva
authors.initials: E
authors.lastname: Zebedin-Brandl
authors.forename: Dagmar
authors.initials: D
authors.lastname: Gotthardt
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Warsch
authors.forename: Eva
authors.initials: E
authors.lastname: Eckelhart
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kantner
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.forename: Dagmar
authors.initials: D
authors.lastname: Stoiber