Journal Article

STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity

Strobl, Birgit, Klein, Klara, Vogl, Claus, Meissl, Katrin, Simonović, Natalija, Sexl, Veronika, Amenitsch, Lena, Witalisz-Siepracka, Agnieszka, Puga, Ana, Dohnal, Alexander, Poelzl, Andrea, Lassnig, Caroline, Müller, Mathias, Bosmann, Markus

2020

Overview

Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1β isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1α ( ) or the STAT1β ( ) isoform. NK cells from mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 ( ). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Alternative splicing / Animals / Antibodies / Antineoplastic drugs / Antitumor agents / Bone marrow / Bone Marrow Transplantation / Cell Line, Tumor / Cells / Cytokines / Cytotoxicity / Cytotoxicity, Immunologic / Dendritic cells / Flow cytometry / Gene expression / IL-15Rα / Immune system / Immunologic Surveillance - drug effects / Immunologic Surveillance - immunology / Immunology / Immunosuppressive agents / interferon / Interferon gamma Receptor / Interferon-Stimulated Gene Factor 3 - deficiency / Interferon-Stimulated Gene Factor 3 - genetics / Interferon-Stimulated Gene Factor 3 - immunology / Interleukin 15 / Interleukin 15 receptors / Interleukin-15 - pharmacology / Interleukin-15 Receptor alpha Subunit / Isoforms / Killer Cells, Natural - cytology / Killer Cells, Natural - drug effects / Killer Cells, Natural - immunology / Kinases / Laboratories / Lymphocyte Depletion / Lymphoid Tissue - cytology / Lymphoma - immunology / Lymphoma - pathology / Lymphopoiesis - drug effects / Lymphopoiesis - physiology / Macrophages / Maturation / Medical prognosis / MHC class I / Mice / Mice, Inbred C57BL / Mice, Knockout / Monocytes / Natural killer cells / NK cells / Organ Specificity / Protein Isoforms - genetics / Protein Isoforms - immunology / Proteins / Receptors, Interferon - deficiency / signal transduction / Specific Pathogen-Free Organisms / Spleen / Spleen - cytology / Stat1 protein / STAT1 Transcription Factor - deficiency / STAT1 Transcription Factor - genetics / STAT1 Transcription Factor - immunology / Transcription factors / Tumor cells / Tumors / γ-Interferon